WO2000021543A1 - Methode et composition permettant de traiter l'ischemie et la drepanocytose - Google Patents

Methode et composition permettant de traiter l'ischemie et la drepanocytose Download PDF

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Publication number
WO2000021543A1
WO2000021543A1 PCT/US1999/023706 US9923706W WO0021543A1 WO 2000021543 A1 WO2000021543 A1 WO 2000021543A1 US 9923706 W US9923706 W US 9923706W WO 0021543 A1 WO0021543 A1 WO 0021543A1
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Prior art keywords
phosphate
fructose
approximately
polyoxypropylene
oxygen
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PCT/US1999/023706
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English (en)
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R. Martin Emanuele
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Cytrx Corporation
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Priority to AU13128/00A priority Critical patent/AU1312800A/en
Publication of WO2000021543A1 publication Critical patent/WO2000021543A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • the present invention relates to the administration of compounds with high energy bonds such as fructose 1,6, diphosphate or fructose 1,3 diphosphate or a combination of the two compounds.
  • compounds with high energy bonds such as fructose 1,6, diphosphate or fructose 1,3 diphosphate or a combination of the two compounds.
  • other compounds that shift the oxygen dissociation curve for hemoglobin to the right and prevent dehydration of sickle red blood cells are considered to be encompassed by the present invention.
  • 1,6 FDP might potentially be useful as a medical treatment for patients and victims suffering from medical crises such as strokes, cardiac arrest, heart attack, sickle cell anemia, suffocation, loss of blood due to injury, shooting, or stabbing, etc.
  • medical crises such as strokes, cardiac arrest, heart attack, sickle cell anemia, suffocation, loss of blood due to injury, shooting, or stabbing, etc.
  • Glycolysis is a fundamental biological process which is essential to the generation and use of energy by cells.
  • a molecule of glucose a molecule of glucose
  • 6-carbon sugar is broken apart to form 2 molecules of pyruvic acid, containing 3 carbons each, in a series of ten distinct reactions which are controlled by enzymes.
  • pyruvate is converted into carbon dioxide and water, if enough oxygen is present in the cells, via the Krebs cycle.
  • pyruvate is converted into lactic acid, via a different pathway.
  • Glycolysis is discussed in detail in nearly any textbook on biochemistry, physiology, or cell biology; see, e.g., any edition of Stryer's or Lehninger's Biochemistry, Guyton's Medical Physiology, or Alberts et al, Molecular Biology of the Cell.
  • FDP Fructose- 1,6-diphosphate
  • FDP has a very short half-life in the blood and therefore, the molecule must be delivered as efficiently as possible to the desired site.
  • Another significant problem in treating ische ic tissue is that blood flow, by definition, is very poor in ischemic tissue. Since injected FDP relies on blood flow to reach the ischemic tissue what is needed is a composition and method that that can increase blood flow especially in ischemic issue and more efficiently deliver FDP to the ischemic tissue.
  • high energy compound includes, but is not limited to, 1,3 diphosphoglycerate, 2,3 diphosphoglycerate, 2 phosphoglycerate, 3 phosphoglycerate, fructose diphosphate, glyceraldehyde 3-phosphate, 3 phosphoglycerol phosphate, fructose 6 phosphate and glucose 6 phosphate.
  • FDP is used collectively for both fructose 1,6, diphosphate (1,6 FDP) or fructose 1,3 diphosphate (1,3 FDP).
  • 1 -3 DPG means 1,3 diphosphoglycerate.
  • 2,3 DPG means 2,3 diphosphoglycerate.
  • the present invention is a composition and method for treating ischemia comprising administering an effective amount of a polyoxypropylene/polyoxyethylene copolymer and an effective amount of a high energy compound such as fructose 1,6 diphosphate or fructose 1,3 diphosphate or 2,3 DPG or a combination thereof to a patient in need thereof.
  • a high energy compound such as fructose 1,6 diphosphate or fructose 1,3 diphosphate or 2,3 DPG or a combination thereof
  • FDP FDP
  • the present invention is also a method of treating an ischemic tissue comprising administering an effective amount of a composition comprising an effective amount of a polyoxypropylene/polyoxyethylene copolymer and an effective amount of FDP in a pharmaceutically acceptable carrier.
  • the preferred polyoxypropylene/polyoxyethylene copolymer is an ethylene oxide-propylene oxide condensation product with the following general formula:
  • a is an integer such that the hydrophobe represented by (C 3 H 6 O) has a molecular weight of approximately 950 to 4000, preferably approximately 1200 to 3500, and b is an integer such that the hydrophile portion represented by (C 2 H 4 O) constitutes approximately 50% to 95% by weight of the compound.
  • the preferred polyoxypropylene/polyoxyethylene copolymer for use in the composition and method of the present invention is a copolymer having the following formula:
  • the present invention is effective in treating a wide variety of diseases and disease states.
  • the present invention is effective in treating those conditions in which the tissue is ischemic. This includes, but is not limited to, myocardial infarction, angina, stroke, severe trauma, transfusion, bypass surgery, shock, acute respiratory distress, pulmonary embolism, and sickle cell anemia.
  • the present invention also includes the treatment of ischemic events with compounds that shift the oxygen dissociation curve for hemoglobin to the right.
  • the compounds include, but are not limited to, an effective amount of 1, 3 diphosphoglycerate, 2 phosphoglycerate, 3 phosphoglycerate, 2,3 diphosphoglycerate, fructose diphosphate, glyceraldehyde 3-phosphate, 3 phosphoglycerol phosphate, fructose 6 phosphate and glucose 6 phosphate.
  • a pharmaceutically acceptable carrier which can optionally include a polyoxypropylene/polyoxyethylene copolymer having the following formula:
  • Another embodiment of the present invention is a method for treating sickle cell disease comprising the administration of an effective amount of a sugar, preferably a phosphorylated sugar to a patient with sickle cell disease wherein the dehydration of red blood cells is reduced.
  • a sugar preferably a phosphorylated sugar
  • the compounds that can be used in this embodiment of the present invention includes, but is not limited to, 1, 3 diphosphoglycerate, 2 phosphoglycerate, 3 phosphoglycerate, 2,3 diphosphoglycerate, fructose diphosphate, glyceraldehyde 3-phosphate, 3 phosphoglycerol phosphate, fructose 6 phosphate and glucose 6 phosphate.
  • the sugars can optionally be combined with a polyoxypropylene/polyoxyethylene copolymer.
  • Figure 1 shows the effect of poioxamer 188, fructose diphosphate (FDP) and the combination of poioxamer 188 and FDP on tissue salvage in a rabbit model of myocardial ischemia.
  • Figure 2 shows the effect of poioxamer 188, FDP and DPG on dense cell (dehydrataed cell) formation in blood from a sickle cell patient.
  • One embodiment of the present invention is a composition and method comprising an effective amount of a polyoxypropylene/polyoxyethylene copolymer and an effective amount of FDP (fructose 1,6 diphosphate or fructose 1,3 diphosphate or a combination thereof) in a pharmaceutically acceptable carrier.
  • FDP fructose 1,6 diphosphate or fructose 1,3 diphosphate or a combination thereof
  • the present invention is also a method of treating a disease associated with ischemia comprising administering an effective amount of a composition comprising an effective amount of a polyoxypropylene/polyoxyethylene copolymer and an effective amount of FDP in a pharmaceutically acceptable carrier.
  • the fructose 1,6 diphosphate or fructose 1,3 diphosphate used in the present invention can be purchased from Boehringer Mannheim, Germany as well as Biochemcia Foscama in Italy.
  • the two FDP molecules can be partially lyophilized for storage as described in U.S. Patent No. 5,731,291 which is incorporated herein by reference.
  • the preferred daily dose of FDP for intravenous administration will generally be between approximately 10 to about 1,000 mg/kg (i.e., milligrams of FDP per kilogram of patient body weight) with a preferred daily dose of between 25 and 300 mg/kg. It is to be understood that FDP as used according to the present invention can be fructose 1,6 diphosphate, fructose 1,3 diphosphate or an effective combination of the two compounds.
  • Any suitable (i.e., pharmacologically acceptable) salt of FDP can be used, such as a sodium salt, or divalent salts such as calcium or magnesium salts, or mixtures thereof.
  • potassium salts should not be administered intravenously, since an abrupt infusion might interfere with cardiac functioning and certain other cellular functions.
  • Other salts of FDP such as calcium, barium, or cyclohexylammonium salts can also be used in the present invention.
  • oxygen to tissues depends upon a number of factors including, but not limited to, the volume of blood flow, the number of red blood cells, the concentration of hemoglobin in the red blood cells, the oxygen affinity of the hemoglobin and, in certain species, on the molar ratio of intraerythrocytic hemoglobins with high and low oxygen affinity.
  • the oxygen affinity of hemoglobin depends on four factors as well, namely: (1) the partial pressure of oxygen; (2) the pH; (3) the concentration of the allosteric effective 2,3-diphosphoglycerate (DPG) in the hemoglobin; and (4) the concentration of carbon dioxide.
  • DPG allosteric effective 2,3-diphosphoglycerate
  • the effect of the partial pressure of oxygen and the pH on the ability of hemoglobin to bind oxygen is best illustrated by examination of the oxygen saturation curve of hemoglobin.
  • An oxygen saturation curve plots the percentage of total oxygen-binding sites of a hemoglobin molecule that are occupied by oxygen molecules when solutions of the hemoglobin molecule are in equilibrium with different partial pressures of oxygen in the gas phase.
  • the oxygen saturation curve for hemoglobin is sigmoid.
  • binding the first molecule of oxygen increases the affinity of the remaining hemoglobin for binding additional oxygen molecules.
  • a plateau is approached at which each of the hemoglobin molecules is saturated and contains the upper limit of four molecules of oxygen.
  • the reversible binding of oxygen by hemoglobin is accompanied by the release of protons, according to the equation:
  • the partial pressure of oxygen in the air spaces is approximately 90 to 100 mm Hg and the pH is also high relative to normal blood pH (up to 7.6). Therefore, hemoglobin will tend to become almost maximally saturated with oxygen in the lungs. At that pressure and pH, hemoglobin is approximately 98 percent saturated with oxygen.
  • the partial pressure of oxygen is only about 25 to 40 mm Hg and the pH is also relatively low (about 7.2 to 7.3). Because muscle cells use oxygen at a high rate thereby lowering the local concentration of oxygen, the release of some of the bound oxygen to the tissue is favored.
  • hemoglobin As the blood passes through the capillaries in the muscles, oxygen will be released from the nearly saturated hemoglobin in the red blood cells into the blood plasma and thence into the muscle cells. Hemoglobin will release about a third of its bound oxygen as it passes through the muscle capillaries, so that when it leaves the muscle, it will be only about 64 percent saturated. In general, the hemoglobin in the venous blood leaving the tissue cycles between about 65 and 97 percent saturation with oxygen in its repeated circuits between the lungs and the peripheral tissues. Thus, oxygen partial pressure and pH function together to effect the release of oxygen by hemoglobin
  • DPG allosteric effector 2, 3 -diphosphoglycerate
  • DPG is the normal physiological effector of hemoglobin in mammalian erythrocytes. DPG regulates the oxygen-binding affinity of hemoglobin in the red blood cells in relationship to the oxygen partial pressure in the lungs. In general, the higher the concentration of DPG in the cell, the lower the affinity of hemoglobin for oxygen.
  • the concentration of DPG in the erythrocytes is higher than in normal individuals.
  • the partial pressure of oxygen is significantly less.
  • the partial pressure of oxygen in the tissues is less.
  • the DPG level in the red blood cells increases, causing more DPG to be bound and the oxygen affinity of the hemoglobin to decrease.
  • Increases in the DPG level of red cells also occur in patients suffering from hypoxia. This adjustment allows the hemoglobin to release its bound oxygen more readily to the tissues to compensate for the decreased oxygenation of hemoglobin in the lungs.
  • the reverse change occurs when people acclimated to high altitudes and descend to lower altitudes.
  • hemoglobin As normally isolated from blood, hemoglobin contains a considerable amount of DPG. When hemoglobin is "stripped" of its DPG, it shows a much higher affinity for oxygen. When DPG is increased, the oxygen binding affinity of hemoglobin decreases. A physiologic allosteric effector such as DPG is therefore essential for the normal release of oxygen from hemoglobin in the tissues.
  • the compounds that can be used to effect this "right shift" in the oxygen dissociation curve include, but are not limited to, 1, 3 diphosphoglycerate, 2,3 diphosphoglycerate, 2 phosphoglycerate, 3 phosphoglycerate, fructose diphosphate, glyceraldehyde 3-phosphate, 3 phosphoglycerol phosphate, fructose 6 phosphate and glucose 6 phosphate.
  • the dose of compounds causing a shift in the oxygen dissociation curve to the right will be dependent upon the compound.
  • an intravenous bolus injection of 50 mg/kg can be administered every 4 - 6 hours for 12 - 72 hours or until the ischemic event resolves.
  • the compounds can be administered either separately or in combination with a polyoxypropylene/polyoxyethylene copolymer.
  • the preferred polyoxypropylene/polyoxyethylene copolymers that are used optionally in combination with the compounds described herein are an ethylene oxide-propylene oxide condensation product with the following general formula: HO(C H O) (C H O) (C H O) H
  • a is an integer such that the hydrophobe represented by (C 3 H 6 O) has a molecular weight of approximately 950 to 4000, preferably approximately 1200 to 3500, and b is an integer such that the hydrophile portion represented by
  • the surface-active copolymer can be purchased from CytRx Corporation, Norcross, Ga.
  • the preferred polyoxypropylene/polyoxyethylene copolymer for use in the composition and method of the present invention is a copolymer having the following formula:
  • the polyoxypropylene/polyoxyethylene copolymers blocks are formed by condensation of ethylene oxide and propylene oxide at elevated temperature and pressure in the presence of a basic catalyst. There is some statistical variation in the number of monomer units which combine to form a polymer chain in each copolymer. The molecular weights given are approximations of the average weight of copolymer molecule in each preparation.
  • polyoxypropylene/polyoxyethylene copolymers includes molecules that may be slightly higher or lower in molecular weight than the molecular weight stated. It is to be understood that the blocks of propylene oxide and ethylene oxide do not have to be pure. Small amounts of other materials can be admixed so long as the overall physical chemical properties are not substantially changed.
  • polyoxypropylene/polyoxyethylene copolymers described in the '492 patent are a less polydisperse population of molecules than the prior art polyoxypropylene/polyoxyethylene copolymers, the biological activity of the copolymers is better defined and more predictable.
  • the polyoxypropylene/polyoxyethylene copolymers described in the '492 patent are also substantially free of unsaturation and are less renal toxic.
  • Illustrative ethylene oxide-propylene oxide condensation products which may be employed in the preparation of the present invention include, but are not limited to, the following copolymers:
  • the effective dose of polyoxypropylene/ polyoxyethylene copolymers used to practice the present invention is between approximately 50 and 2,500 mg/kg.
  • the preferred dose of surface active copolymer used to practice the present invention is between approximately 500 to 2,00000 mg/kg with the most preferred dose between approximately 1,000 to 2,000 mg/kg.
  • the aforementioned dosages of the surface active copolymer used to practice the present invention are typically evenly administered as a continuous infusion over a 4 to 72 hour period.
  • the polyoxypropylene/polyoxyethylene copolymers used to practice the present invention may be administered at a dose of 30 mg/kg/hr for 48 hours.
  • the present invention also includes the separate administration of polyoxypropylene/polyoxyethylene copolymer and FDP.
  • the polyoxypropylene/polyoxyethylene copolymer may be administered before or after the administration of FDP.
  • the preferred method of administering the composition according to the present invention is to have the polyoxypropylene/polyoxyethylene copolymer and the FDP mixed in a pharmaceutically acceptable carrier liquid.
  • Pharmaceutically acceptable carrier liquids include, but are not limited to, dextrose solution, citrate solution, Ringer's lactate solution and normal saline solution. All of these solutions must be osmotically acceptable for injection into a human or animal.
  • Another embodiment of the present invention is a method for treating sickle cell disease comprising the administration of an effective amount of a sugar, preferably a phosphorylated sugar to a patient with sickle cell disease wherein the dehydration and subsequent sickling of red blood cells is reduced.
  • a sugar preferably a phosphorylated sugar
  • the compounds that can be used in this embodiment of the present invention includes, but is not limited to, 1, 3 diphosphoglycerate, 2 phosphoglycerate, 3 phosphoglycerate, 2,3 diphosphoglycerate, fructose diphosphate, glyceraldehyde 3-phosphate, 3 phosphoglycerol phosphate, fructose 6 phosphate and glucose 6 phosphate.
  • the sugars can optionally be combined with a polyoxypropylene/polyoxyethylene copolymer as defined herein.
  • the preferred daily dose of phosphorylated sugar for intravenous administration to treat sickle cell disease is between approximately 10 to about 1,000 mg/kg (i.e., milligrams of sugar per kilogram of patient body weight) with a preferred daily dose of between 25 and 300 mg/kg.
  • composition of the present invention may be employed by admixing with blood in any standard manner.
  • the solutions are intravenously injected into the blood stream either as a bolus, slow drip, programmed infusion or combination there of.
  • the solutions are generally admixed with the blood in a manner so as to maintain a substantially steady venous pressure.
  • EXAMPLE 1 For treating ischemia associated with sickle cell disease in a 70 Kg patient with sickle cell disease in sickle cell crises, 3,500 mg of FDP is added to 250 ml of 0.9% sodium chloride solution containing 12,600 mg of an ethylene oxide-propylene oxide copolymer with the following general formula:
  • the solution comprising the present invention is injected intravenously into an appropriate vein at a rate of 0.7 ml per minute for a period of 6 hours.
  • the aforementioned procedure can be repeated as necessary until the crisis resolves or dose limiting toxicities are noticed.
  • EXAMPLE 2 For treating ischemia associated with sickle cell disease in a 70 Kg patient with sickle cell disease in sickle cell crisis, a loading solution and an infusion solution are prepared as follows: For the loading solution, 3,500 mg of Fructose 1,3 diphosphate is added to 100 ml of 0.9% sodium chloride solution containing 7,000 mg of an ethylene oxide-propylene oxide copolymer with the following general formula:
  • the infusion solution is thoroughly mixed to form a homogeneous solution.
  • the loading solution comprising the present invention is injected intravenously into an appropriate vein at a rate of 1.6 ml per minute for one hour, -jnmediately following the loading infusion, the infusion solution is injected intravenously at a rate of 0.7 ml per minute for 47 hours.
  • EXAMPLE 3 This Example shows the ability of poioxamer 188, alone and in combination with FDP, to improve myocardial blood flow and contractile function during and after an episode of myocardial ischemia. Myocardial "stunning" or reduction in contractile function is routinely observed upon reperfusion of ischemic areas.
  • mice Male white rabbits (4-5 lbs.) were used in this Example. Following induction with thiopental Na (15 mg/kg i.v.), the rabbits were anesthetized and maintained with isoflurane (2.5% MAC) positive pressure via a ventilator with 80% 0 2 . Rabbits were fitted with an arterial and venous catheter for measurement of arterial blood pressure and delivery of drugs, respectively. Lead II ECG electrodes are positioned to measure the electrocardiogram. A transducer-tipped catheter (Millar®) was inserted into the left cardiac ventricle via the left carotid artery to measure left ventricular pressure (LVP) and the signal differentiated to yield dLVP/dt (time)- ⁇ , a measure of cardiac contractile force.
  • LVP left ventricular pressure
  • the heart was exposed by a left side thoracotomy (5 th intracostal space). Heart rate was measured via tachometer driven by LVP signal.
  • a suture (0 silk) is placed around the left anterior descending (LAD) coronary artery at its origin, and both ends of this suture placed through a small polyethylene tube. Following a 30- min equilibration period, all hemodynamic variables were monitored for 20 min.
  • the LAD artery was then occluded by sliding the polyethylene tube down the suture ends to completely close the artery and maintained by clamping the polyethylene tube with a hemostat. After 20 min of occlusion, the ligature was loosened and blood flow allowed to resume. Infarct size was determined relative to area at risk using tetrazolium dye uptake. There were four experiment groups of 5 rabbits each:
  • Control Group received only drug vehicle.
  • Drug Group A received a dose of 200 mg/kg of poioxamer 188 (FLOCOR).
  • Drug Group B received a 100 mg/kg dose of fructose 1-6 diphosphate (DFP).
  • Combination Drug Group received the combination of poioxamer 188 and fructose 1-6 diphosphate at the dose levels used in group A and B.
  • the drugs or vehicle were infused over 20 sec in a volume of 10 ml at +1 min after the coronary artery occlusion.
  • the results are shown in Figure 1.
  • the combination of poioxamer 188 and FDP had the greatest effect on the reducing the infarct size relative to the area at risk.
  • Fig. 2 shows the relative percent change from the control.
  • Poioxamer 188 0.5 mg/ml
  • FDP and DPG both at 1.0 mg/ml
  • the combination of poioxamer 188 + FDP or DPG was not different from the sugars alone.

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Abstract

L'invention concerne une composition et une méthode permettant de traiter l'ischémie, comprenant une quantité efficace d'un copolymère de polyosypropylène/polyoxyéthylène et une quantité efficace d'un composé très énergétique. Selon un autre mode de réalisation, l'invention concerne un procédé permettant de traiter la drépanocytose par administration d'une quantité efficace d'un composé très énergétique à un patient atteint de drépanocytose.
PCT/US1999/023706 1998-10-09 1999-10-08 Methode et composition permettant de traiter l'ischemie et la drepanocytose WO2000021543A1 (fr)

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US10378298P 1998-10-09 1998-10-09
US60/103,782 1998-10-09
US13338999P 1999-05-10 1999-05-10
US60/133,389 1999-05-10

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008124088A2 (fr) * 2007-04-05 2008-10-16 Phrixus Pharmaceuticals, Inc. Compositions et procédés pour le traitement de l'insuffisance cardiaque
US9155758B2 (en) 2006-08-01 2015-10-13 Phrixus Pharmaceuticals, Inc. Treatment of chronic progressive heart failure
US20160038515A1 (en) * 2013-03-15 2016-02-11 M. Alphabet 3., L.L.C. Methods and compositions for enhancing oxygen levels in tissues
US20220304966A1 (en) * 2017-02-27 2022-09-29 Vanderbilt University Citrulline for treatment of sickle cell crisis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182106A (en) * 1986-05-15 1993-01-26 Emory University Method for treating hypothermia
US5516526A (en) * 1993-07-30 1996-05-14 Da La Torre; Jack Compositions containing DMSO and Fructose 1,6-diphosphate
US5523492A (en) * 1991-03-19 1996-06-04 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
US5731291A (en) * 1996-05-08 1998-03-24 Cypros Pharmaceutical Corp. Partially lyophilized fructose-1,6-diphosphate (FDP) for injection into humans

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182106A (en) * 1986-05-15 1993-01-26 Emory University Method for treating hypothermia
US5523492A (en) * 1991-03-19 1996-06-04 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
US5516526A (en) * 1993-07-30 1996-05-14 Da La Torre; Jack Compositions containing DMSO and Fructose 1,6-diphosphate
US5731291A (en) * 1996-05-08 1998-03-24 Cypros Pharmaceutical Corp. Partially lyophilized fructose-1,6-diphosphate (FDP) for injection into humans

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9155758B2 (en) 2006-08-01 2015-10-13 Phrixus Pharmaceuticals, Inc. Treatment of chronic progressive heart failure
WO2008124088A2 (fr) * 2007-04-05 2008-10-16 Phrixus Pharmaceuticals, Inc. Compositions et procédés pour le traitement de l'insuffisance cardiaque
WO2008124088A3 (fr) * 2007-04-05 2009-03-12 Phrixus Pharmaceuticals Inc Compositions et procédés pour le traitement de l'insuffisance cardiaque
US8372387B2 (en) 2007-04-05 2013-02-12 Phrixus Pharmaceuticals, Inc. Compositions and methods for the treatment of heart failure
US20160038515A1 (en) * 2013-03-15 2016-02-11 M. Alphabet 3., L.L.C. Methods and compositions for enhancing oxygen levels in tissues
US10159688B2 (en) * 2013-03-15 2018-12-25 M. Alphabet 3, L.L.C. Methods and compositions for enhancing oxygen levels in tissues
US20220304966A1 (en) * 2017-02-27 2022-09-29 Vanderbilt University Citrulline for treatment of sickle cell crisis

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