WO2001022960A1 - Traitement de l'asphyxie par le monoxyde de carbone - Google Patents
Traitement de l'asphyxie par le monoxyde de carbone Download PDFInfo
- Publication number
- WO2001022960A1 WO2001022960A1 PCT/US2000/041016 US0041016W WO0122960A1 WO 2001022960 A1 WO2001022960 A1 WO 2001022960A1 US 0041016 W US0041016 W US 0041016W WO 0122960 A1 WO0122960 A1 WO 0122960A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- adenosine
- carbon monoxide
- poisoning
- neuromodulator
- neuromodulators
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
Definitions
- This invention relates to the treatment of humans having carbon monoxide poisoning. More particularly, this invention relates to various neuromodulatory agents that decrease excitotoxicity and/or apoptosis.
- Such molecules include neuromodulators of excitatory neurotransmitters, cerebral adenosine levels, K + channels, nitric oxide, and PARP.
- the function of the brain is dependent on a continuous supply of oxygen and glucose. Irreversible brain damage is induced if blood flow is reduced below about 10 ml/ 100 g tissue/min, and can occur within a few minutes if flow is completely interrupted. See, D.W. Choi, et al., "The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death," Ann. Neurol., 13, 171-182 (1990). It is well recognized that carbon monoxide produces tissue hypoxia by competing with oxygen for binding sites on hemoglobin. Non-CO induced hypoxic-ischemia is accomplished by a brief increase in intracerebral adenosine, which may act as an endogenous neuroprotector.
- Adensoine By stimulating Ai receptors, adensoine blocks excitatory amino acids from causing cerebral damage after ischemia. Adenosine alters presynaptic calcium influx and the subsequent release of neuronal ecitotoxins such as glutamate. Furthermore, by stimulating A 2 receptors, adensoine increases cerebral blood flow, conteracting local brain ischemia. However, adenosine may contribute to neuronal injury after ischemic or hypoxic injury.
- nitric oxide that can react with superoxide to form the toxic compound peroxynitrite.
- nitric oxide and peroxynitrite can cause DNA damage, which activates poly(ADP-ribose) polymerase, an enzyme implicated in leading to cell death due to energy depletion and/or apoptosis.
- the central nervous system is one of the most sensitive areas to carbon monoxide poisoning. Acutely, patients may have headaches, dizziness, and ataxia at COHB concentrations of 30 to 40%, and syncope, seizures and coma at 50 to 60%. Several hours after exposure in severe cases, CT scans show decreased density in the cerebral white matter, globus pallidus, and cerebellum, areas that exhibit poorly developed blood supply. Although carbon monoxide toxicity affects various parts of the brain, particularly the hippocampus, the presence of low density areas in the globus pallidus and cerebral white matter correlate best with poor neurological outcome.
- Another object of the present invention is to provide methods for treating the effects of carbon monoxide poisoning.
- the present invention provides a method for treating sever carbon monoxide poisoning using neuromodulators.
- neuromodulators may be used in the treatment of severe carbon monoxide (CO) poisoning.
- CO carbon monoxide
- These neuromodulators include those that prevent the release of excitatory neurotransmitters, such as riluzole, and molecules that competitively and non-competitively antagonize glutamate receptors, particularly of the NMD A type.
- Another class of neuromodulators that are useful in the treatment of carbon monoxide poisoning includes adenosine and its derivatives that have a binding affinity for the Ai or A receptors, such as N- cyclochloro-P-adenosine (CCPA).
- CCPA N- cyclochloro-P-adenosine
- adenosine transport and metabolism by either inhibiting adenosine deaminase or adenosine kinase or nucleoside transporters.
- Another effective class of neuromodulators includes arginine derivative that inhibit nitric oxide systhetase (NOS), such as L-nitro-arginine-melhyl-ester (L-NAME).
- NOS nitric oxide systhetase
- L-NAME L-nitro-arginine-melhyl-ester
- Another class of therapeutic drugs includes antioxidants such as dimethyl sulfoxide (DMSO).
- Another class of neuroprotective agents that are effective in treating carbon monoxide poisoning includes molecules that inhibitor poly(ADP-ribose) polymerase (PARP), such as 3-aminobenzamide and 5-aminoisoquinolinone.
- PARP poly(ADP-ribose) polymerase
- Another class of neuromodulatory agents includes molecules such that open potassium channels, particularly of the maxi K + channel type, such as BMS 204352.
- N-methyl-D-aspartate (NMD A) receptors following ischemic events is effective in attenuating intracellular calcium buildup and subsequent neuronal necrosis.
- NMD A N-methyl-D-aspartate
- glutamate is released from neurotransmitter pools in neurons depolarized by the elevation of extracellular potassium. See, J. Drejer et al., "Cellular origin of ischemia-induced glutamate release from brain tissue in vivo and in vitro," Journal ofNeurochemistry, 45, 1, 145-151 (1985).
- neuromodulators that inhibit the presynaptic release of glutamate and molecules that competitively and non-competitively antagonize glutamate receptors of the NMDA type.
- NMDA antagonists such as MK-801, ketamine, APV and riluzole have been successful in attenuating calcium-induced neuronal necrosis during ischemia.
- riluzole is preferred.
- Riluzole is sold under the name RILUTEK ® by Rhone-Poulenc Rorer.
- a therapeutically effective amount of riluzole is from about 3 mg/kg to about 30 mg/kg in pharmaceutically acceptable carrier, preferably from about 5 mg/kg to about 10 mg/kg, and most preferably about 8 mg/kg. While in many cases riluzole need only be given once, it should be understood that it may be given daily as needed until the patent has recovered. However, the dosage can vary with the body weight of the patient treated.
- Intervention in cerebral levels of adenosine provides a treatment for carbon monoxide poisoning.
- Concentrations of adenosine in the brain increase during other insults comparable to carbon monoxide poisoning, such as ischemia, and hypoxia.
- adenosine is rapidly formed during ischemic/hypoxic events and is subsequently transported into the extracellular space. See, T. Zetterstrom et al., "Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre," Neurosci. Letters, 29, 111-115 (1982). It has been found through neurobehavioral studies that adenosine may have neuroprotective properties.
- a class of neuromodulators that effectively intervenes in cerebral levels of adenosine that are useful in the treatment of carbon monoxide poisoning includes derivatives of adenosine that have a binding affinity for the Ai or A 2 receptors. These derivatives include molecules that inhibit adenosine deaminase (including derivatives of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), molecules that inhibit adenosine kinase, and molecules that inhibit nucleoside transport.
- a therapeutically effective amount of EHNA is generally from about 4.0 mg/kg to about 10.0 mg/kg in pharmaceutically acceptable carrier.
- a particularly preferred neuromodulator is N-cyclochloro-P-adenosine (CCPA).
- CCPA is an adenosine Ai agonist.
- a therapeutically effective amount of CCPA is generally from about 0.1 mg/kg to about 0.7 mg/kg in pharmaceutically acceptable carrier, preferably from abut 0.2 mg/kg to about 0.4 mg/kg, and most preferably about 0.3 mg/kg.
- L-NAME L-nitro-arginine-melhyl-ester
- a therapeutically effective amount of L-NAME is from about 5 mg/kg to about 30 mg/kg in pharmaceutically acceptable carrier normal, preferably from abut 10 mg/kg to about 20 mg/kg, and most preferably about 15 mg/kg.
- An antioxidant that is effective in the treatment of carbon monoxide poisoning is dimethyl sulfoxide (DMSO).
- DMSO dimethyl sulfoxide
- DMSO dimethyl sulfoxide
- DMSO dimethyl sulfoxide
- a therapeutically effective amount of PARP inhibitor is generally from about 5.0 mg/kg to about 30.0 mg/kg in pharmaceutically acceptable carrier, preferably about 10.0 mg/kg.
- potassium channel openers such as ligand- activated, voltage-gated, and calcium-activated channels, particularly of the maxi K + type, are effective in treating carbon monoxide poisoning.
- Potassium channel openers participate in a large number of important cellular functions, such as control of cell electrical excitability and excitation/response coupling.
- the dosages of these compounds are known to those skilled in the art. Specific examples include BMS 204352 (Bristol-Myers Squibb).
- the active compounds of this invention are typically administered in a pharmaceutically acceptable carrier through appropriate routes such as parenterally, i.e., intravenously or intramuscularly, or by oral administration.
- parenteral administration the active compounds can be suspensions before use.
- Sterile water, physiological saline, e.g., phosphate buffered saline (PBS) can be used conveniently as the pharmaceutically acceptable carriers or diluents.
- solvents including but not limited to acetates, citrates or phosphate buffers, sodium chloride, dextrose, fixed oils, glycerine, polyethylene glycol, propylene glycol, benzyl alcohol, methyl parabens, ascorbic acid, sodium bisulfite, and the like.
- the active compounds of this invention are administered at a therapeutically effective amount to achieve the desired therapeutic effect without causing any serious adverse effects in the patent treated.
- the active compounds can also be delivered orally in enclosed gelatin capsules or compressed tablets. Capsules and tablets can be prepared in any conventional manner.
- the active compounds can also be administered topically. Topical formulations are generally known in the art including creams, gels, ointments, lotions, powders, pastes, suspensions, sprays and aerosols. When DMSO is the antioxidant of choice, it is preferably given topically.
- Hyperbaric oxygen (HBO) therapy is the only treatment presently available for patients who have suffered from carbon monoxide poisoning. Although it has been shown that HBO speeds the disassociation of carbon monoxide from hemoglobin, thereby reducing carboxyhemoglobinernia, little has actually been described relative to its clinical effectiveness involving CO-induced neurological degeneration. At present, there have been no reports describing the synaptic manipulation of the PARS system during carbon monoxide poisoning, nor has there been a comparison with other novel treatments, such as NMDA antagonists and the clinically accepted treatment, HBO therapy.
- mice Male Wistar rats (280-350 grams)(Charles River, Raleigh, NC) were housed under diurnal light conditions and constant temperature (23 °C.) with free access to food and water for at least three days prior to the neurosurgical procedure.
- the animals were anesthetized using sodium pentobarbital i.p. (40 mg/kg) and the skull exposed.
- a small burr hole (0.75 mm) was then made according to the stereotaxic coordinates 1 mm posterior, 1.5 mm lateral and 4.5 mm deep to bregma to assure lateral ventricle placement.
- a non-penetrating microdialysis probe guide (Harvard Apparatus, Boston, MA) was inserted into the hole and two stainless steel screws were placed 1 cm from the guide in a triangular pattern. Dental acrylic was used to bond the guide to the permanently implanted screws. Animals were allowed to recover for three to five days prior to the first microdialysis sampling. The placement of the microdialysis probe in the ventricle was confirmed by post experimental dissection. To simulate severe carbon monoxide poisoning that can lead to delayed neurological sequelae, a protocol that provided for a 60 minute soaking period ending in loss of consciousness was used.
- the infusion and effluent tubing were passed through a six cm section of size 16 silicone tubing (Cole-Parmer, Niles, IL), which was attached to the probe holder to protect the rigid base of the probe shaft.
- the probe holder was inserted into the permanently implanted probe guide so that the tip of the probe was situated 4.5 mm below the surface of the dura in the lateral ventricular space. This site was selected in order to measure extra cellular fluid from the CSF.
- the animals were placed in individual acrylic cages (30.5 x
- Mobile phase B was a mixture of methanol and 4 mM KH PO 4 (70/30 v/v). Before using, both mobile phases were filtered through a 0.45 ⁇ m filter and helium degassed.
- the animals were sacrificed at one, two, four, six, twelve and twenty-four hours to determine the optimal time for peak PARS activity.
- Baseline Group Unpoisoned and untreated mice stayed in the carbon monoxide exposure chamber for one hour of air and then were removed from the chamber. One hour post removal, the animals were euthanized to determine baseline PARS activity. Peak PARS Activity Group: Poisoned mice were recovered following the optimal activity time (1, 2, 4, 8, 12, or 24 hours) in room air and then sacrificed.
- DMSO fetal sulfate
- CCPA 0.3 mg/kg
- Vehicle control The vehicle controls were divided into two groups: One group was poisoned and received the sham injection, while the other group was unpoisoned, while receiving the sham vehicle. All sham vehicle injections were administered in precisely the same manner as the experimental drug deliveries.
- mice were anesthetized with sodium pentobarbital (50 mg/kg IP) and killed by decapitation.
- the brains were rapidly removed and frozen whole in isopentane (-30°C).
- the cortical tissue was dissected out and prepared according to the method of LaPlaca (1999).
- the tissue was processed by homogenization in a Dounce homogenizer in 50 mM Tris (pH 6.8) containing 25 mM MgCl and protease inhibitor cocktail (Boehringer Mannheim, Indianapolis IN); 0.5 ml of buffer/50 mg of tissue).
- the resulting pellet was subjected to two more washes of 50% TCA and two washes of ice-cold acetone. After a brief air- drying, the pellet was dissolved in SDS-PAGE sample buffer containing 4 M urea and will be boiled at 90°C. for 15 minutes. The PARS protein was separated on an 8% SDS-PAGE. The gel was fixed, dried and exposed to a Phophorlinage cassette (Molecular Dynamics, Sunnyvale C A). The end result was a measure of PARS activity by comparing phosphor illumination counts to a control.
- the neurobehavioral experimental and control groups were divided into two divisions in order to test for both learning (post) and memory (pre) capabilities of the neuroprotective effects of 3-aminobenzamide. This agent was compared to the other neuromodulators used in this invention as well as current clinically accepted treatment for carbon monoxide (i.e., hyperbaric oxygen).
- Post-training CO exposure Learning was measured by first exposing the mice to CO, followed by the acquisition of the passive avoidance task 7 days later. A retention test for step-down latency will be performed 24 hours subsequent to the learning task.
- Pre-Training CO exposure Memory was assessed by teaching the mice the passive avoidance learning task first, followed by the carbon monoxide exposure 24 hours later. The retention test for step-down latency will be given seven days later.
- the passive avoidance test measures the ability of an animal to retain and retrieve a consolidated memory.
- the apparatus consisted of a grid floor with a rectangular acrylic glass wall (30 x 30 x 40 cm). At the center of the grid a 4 x 4 x 4 cm wooden platform is fixed. Electric shock (1 Hz, 500ms, 35 V DC, 15 mAmps) was delivered to the grid by an isolated stimulator (SEN-3201, SS-201 J, Nihon Koden, Japan). Illumination was provided by a 15-W lamp hanging above the apparatus.
- Passive Avoidance Retention Test To assess retention in trained mice, testing was carried out in a manner similar to that of training, except that an electric shock was not delivered to the grid floor. Each mouse was placed on the platform, and step-down latency recorded with an upper cut-off time of 300 seconds.
- mice Following each animal's retention test, the mice were immediately anesthetized with sodium pentobarbital (50 mg/kg i.p.) and perfused transcardially with 150 ml of 0.9% saline containing heparin followed by a 150 ml of a solution containing 3.5% formaldehyde and 0.9% saline in 0.1M phosphate buffer (pH 7.2).
- the brains were removed and kept in the solution of the same fixative for 1 to 2 weeks.
- a block containing the hippocampal area was then cut coronally, dehydrated with graded alcohol, and embedded in paraffin. Coronal sections, 10 ⁇ m thick, were cut from the hippocampal block on a microtome.
- a section 1.5 mm in length of the hippocampal CA1 pyramidal cell layer was selected (approximate center of the CA1 PC layer) and stained by malgen nuclear reaction using Schiff s reagent.
- the number of pyramidal cells in the CA1 subfield were counted by a blinded observer using ImagePro-1998.
- This example illustrates the neuroprotective effects of glutamate antagonism on memory following acute carbon monoxide poisoning.
- CO carbon monoxide
- DAS delayed -neurologic sequelae-
- This example illustrates the protective effects of experimental neurodepressors, on learning and memory following carbon monoxide poisoning.
- This example illustrates the efficacy of L-NAME and CCPA in preventing delayed sequelae after CO poisoning.
- mice Male Swiss- Webster mice were exposed to CO: 1,000 ppm for 40 minutes and 50,000 ppm until loss of consciousness (LOC) and were treated 15 minutes after LOC.
- the experimental groups received either CCPA (0.3 mg/kg) or L-
- NAME (15 mg/kg), while controls were untreated. All animals underwent passive avoidance training either 24 hours before (PRE) or 7 days after (POST) poisoning with CO. Learning and memory was assessed by measuring step-down latency (SDL) at 7 days (PRE-Memory) or 8 days (POST-Learning) subsequent to exposure. SDL was compared among groups with Kruskal-Wallis non-parametric ANOVA followed by Dunn's test for multiple comparisons.
- L-NAME and CCPA were both found to be protective of both learning and memory in a mouse model of acute CO poisoning. These drugs prevent delayed neurological sequelae by their neurodepressant effects in countering excitatory amino acids such as glutamate.
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Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AU14934/01A AU1493401A (en) | 1999-09-30 | 2000-09-28 | Treatment of carbon monoxide poisoning |
Applications Claiming Priority (2)
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US15719899P | 1999-09-30 | 1999-09-30 | |
US60/157,198 | 1999-09-30 |
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WO2001022960A1 true WO2001022960A1 (fr) | 2001-04-05 |
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PCT/US2000/041016 WO2001022960A1 (fr) | 1999-09-30 | 2000-09-28 | Traitement de l'asphyxie par le monoxyde de carbone |
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WO (1) | WO2001022960A1 (fr) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008127456A3 (fr) * | 2006-12-07 | 2008-12-11 | Lyotropic Therapeutics Inc | Compositions pour l'inversion et la détoxification des anesthétiques et d'autres composés et procédés d'utilisation de ces compositions |
US7968124B2 (en) * | 2004-07-13 | 2011-06-28 | Lyotropic Therapeutics, Inc. | Compositions for the reversal and detoxification of anesthetics and other compounds and methods of their use |
US9078888B2 (en) | 2007-01-22 | 2015-07-14 | Gtx, Inc. | Nuclear receptor binding agents |
CN104814952A (zh) * | 2015-04-16 | 2015-08-05 | 嘉兴学院 | 一种促进一氧化碳释放剂释放一氧化碳并防止形成沉淀的方法 |
WO2015179344A1 (fr) * | 2014-05-22 | 2015-11-26 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Utilisation de microperoxidases pour le traitement de la carboxyhémoglobinémie |
US9604931B2 (en) | 2007-01-22 | 2017-03-28 | Gtx, Inc. | Nuclear receptor binding agents |
US9623021B2 (en) | 2007-01-22 | 2017-04-18 | Gtx, Inc. | Nuclear receptor binding agents |
RU2723165C1 (ru) * | 2019-05-20 | 2020-06-09 | Александра Павловна Савченко | Способ снижения тяжести отдаленных последствий отравлений оксидом углерода |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5496836A (en) * | 1994-05-05 | 1996-03-05 | Mount Sinai School Of Medicine Of The City University Of New York | Use of famotidine and related compounds in the treatment of movement disorders |
-
2000
- 2000-09-28 AU AU14934/01A patent/AU1493401A/en not_active Abandoned
- 2000-09-28 WO PCT/US2000/041016 patent/WO2001022960A1/fr active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5496836A (en) * | 1994-05-05 | 1996-03-05 | Mount Sinai School Of Medicine Of The City University Of New York | Use of famotidine and related compounds in the treatment of movement disorders |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7968124B2 (en) * | 2004-07-13 | 2011-06-28 | Lyotropic Therapeutics, Inc. | Compositions for the reversal and detoxification of anesthetics and other compounds and methods of their use |
WO2008127456A3 (fr) * | 2006-12-07 | 2008-12-11 | Lyotropic Therapeutics Inc | Compositions pour l'inversion et la détoxification des anesthétiques et d'autres composés et procédés d'utilisation de ces compositions |
US9078888B2 (en) | 2007-01-22 | 2015-07-14 | Gtx, Inc. | Nuclear receptor binding agents |
US9604931B2 (en) | 2007-01-22 | 2017-03-28 | Gtx, Inc. | Nuclear receptor binding agents |
US9623021B2 (en) | 2007-01-22 | 2017-04-18 | Gtx, Inc. | Nuclear receptor binding agents |
WO2015179344A1 (fr) * | 2014-05-22 | 2015-11-26 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Utilisation de microperoxidases pour le traitement de la carboxyhémoglobinémie |
AU2015264362B2 (en) * | 2014-05-22 | 2020-05-07 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Use of microperoxidases for the treatment of carboxyhemoglobinemia |
US10980864B2 (en) | 2014-05-22 | 2021-04-20 | University of Pittsburgh—of the Commonwealth System of Higher Education | Use of microperoxidases for the treatment of carboxyhemoglobinemia |
CN104814952A (zh) * | 2015-04-16 | 2015-08-05 | 嘉兴学院 | 一种促进一氧化碳释放剂释放一氧化碳并防止形成沉淀的方法 |
CN104814952B (zh) * | 2015-04-16 | 2017-12-26 | 嘉兴学院 | 一种促进一氧化碳释放剂释放一氧化碳并防止形成沉淀的方法 |
RU2723165C1 (ru) * | 2019-05-20 | 2020-06-09 | Александра Павловна Савченко | Способ снижения тяжести отдаленных последствий отравлений оксидом углерода |
RU2723165C9 (ru) * | 2019-05-20 | 2020-09-03 | Александра Викторовна Савченко | Способ снижения тяжести отдаленных последствий отравлений оксидом углерода |
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