CN1638781A - Carbon monoxide as a biomarker and therapeutic agent - Google Patents
Carbon monoxide as a biomarker and therapeutic agent Download PDFInfo
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- CN1638781A CN1638781A CNA028292995A CN02829299A CN1638781A CN 1638781 A CN1638781 A CN 1638781A CN A028292995 A CNA028292995 A CN A028292995A CN 02829299 A CN02829299 A CN 02829299A CN 1638781 A CN1638781 A CN 1638781A
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- 210000001550 testis Anatomy 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
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Abstract
The present invention relates to the user of carbon monoxide (CO) as a biomarker and therapeutic agent of heart, lung, liver, spleen, brain, skin and kidney diseases and other conditions and disease states including, for example, asthma, emphysema, bronchitis, adult respiratory distress syndrome, sepsis, cystic fibrosis, pneumonia, interstitial lung diseases, idiopathic pulmonary diseases, other lung diseases including primary pulmonary hypertension, secondary pulmonary hypertension, cancers, including lung, larynx and throat cancer, arthritis, wound healing, Parkinson's disease, Alzheimer's disease, peripheral vascular disease and pulmonary vascular thrombotic diseases such as pulmonary embolism. CO may be used to provide anti-inflammatory relief in patients suffering from oxidative stress and other conditions especially including sepsis and septic shock. In addition, carbon monoxide may be used as a biomarker or therapeutic agent for reducing respiratory distress in lung transplant patients and to reduce or inhibit oxidative stress and inflammation in transplant patients.
Description
Technical field
The present invention relates to carbon monoxide (CO) in following disease as biomarker and therapeutic agent purposes, described disease is the heart, lung, liver, spleen, brain, skin and kidney disease and other diseases (disease state), for example comprise, asthma, emphysema, bronchitis, adult respiratory distress syndrome (adult respiratorydistress syndrome), sepsis (sepsis), cystic fibrosis, pneumonia, interstitial lung disease (interstitiallung disease), the special property sent out lung disease (idiopathic pulmonary diseases), other lung diseases comprise primary pulmonary hypertension, the Secondary cases pulmonary hypertension, cancer comprises lung, the cancer of larynx (larynx) and pharynx (throat), arthritis, wound healing, parkinson (Parkinson ' s disease), Alzheimer (Alzheimer ' s disease), peripheral blood vessel and pulmonary artery thrombosis disease (pulmonary vascular thrombotic diseases) are as pulmonary infarction (pulmonaryembolism).CO can be used for comprising especially that for suffering from oxidative stress (oxidative stress) and other diseases the patient of sepsis and septic shock provides antiinflammatory to alleviate.In addition, CO can be used for transplanting preceding storage organ.In addition, carbon monoxide can be used as biomarker or therapeutic agent reduces the RD that the lung transplantation patient is taken place, and reduces or suppress oxidative stress, inflammation or the repulsion of the graft of transplant patient.
Background technology
The first step of Heme oxygenase (HO) catalytic degradation haemachrome and the step of speed limit produce the biliverdin IXa of equimolar amounts, carbon monoxide (CO), and ferrum (Choi etc., Am.J.Respir.Cell Mol.Biol.15:9-19; And Maines, Annu.Rev.Pharmacol.Toxicol.37:517-554).Three kinds of isoform: HO-1 that have HO are can be highly inductive, and HO-2 and HO-3 are that (Choi's constitutive expression etc. see above, and Maines sees above, and reach McCoubrey etc., E.J.Bioch.247:725-732).Although haemachrome is the main substrate of HO-1, multiple non-heme preparation comprises heavy metal, cytokine, hormone, endotoxin and heat shock (heat shock) also are to express the strong inducer of HO-1 (Choi etc. see above, Maines, see above, and Tenhunen etc., J.Lab.Clin.Med.75:410-421).This species diversity of HO-1 inducer provides further support: HO-1 for following supposition (speculation), except its effect in hemachrome degradation, also can play a crucial role in keeping intracellular environment stable state (homeostasis).And, HO-1 is induced by the multiple preparation height of oxidative stress that causes, described preparation comprises hydrogen peroxide, glutathion is exhausted thing (depletor), UV radiation, endotoxin and hyperoxia (hyperoxia) (Choi etc., see above, Maines sees above and Proc.Natl.Acad.Sci.USA.86:99-103 such as Keyse).A kind of explanation of this discovery be HO-1 can as adapt to and/or the crucial biomolecule of defence oxidative stress (Choi etc. see above, Lee etc., Proc Natl Acad Sci USA93:10393-10398; Otterbein etc., Am.J.J.Respir.Cell Mol.Biol.13:595-601; Poss etc., Proc.Natl.Acad.Sci.USA.94:10925-10930; Vile, etc., Proc.Natl.Acad.Sci.91:2607-2610; Abraham etc., Proc.Natl.Acad.Sci.USA.92:6798-6802; And Vile and Tyrrell, J.Biol.Chem.268:14678-14681).We can provide protection to resist and hyperoxia and the relevant oxidative stress (Lee etc. of lipopolysaccharide-inductivity tissue injury with external in body with the verified endogenous HO-1 that induces of other laboratorys by laboratory; see above; Otterbein; Deng; see above and Taylor etc., Am.J.Physiol.18:L582-L591).We also prove by the exogenous HO-1 of giving of gene transfer; the protection of opposing oxidative tissue damage (oxidant tissue injury) and initiation (elicit) tolerance (Otterbein etc., Am.J.Resp.Crit.Care Med.157:A565 (Abstr)) to high oxidative stress (hyperoxic stress) can be provided.
Carbon monoxide (CO) is gas molecule (Haldane, the Biochem.J.21:1068-1075 that lived organism is had known toxicity and lethal; With Chance etc., 1970, Ann.NY Acad Sci.174:193-204.).Yet, different with the toxic known case of CO, based on some crucial discoveries, CO there has been new interest again as the regulatory molecule in cell and the bioprocess (process) in recent years.Mammalian cell has the ability that generates endogenous CO, and it mainly generates CO (Choi etc. see above and Maines, see above) by Heme oxygenase (HO) catalysis haemachrome.The cell total output of CO mainly produces (Marilena, Biochem.Mol.Med.61:136-142 and Verma are etc., 1993, Science 259:381-384) by HO degraded haemachrome.In addition, the CO similar to the gas molecule nitrogen oxide, (Verma etc. in the regulation and control neuron transmits, see above and Xhuo, Deng, Science 260:1946-1950) and mediate (Morita, and Kourembanas in the vasomotion tensity (vasomotor tone), 1995, J.Clin.Invest.96:2676-2682.; Morita etc., 1995 Proc.Natl.Acad.Sci.USA 92:-1479; With Goda etc., 1998, J.Clin.Inv.101:604-12) play an important role.Other documents that relate to the CO biological agent comprise Pinsky etc., United States Patent (USP) 6,316,403, Sato etc., J.Immunol.166:4185-4194 (2001); Fujita etc., Nat.Med.7 (5): 598-604 (2001); Nachar etc., HighAltitude Medicine ﹠amp; Biology 2:377-385 (2001); Vassalli etc., Crit.Care.Med.29:359-366 (2001); Otterbein etc., Am.J.Physiol.Lung Cell Mol.Physiol.276:L688-L694 (1999); Cardell etc., Brit.J.Pharmacol.124:1065-1068 (1998); Otterbein etc., Nat.Med.6 (4): 422-428 (2000); And Otterbein etc., Am.J.PhysiolLung Cell Mol.Physiol, 279:L1029-L1037 (2000).
By immunocyte, the septic shock and the sepsis syndrome (sepsis syndrome) that cause of mononuclear cell and macrophage overstimulation particularly still is inpatient's one of cause of disease that mainly causes death.Parillo, etc., Ann.Intern.Med.113,991-992 (1992).Observed pathophysiological change in sepsis, usually not because infectious pathogen self, but because short scorching (pro-inflammatory) cytokine of generation out of control and chemotactic factor, comprise TNF-α, IL-1, and MIP-1, causing LR (recruitment), capillary percolation reaches the lethal effect that finally participates in sepsis.Beutler etc., 232,977-980 (1986); Netea etc., Immunology 94,340-344 (1998); And Wolpe etc., J.Exp.Med.167,570-581 (1988).Lipopolysaccharide (LPS) is the component of gram-negative bacterial cell wall, be sepsis main diseases because of, and when giving macrophage or mice, simulated identical inflammatory reaction experimental.After giving LPS, these pro-inflammatory mediators (mediator) increase rapidly but are temporary transient, it can be by one group of anti-inflammatory cytokines downward modulation afterwards, and described cytokine comprises that IL-10 INTERLEUKIN-10 (IL-10) and interleukin-4 (IL-4) suppress described proinflammatory cytokine and chemotactic factor is synthetic.J.Exp.Med.177，1205-1208(1993)。LPS at first at cell surface in conjunction with CD14 and epidermis receptor sample (toll-like) receptor (TLR) 2 (or 4), (Yang, Deng, Nature 395:284-288 (1998) and Chow, Deng, J.Biol.Chem.274:10689-10692 (1999) shows as activation mitogen-activated protein(MAP) (MAP) kinase pathways then, it comprises p38, p42/p44 ERK and JNK (MAP) kinases.Liu etc., J.Immunol.153,2642-2652 (1994); Hambleton etc., Proc.Natl.Acad.Sci.USA.93,2274-2778 (1996); Han etc., J.Biol.Chem.268,25009-25014 (1993); Han etc., Science 265,808-811 (1994); Sanghera etc., J.Immunol.156,4457-4465 (1996) and Raingeaud etc., J.Biol.Chem.270,7420-7426 (1995).The activation of these signaling molecules, the downstream cytokine expression, and the embodiment of the relation between physiological function investigation is active line.
U.S. government subsidizes numbering HL60234 to causing research of the present invention with one or more of NIH, and AI42365 and HL55330 provide support.So U.S. government keeps specific right to the present invention.
Summary of the invention
The present invention relates to oxidated stress (oxidative stress) the new pharmaceutical composition that transmits of the patient of influence, the carbon monoxide of the valid density in the described compositions air inclusion mixture, this mixture comprise oxygen and the optional nitrogen (and other a small amount of optional gas compositions) that comprises.The present invention relates to the generation of postponing oxidative stress on the other hand, suppress or alleviate the method for oxidative stress effect, described method comprises and transmits the treatment gas comprise carbon monoxide, and its amount and time are enough to effectively postpone patient's oxidative stress generation, suppresses or alleviates the oxidative stress effect.It is unexpected that discovery transmit and comprise low concentration (promptly, the gas concentration scope from about 1ppb (partly/1,000,000,000 (part per billion)) to about 3,000ppm (preferably in this scope, being higher than about 0.1ppm), preferably from about 1ppm to about 2,800ppm, more preferably from about 25ppm to about 750ppm, very more preferably from about 50ppm to about 500ppm, for example, the therapeutic gas of carbon monoxide about 250ppm), be to postpone patient's oxidative stress to take place, suppress or reverse the very effective method of (reverse) oxidative stress effect.This is an afterclap.Here be noted that in the methods of the invention, sometimes also available such therapeutic gas compositions, wherein the amount of carbon monoxide surpasses 0.3%, and this depends on the disease of being treated.
The present invention relates to the purposes of CO (carbon monoxide converter) gas in the preparation medicine on the other hand, this medicine is used for the treatment of to be suffered from or easily suffers from emphysema (emphysema), bronchitis, cystic fibrosis, pneumonia, interstitial lung disease, wound healing, arthritis, the patient of parkinson and/or Alzheimer.
The present invention relates to CO (carbon monoxide converter) gas on the other hand in the purposes of preparation in the medicine, and this medicine is used for the treatment of to be suffered from or easily suffer from kidney, the patient of the local inflammation of spleen and/or skin.
The present invention also provides to come with carbon monoxide to determine that as biomarker patient suffers from oxidative stress, or easy trouble or just suffering from the method that several were secondary to or caused the disease of oxidative stress, described disease for example, asthma, emphysema, bronchitis, adult respiratory distress syndrome, sepsis, cystic fibrosis, pneumonia, interstitial lung disease, the special property sent out lung disease, other lung diseases comprise primary pulmonary hypertension, the Secondary cases pulmonary hypertension, cancer comprises lung, the cancer of larynx and pharynx, arthritis, wound healing, parkinson, Alzheimer, peripheral blood vessel and lung vascular thrombosis formation property disease such as pulmonary infarction, and other.But described method comprises the carbon monoxide that detects in the patient respiration carbon monoxide of detection level is arranged in determining whether to breathe.But if occur the carbon monoxide of detection level in the patient respiration, this patient is diagnosable to be had oxidative stress or has oxidative stress.Oxidative stress performance (manifestation) is the form of one or more above-mentioned disease.After this diagnosis, can take suitable therapeutic step or other steps to alleviate or treat the situation that causes (responsible for) patient's oxidative stress.Among the embodiment, described method comprises the carbon monoxide of measuring in the patient expired breathing, and the amount of carbon monoxide represents that at least about 1ppm this patient easily suffers from sepsis or septic shock in the wherein said breathing.
Another aspect of the present invention involves the discovery among some patients, give oxidative stress, the particularly oxidative stress that causes by hyperoxia or sepsis that patient can be used for inducing patient's HO-1 enzyme and prevents or limit patient the carbon monoxide of effective dose.The HO-1 enzyme is kept the homeostasis of described patient's cell by hint.
The present invention relates on the other hand and uses carbon monoxide to postpone the generation of oxidative stress, suppresses or alleviates the oxidative stress effect, and this oxidative stress comes across transplant patient, organ transplantation patient especially, especially but not only refer to the lung transplantation patient.
The present invention relates to the inhibition patient on the other hand and produces proinflammatory cytokine such as TNF-α, IL-1 β, and IL-6, and MIP-1 β, and strengthen the method that produces (expression) anti-inflammatory cytokines IL-10 and IL-4, this method comprises the CO that gives patient's effective dose.
The present invention relates to the method that preservation (preserve) is used for transplanted organ or tissue on the other hand, and it comprises that the medium to depot organ or tissue adds the carbon monoxide of preserving effective dose or concentration.In this respect of the present invention, the carbon monoxide that comprises effective dose can reduce, suppresses or reduce the formation of (alleviate) active oxygen (reactiveoxygen) at depot organ or tissue, and organ graft can effectively be stored and the time of not oxidated infringement (oxidative damage) thereby prolong.In one embodiment, described method comprises provides the medium that contains carbon monoxide, and described organ is stored in the described medium, and wherein the amount of the carbon monoxide that exists in this medium is enough to improve the bin stability of described organ.
The present invention relates to prevention on the other hand or reduces the method for the probability of the infringement that is caused by oxidative stress, and this infringement is relevant with patient's hyperoxia, and the carbon monoxide that described method comprises effective dose gives the hyperoxia patient.
Unless otherwise defined, all technology used herein are identical with the implication of the affiliated field of the present invention those skilled in the art's common sense with scientific terminology.Although use description to practice below or detect appropriate method of the present invention and material, also can use other and those identical or similar method well-known in the art and materials as herein described.All publications mentioned in this article, patent application, patent and other lists of references all are incorporated herein by reference in full.If any conflict,, comprise that definition is as the criterion with description of the present invention.In addition, described material, method and embodiment all are in order to illustrate rather than to be restriction.
Summary of the invention
With as the description the present invention that gives a definition.
What term used herein " carbon monoxide " (or " CO ") was described is that carbon monoxide molecule is a gaseous state, is compressed into liquid state, or water-soluble solution.In description in the whole text, with term " carbon monoxide compositions " or " pharmaceutical composition that contains carbon monoxide " gas or fluid composition are described, this compositions contains the carbon monoxide that can give patient and/or organ.Which kind of form knack operator can distinguish, gas for example, and liquid, or comprise this pharmaceutical compositions of gas and two kinds of forms of liquid, be preferred for concrete application.
Term used herein " effective dose " and " treatment effectively ", finger gives with a certain amount of or concentration carbon monoxide in a period of time, it comprises acute or chronic giving, and cycle or give continuously, these give can produce aspect Expected Results or the physiology result at it is effective.For gas, the common scope of the carbon monoxide of effective dose is from about 0.0000001% to about 0.3% weight ratio, for example, from 0.0001% to about 0.25% weight ratio, preferably at least about 0.001%, for example, at least about 0.005%, 0.010%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.08%, 0.10%, 0.15%, 0.20%, 0.22%, or the carbon monoxide of 0.24% weight ratio.Preferable range for example comprises, from 0.001% to about 0.24%, from about 0.005% to about 0.22%, from about 0.005% to about 0.05%, from about 0.010% to about 0.20%, from about 0.02% to about 0.15%, from about 0.025% to about 0.10%, or from about 0.03% to about 0.08%, or from about 0.04% to about 0.06%.For the liquid solution of CO, the scope of effective dose is usually from about 0.0001 to about 0.0044g CO/100g liquid, for example, and at least about 0.0001,0.0002,0.0004,0.0006,0.0008,0.0010,0.0013,0.0014,0.0015,0.0016,0.0018,0.0020,0.0021,0.0022,0.0024,0.0026,0.0028,0.0030,0.0032,0.0035,0.0037,0.0040, or 0.0042g CO/100g aqueous solution.Preferable range for example comprises, about 0.0010 to about 0.0030g CO/100g liquid, and about 0.0015 arrives about 0.0026g CO/100g liquid, or from about 0.0018 to about 0.0024g CO/100g liquid.Aspect the generation or effect that reduce inflammatory cytokine, the effective dose of carbon monoxide can be for example to be enough to suppress TNF-α, IL-1, the amount of L-6 and MIP-1 and other generation and/or effect.Perhaps, it may be the amount that is enough to induce or increase anti-inflammatory cytokines such as IL-10 and other generation.With regard to transplant patient, the effective dose of carbon monoxide is to give transplant patient to reduce the amount that causes the probability of repulsion owing to adverse immune response.With regard to the organ that preservation is used to transplant through storing, the effective dose of carbon monoxide can be to add to, (for example, be blown into (bubble)) store in the medium of described transplant organ, thereby strengthen the preservation of (enhance) described organ, and reduce the amount that described organ is subjected to the probability of oxidative damage to a certain degree.Knack operator can understand according to the present invention the amount that also can use beyond above-mentioned scope.
The used term of description " patient " is described in the whole text is the people that treats according to the inventive method or inhuman animal.The present invention is clearly expected to be used for the veterinary.This term includes but not limited to mammal, for example, and people, other primates, pig, rodent such as mice and rat, rabbit, Cavia porcellus, hamster, cattle (cow), horse, cat, Canis familiaris L., sheep and goat.
Term used herein " treatment " is used for describe postponing disease and takes place, suppresses or the influence that palliates a disease, described disease for example, emphysema, bronchitis, arthritis, cystic fibrosis, pneumonia, interstitial lung disease, parkinson, Alzheimer, or kidney, spleen, or the inflammation of skin.Under the wound healing situation, this term description accelerating wound, for example, accelerate skin wound healing.Be considered to the individuality of disease-susceptible humans described herein may special benefit in the present invention, this is main because prophylactic treatment can just begin before described disease has any sign.Knack operator will appreciate that, by any known method in this area, for example, by doctor's diagnosis, can determine that patient easily suffers from any disease described herein.
It is a small amount of and be the carbon monoxide of detection limit that term " biomarker " but be used for is described in that patient respiration produces, it produces evidence to show that patient easily suffers from oxidative stress, or be in the oxidative stress commitment, or suffered from oxidative stress, easily suffer from or suffer from one or more and be secondary to the disease that maybe can cause oxidative stress.The CO content that can be used as biomarker in the patient respiration can hang down 0.001ppm, but usually at least about 0.1ppm.
Preparation atmospheric CO compositions
The CO compositions can be the atmospheric CO compositions.Can be used for Compressed Gas (compressed gas) or gas-pressurized (pressurized gas) in the method for the present invention, can obtain from any commercial source, and can be arranged in the container (vessel) of the suitable preservation Compressed Gas of any kind.For example, compression or gas-pressurized can provide medical Compressed Gas for example to obtain in the source of oxygen from any.The Compressed Gas that comprises the used carbon monoxide of the inventive method can be provided, thereby in same container, mix gas (for example, CO, the CO of all required final compositions
2, O
2, N
2).Optional, the inventive method can be carried out with a plurality of containers that contain all gases.For example, can provide the single container that contains carbon monoxide, contain or do not contain other gases, its content can optionally mix with indoor gas or with the contents mixed of other containers, for example, contain aerobic, nitrogen, carbon dioxide, helium, Compressed Gas, or any other suitable gas or its mixture.
The gas composition that gives patient according to the present invention comprises 0% nitrogen to about 79% weight ratio usually, about 21% oxygen to about 100% weight ratio, (it is about 3 that corresponding about 1ppb or 0.001ppm arrive, carbon monoxide 000ppm) to about 0.3% weight ratio with about 0.0000001%.Preferably, the amount of nitrogen is about 79% weight ratio in the described gas composition, and the amount of oxygen is about 21% weight ratio, and the amount of carbon monoxide is about 0.0001% to about 0.25% weight ratio, preferably at least about 0.001%, for example, at least about 0.005%, 0.010%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.08%, 0.10%, 0.15%, 0.20%, 0.22%, or the carbon monoxide of 0.24% weight ratio.Preferable range comprises 0.005% to about 0.24%, about 0.01% to about 0.22%, and about 0.08% to about 0.20%.It should be noted that atmospheric CO compositions according to application, but short-term is used (for example, one or breathe several times) with the carbonomonoxide concentration that is higher than 0.3% (as 1% or higher).
The atmospheric CO compositions can be used for making the environment (atmosphere) that comprises carbon monoxide gas.The environment that comprises the carbon monoxide gas of proper level can followingly produce, for example, the container that contains the Compressed Gas that comprises carbon monoxide gas is provided, and described Compressed Gas is discharged into the environment that chamber or space are formed on the carbon monoxide gas that comprises in chamber or the space from described container.Perhaps, described gas can be discharged in a kind of instrument that makes gas reach maximum concentration in breathing mask or air tube, thereby making the environment that comprises carbon monoxide gas in breathing mask or air tube, is this indoor unique people who is exposed to the carbon monoxide of obvious level to guarantee this patient.
Carbon monoxide level in the atmosphere can be measured or detect with any means known in the art.These methods comprise Electrochemical Detection, gas chromatography, and radiosiotope counting, INFRARED ABSORPTION, colorimetry, and (for example see Sunderman etc., Clin.Chem.28:2026-2032,1982 based on the electrochemical method of selective membrane; Ingi etc., Neuron 16:835-842,1996).Inferior hundred several grades very much (Sub-partsper million) carbon monoxide levels can pass through, and for example, gas chromatogram and emitting isotope are counted and detected.In addition, infrared gas sensor during carbon monoxide level in Asia-ppm scope known in the art can be used (midinfrared gas sensor) (is for example seen in biological tissue, Morimoto etc., Am.J.Physiol.Heart.Circ.Physiol 280:H482-H488,2001) measure.Carbon monoxide sensor and gas-detecting device can be bought from a lot of producers.
Preparation liquid carbon monoxide compositions
The carbon monoxide compositions can be a liquid carbon monoxide compositions.Liquid can be dissolved into any means known in the art and make the carbon monoxide compositions in the liquid.For example, described liquid can be placed in so-called " CO
2Incubator " and be exposed to the carbon monoxide of continuous flow, preferably use carbon dioxide balance, carbon monoxide reaches ideal concentration in liquid.Among another embodiment, carbon monoxide gas can directly " be blown into " and charge into liquid, and carbon monoxide reaches ideal concentration in liquid.The amount of dissolved carbon monoxide can reduce with temperature in aqueous solution known increases.In another embodiment, suitable liquid can be flowed through and be allowed the tubing (tubing) of gas diffusion, wherein said tubing is comprising operation in the environment of carbon monoxide (for example, using the instrument of device such as extracorporeal membrane oxygenation device (extracorporeal membrane oxygenator)).Carbon monoxide is diffused into and produces liquid carbon monoxide compositions in the liquid.
In the embodiment, described liquid can be fit to give patient's liquid (for example seeing Oxford Textbook of Surgery, Morris and Malt, Eds., OxfordUniversity Press (1994)) for any those skilled in the art are known.Usually, described liquid is aqueous solution.Suitable solution embodiment comprises phosphate buffered saline (PBS) (PBS), Celsior
TM, Perfadex
TM, section's woods solution (Collins solution), citrate solution, and University of Wisconsin (UW) solution (Oxford Textbook ofSurgery, Morris and Malt, Eds., Oxford University Press (1994)).
Any suitable liquid available gas diffusant (diffuser) is saturated to the carbon monoxide of a series of (set) concentration.Perhaps, can be with the prefabricated solution of the carbon monoxide that comprises given level through quality control.By accurately controlling dosage with the instrument (measurement) of the film that is connected to carbonyl analyzer, ventilative but obstructed liquid.Solution can be saturated to required valid density and maintain these levels.
With carbon monoxide combination treatment patient
Can known in the artly give patient's method by any, treat patient with the carbon monoxide compositions with gas and/or liquid.The carbon monoxide compositions can have been diagnosed or determine and easily for example suffer from emphysema, tracheitis, arthritis, cystic fibrosis, pneumonia, interstitial lung disease, parkinson, Alzheimer, or kidney, the patient of the inflammation of spleen or skin; Perhaps be used to promote wound healing, for example, cure not relevant skin wound with surgical operation.The system of the present invention includes (for example gives patient's liquid or atmospheric CO compositions, by sucking and/or picked-up), and with described compositions topical administration patient's lung (for example, by suck or trachea in give), the joint (for example, by injecting (infusion) or transdermal administration), skin (for example, by injection or by described compositions is used for skin surface), and other organs (for example, by picked-up, be blown into (insufflation), and/or import the abdominal cavity).
Systems communicate (delivery) carbon monoxide
But atmospheric CO compositions systems communicate is given patient.Common through port of atmospheric CO compositions or nasal meatus suck feeding drug into pulmones, and wherein said carbon monoxide can directly apply its effect or be easy to be absorbed the blood flow that enters patient.The concentration of used reactive compound (CO) can depend on the absorption of carbon monoxide in the therapeutic gas compositions, distributes deactivation and secreting rate (usually by breathing) and the known factor of other those skilled in the art.Will also be understood that, for any concrete experimenter, concrete dosage should be adjusted in time according to the personnel's of individual need and enforcement or the administration of supervision group compound professional judgment, and aforesaid concentration range is exemplary, rather than is the scope or the practice of the desired compositions of restriction.The invention still further relates to the acute of CO, subacute and chronic administration, described administering mode for example depends on, described patient disease's seriousness and persistence.CO can be enough to treat disease and show in a period of time of expection pharmacology or biological effect that (comprising variable interval ground administration) is delivered to the patient.
Following is the embodiment of certain methods and equipment, and they can be used to give patient with the atmospheric CO compositions.
Respirator (ventilator)
Can buy medical grade CO (multiple concentration can be arranged), the gas that described CO and air or other contain oxygen is mixed in (for example, 21% O in the gas-pressurized standard can
2, 79% N
2).Described gas is nonreactive activity (non-reactive), and the inventive method desired concn is well below flammable range (in the air 10%).In hospital, infer and will make it there in blender (blender), to mix with gas delivery to bedside with oxygen or room air, reach required ppm concentration.The patient sucks admixture of gas by respirator, and the flow rate of respirator is set according to patient's level of comfort and needs.Can determine this flow rate by lung figure (being breathing rate, tidal volume etc.).Can will prevent that the patient from unnecessarily accepting to surpass automatic anti-fault mechanism (fail-safe mechamism) design of carbon monoxide of aequum in delivery system.Patient's CO level can be monitored by studying following index: the carboxyhemoglobin (COHb) that can survey in (1) venous blood and, the exhalation CO that collect from the respirator sidepiece (2).Can regulate the CO exposure according to patient's health status and mark.If necessary, also can wash out CO by sucking 100% oxygen.CO is not by metabolic, therefore removes a very little part and is converted to CO
2, what suck are all breathed out at last.CO can with the O of any level
2Mix, send CO and do not cause subsequently hypoxia situation with therapeutic.
Face shield and curtain (Tent)
The admixture of gas such as the method for preparing that contain CO, thus allow the patient by face shield or the passive suction of curtain.Inhaled concentration can change, and by changing the O of suction 100% simply into
2Wash.Available automatic anti-fault mechanism is at face shield or curtain or monitor the CO level in its vicinity, and described automatic anti-fault mechanism can prevent to suck the CO of excessive concentrations.
Portable inhaler (Portable inhaler)
Pressurization CO can be packed into portable inhaler and suck the dosage of process metering, for example makes the receptor of not being in hospital accept intermittent the treatment.The CO of variable concentrations can be packaged in the container.This instrument can be simply to just having the little storage tank (for example being lower than 5kg) that containing of on-off valve and pipe dilute CO, from described pipe, the patient can according to standard scheme maybe needs suck CO.
Intravenous artificial lung (Intravenous Artificial Lung)
Be designed to send O
2With removal CO
2Artificial lung (catheter apparatus that is used for the blood gas exchange) can be used for CO and send.After this conduit is implanted, be positioned also can systematicness to send the CO of desired concn or it is delivered to localized site in the large vein.Described sending can be to send high concentration CO for example is close to spleen or kidney to the operation site local delivery (described high concentration is dilution rapidly in blood flow) in the short time, the CO that is exposed to low concentration in the perhaps relatively long time (for example sees Hattler etc., Artif.Organs18 (11): 806-812 (1994); And Golob etc., ASAIO J., 47 (5): 432-437 (2001)).
Normal barometric pressure (Normobaric) chamber
In some cases, patient's integral body need be exposed to CO.The patient must be arranged in the closed cabin that is full of CO, and wherein the level of CO can not cause danger to the patient, and perhaps this level causes acceptable danger but can not make the onlooker be in the danger that is exposed.After finishing exposure, with air (for example, 21% O
2, 79% N
2) be full of this cabin, and use CO analyser analytic sample, before allowing the patient to leave exposure system, retain guaranteeing without any CO.
Fluid composition
The present invention also comprises fluid composition, and it comprises makes the system that is used for and give patient, and for example, per os gives and/or by for example, intravenous, and intra-arterial, intraperitoneal/or be subcutaneously injected into biological intravital carbon monoxide.
With a hydrogenated carbon topical therapeutic organ
Perhaps or in addition, the carbon monoxide compositions can directly give organ, for example, skin, spleen, lung, and/or one or more kidney.Patient's organ is treated in the inside and/or the outside that gas composition directly can be administered to described patient's body.Gas composition knownly can be blown into patient's method with gas with this area is any, directly give patient's internal.For example, usually with gas, carbon dioxide for example, being blown into the patient abdominal cavity comes auxiliary examination in laparoscopy (laproscopic) step (for example to see OxfordTextbook of Surgery, Morris and Malt, Eds., Oxford University Press (1994)).Knack operator can understand the internal that available similar step directly gives the carbon monoxide compositions patient.Described skin and under joint available gas compositions topical therapeutic, it passes through, and for example, makes the gas composition in the normal barometric pressure chamber (above-mentioned) be exposed to infected skin, and/or described carbon monoxide compositions is directly blowed to skin.
Liquid carbon monoxide compositions also can be by topical administration patient organ.The described compositions of liquid form can any method afford patient who gives liquid known in the art.The same with gas composition, fluid composition can be applied directly to the inside and/or the outside organ for the treatment of patient of body.For example, but the administration of liquid form oral administration, for example by making the patient's ingestible capsuleization or the carbon monoxide Aquo-composition of encapsulated dosage not.Another embodiment is, liquid for example can be comprised the saline solution of dissolved CO, is expelled to the patient abdominal cavity in the laparoscopy process.Perhaps or in addition, original position exposure or (exposureor) organ, for example one or more kidney and spleen, available any means known in the art are carried out, for example, (see Oxford Textbook of Surgery, Morris and Malt by wash described organ with liquid carbon monoxide composition in situ, Eds., Oxford University Press (1994)).Described skin can be used the fluid composition Local treatment, by for example, described fluid composition is expelled to skin.Another embodiment is, the described skin of topical therapeutic and under the joint, can be by described fluid composition be applied directly to skin surface, for example by with described liquid pouring or be ejected on the skin and/or with described skin submergence (submerge) in described fluid composition.
Disease
CO (carbon monoxide converter) gas can be used for preparing the medicine that is used for the treatment of following disease: as asthma, and emphysema, bronchitis, adult respiratory distress syndrome, sepsis, cystic fibrosis, pneumonia, interstitial lung disease, the special property sent out lung disease, other lung diseases, comprise primary pulmonary hypertension, Secondary cases pulmonary hypertension, cancer, comprise pulmonary carcinoma, the cancer of larynx and pharynx, arthritis, parkinson, Alzheimer, peripheral blood vessel and lung vascular thrombosis formation property disease such as pulmonary infarction; And be used for the treatment of and suffer from or easily suffer from and be positioned at organ, kidney for example, the patient of the inflammation of spleen and/or skin.The present invention also can be used for helping wound healing, for example, and skin wound healing.Interested especially be the treatment non-surgery operation due to wound.
The present invention also is used in transplant patient, and special organ transplantation patient, particularly lung transplantation patient postpone oxidative stress and take place, or alleviate the oxidative stress effect.Described carbon monoxide compositions also can be used for treating the inflammatory condition of illness of lung or the sepsis that secondary comes across transplant patient or the inflammation of repulsion.On the basis of bound by theory not, the CO of low dosage is considered to by suppressing proinflammatory cytokine such as TNF-α, IL-1, IL-6, the generation of MIP-1 and/or effect, and/or the effect of stimulation or promotion anti-inflammatory cytokines IL-4 and IL-10, and play antiinflammatory.
Term " oxidative stress " has been described and has been produced excessive and disease that cause by the active oxygen that is not subjected to the endogenous antioxidant to check (quench).Oxidative stress can cause by the effect permanent tissue injury that cause of reactive oxygen species (species) at tissue.The physiological phenomenon form of oxidative stress is or appears in the multiple disease: comprise asthma, emphysema, bronchitis, adult respiratory distress syndrome, sepsis or septic shock, cystic fibrosis, pneumonia, interstitial lung disease, the special property sent out lung disease, other lung diseases comprise primary pulmonary hypertension, Secondary cases pulmonary hypertension, the inflammatory diseases of pulmonary carcinoma and lung vascular thrombosis formation property disease such as pulmonary infarction or any lung.
Multiple formation pus and other Pathogenic organisms or their toxin (in general, lipopolysaccharide or LPS bacteria cell wall) that exists in the blood tissues described in term " sepsis ".Sepsis causes those to be exposed to the oxidative stress of the tissue of pathogen or its toxin through regular meeting.Sepsis produces anti-inflammatory cytokines such as TNF-α through being everlasting, and IL-1 becomes when IL-6 and MIP-1 obviously, and its generation meeting descends owing to the carbon monoxide that gives effective dose or reverses.
The present invention can be used for treating inflammation.The basic pathology process described in term " inflammation ", it is included in infected blood vessel and the cytology of surrounding tissue appearance and the dynamic complex body (dynamiccomplex) of histologic reaction, this is to by physics, replying of damage that chemistry or biological preparation cause or abnormal stimulation, it comprises local response and the pathological change that causes thereof, cause injury destruction or the removal of material (injurious material), and replying of causing repairing and heal.This term comprises multiple inflammation such as acute inflammation, allergic inflammation, modificability (alterative) degenerative (degenerative) inflammation, atrophic inflammation, catarrhal inflammation (the most common) at respiratory tract, Groupous inflammation disease (croupous), cellulose purulence (fibrinopurulent) inflammation, fibrinous inflammation, immunoreactivity (immune) inflammation, hypertrophy (hyperplastic orproliferative) inflammation, subacute, serosity and pulp fibers disposition inflammation.Preferentially treatment is positioned at liver according to the inventive method, the heart, (dermatitis for example is by antibacterial for skin, the inflammation that fungus or viral infection and/or allergy or autoimmune response cause), spleen, brain, kidney (bacterial pyelonephritis for example, interstitial nephritis, and relevant sepsis or septic shock and/or glomerulonephritis) and pulmonary passageway (pulmonary tract), the particularly inflammation of lung.
Term " cancer " can be used as general terms and describes any polytype malignant tumor, around its most intrusion, can be transferred to (metastasize) a plurality of positions and may remove the recurrence of (attemptedremoval) back as far as possible, unless treat proper otherwise can cause described patient death.Cancer can be treated with the present composition and method, and it for example comprises, stomach, colon, rectum, liver, pancreas, lung, mammary gland, cervix uteri, body of uterus, ovary, prostate, testis, bladder, kidney, brain/CNS, head and neck, pharynx, Hokdkin disease (Hodgkins disease), Fei Hejiejinshi leukemia (non-Hodgkins leukemia), cutaneous melanoma (melanoma), multiple sarcoma, small cell lung cancer, choriocarcinoma (choriocarcinoma), mouth/pharynx (pharynx), esophagus (oesophagus), larynx, melanoma, kidney and lymphatic cancer (lymphoma), and other.
The present invention can be used to treat the disease that relates to respiratory system, for example, and emphysema, tracheitis, cystic fibrosis, pneumonia, and interstitial lung disease.Term used herein " emphysema " refers to be characterized as the expansible lung disease of alveolar.In such cases, alveolar wall is destroyed, causes bronchioles to lose structural support and subsides when exhaling and (for example see The Merek Manual of Diagnosis and Therapy, I7
ThEdition, Section 6, Chapter 68).Term " tracheitis " refers to be characterized as the lung disease that tracheobronchial tree (tracheobronchialtree) has inflammation.Tracheitis can show effect after infection, for example, and viral infection, for example, general flu; Or bacterial infection, or after being exposed to stimulus object (irritant) (for example see, The Merck Manualof Diagnosis and Therapy, 17th Edition, Section 6, Chapter 69).Term " cystic fibrosis " refers to eccrine hereditary.This disease mainly influences intestines and stomach and respiratory system, and its feature is generally chronic obstructive pulmonary disease (COPD) (for example see The Merck Manual of Diagnosis andTherapy, 17 " Edition, Section 19, Chapter 267).Term " pneumonia " has referred to influence the lung disease of essence (parenchyma), for example also comprise, bacillary, viral, and respiratory (aspiration) pneumonia (is for example seen The Merck Manual of Diagnosis and Therapy, 17 Edition, Section6, Chapter 73).Term " interstitial lung disease " or " spontaneous (idiopathic) interstitial lung disease " refer to the lung disease of one group of cause of disease the unknown, it produces the diffusion pathological change that relates to (interalveolar) interstitial tissue between alveolar usually and (for example sees, The Merck Manual of Diagnosis and Therapy, 17thEdition, Section 6, and Chapter 78).
Term used herein " arthritis " refers to be characterized as the disease of arthritis, and for example comprise, rheumatoid arthritis (RA) (chronic inflammatory polyarthritis, it causes the joint to be damaged usually), psoriatic arthritis (inflammatory arthritis relevant) with psoriasis, ankylosis (ankylosing) spondylitis (spondylitis) (inflammation in Axial sketelon and big periphery (peripheral) joint), and ankylosis (arthrodesis (immobility) or fusion) (are for example seen, The Merck Manual of Diagnosis and Therapy, 17 " Edition; be respectively Section 5, Chapter 50; Section 5, and Chapter 51; Section 5, and Chapter 51; And Section9, Chapter 108).
Term " parkinson " refers to spontaneity, slow advancing property (slowly progressive), degenerative (degenerative) CNS disease, it is characterized by the slow and decline of motion, myotonia (muscularrigidity), rest tremor (resting tremor), and position shakiness (postural instability).″(TheMerck?Manual?of?Diagnosis?and?Therapy，17″Edition，Section?14，Chapter?179)。Term " Alzheimer " refers to be characterized as disease (the The Merck Manual of Diagnosis and Therapy of " carrying out property; irreversible (inexorable) cognitive function forfeiture; it is excessive relevant with the senile plaque quantity on grey matter under cerebral cortex and the cortex; it also comprises neurofibrillary tangles (neurofibrillary tangle) and the amyloid beta of being made up of Protein tau (amyloid) ", 17th Edition, Section 14, and Chapter 171).
The present invention also CO of available low dosage induces patient's HO-1 enzyme, and avoids or limit oxidative stress, particularly the oxidative stress that is caused by hyperoxia or sepsis.Inductive HO-1 is hinted the intracellular stable state that keeps described patient.
Handle (treat) organ and improve storage stability with tissue
The present invention also relates to CO is used for transplanted organ or tissue as storage preservative agent purposes.It is unexpected that the result be, the CO that comprises low dosage in the medium of storing the organ of wanting transplanted can fully reduce the probability of oxidative damage organ when storing, but and fully prolongs the safe storage transplant organ and make it not be subjected to the storage time of irreversibility oxidative damage.Therefore, in embodiment of the present invention, the CO of effective dose being charged into the storage medium with bubble, is before organ is placed in the described medium first or preferably at that time or immediately (shortly thereafter).Also available CO improves the storage stability of the organ of storage certain hour in medium, but in those examples, it is irreversible that oxidative damage originally can become, thereby has limited to the effect of anticipation.
Therefore, the invention provides the storage stability that method improves organ or tissue.By making described organ or tissue be exposed to liquid and/or the atmospheric CO compositions strengthens described storage stability.Make organ or tissue be exposed to the atmospheric CO compositions and can comprise that the environmental chamber of suitable carbon monoxide gas level or zone carry out in any suitable manufacturing.These chambers comprise, for example, incubator and chamber, building it is in order to hold organ in storage solution.Another embodiment is, suitable chamber can be the chamber of environment in the gas that only enters (fed into) chamber is present in, thereby can reach the concentration of carbon monoxide and maintain concentration known and purity, and for example, wherein said chamber seals.For example, CO
2Incubator can be used for making organ to be exposed to the carbon monoxide compositions, wherein provides described carbon monoxide gas with successive stream (flow) from containing this gas containers.
For liquid carbon monoxide compositions, can described organ or tissue be immersed in wholly or in part in any enough big chamber or space, make it be exposed to the carbon monoxide compositions.In embodiment of the present invention, described organ can be placed any suitable container and make the carbon monoxide compositions " scrub (wash over) " and cross described organ, make described organ be exposed to the carbon monoxide compositions, thereby make described organ be exposed to successive carbon monoxide combined stream.In another embodiment, with carbon monoxide compositions perfusion (perfuse) described organ.Term " perfusion " is the discernible term in this area, and it relates to fluid passage (passage), and for example, the carbon monoxide compositions is by the blood vessel of organ or tissue.The method of external and in-situ perfusion organ known in this field.Available carbon monoxide compositions for example pours into perfused organ's (seeing Oxford Textbook of Surgery, Morris andMalt, Eds., Oxford University Press (1994)) by continuous low temperature (hypothermic) machine external.Alternatively, before pouring into described organ with described carbon monoxide compositions, available washing liquid does not for example have the UW solution of carbon monoxide, comes to remove from described organ the blood of donor.Can operate the hemoglobin competition carbon monoxide that this process is avoided donor.Another optionally, described washing liquid can be the carbon monoxide compositions.Another embodiment is, the liquid that is fit to can be by allowing the tubing of gas diffusion, this tubing run through comprise carbon monoxide environment (for example, pass through the chamber, as belt body adventitia oxygenator), prepare liquid carbon monoxide compositions, it can pass through organ (for example, entering organ by described tubing is connected to described organ perfusion) then.
Another embodiment is, described organ can be placed in, and for example, is immersed in the medium or the solution that do not comprise carbon monoxide, and place the chamber, thereby make described medium or solution be made into the carbon monoxide compositions by being exposed to the environment that contains carbon monoxide as herein described.Another example is that described organ can be dipped into the liquid that does not comprise carbon monoxide, and carbon monoxide can be entered described liquid by " air blowing ".
It is considered herein that any or all above-mentioned organ that makes is exposed to liquid carbon monoxide method for compositions, for example washing, submergence or perfusion can be used in the known steps, for example are used in the storage stability that improves organ or tissue in the single step.
Carbon monoxide is as diagnostic tool
Except using CO as therapeutic agent, measure CO may be useful diagnostic tool, and the biological example label is to determine whether patient is in oxidative stress or is in disease state, and wherein CO has hinted for example sepsis or septic shock.Usually, monitor and suspect that be in oxidative stress maybe may be in the patient of oxidative stress, but determine whether in described patient's exhalation is breathed, to detect the carbon monoxide of detection level.If but the carbon monoxide of visible detection level (promptly, the amount of the carbon monoxide in the patient respiration is at least about 0.01ppm), (attending) doctor who accompanies so or care-giver (caregiver) just can begin to give the carbon monoxide of therapeutic dose, treat oxidative stress or any one or more is secondary to or causes the disease of oxidative stress.
In the embodiment, analyze the CO that exists in the patient expired breathing.CO content in the patient respiration is measured by CO monitor (for example, using Logan LR2000), and it is responsive (its sensitivity is low to moderate 1ppb) for the CO that detects from 0 to about 1000ppm.In the method, the experimenter enters breath analyzer with steady flow (5-6l/m) from slow exhalation of functional FVC in the 20-30 interval of second.Made two successfully records, average has been used as all calculating.CO level before each the breathing around the record provides contrast or background value.Any CO level can hint actual or initial (incipient) state of oxidative stress with respect to the raising of background value, clearlys show that at least about the amount of the CO of 1ppm this patient suffers from oxidative stress and maybe will suffer from oxidative stress.
Several embodiments of the present invention have been described.Yet, be understandable that and can do multiple improvement but do not deviate from spirit and scope of the invention.Therefore, other embodiments also within the scope of the claims.
Claims (16)
1. CO (carbon monoxide converter) gas is in the purposes of preparation in the medicine, and described medicine is used for the treatment of to be suffered from or easily suffer from the patient who is selected from following at least a disease: emphysema, bronchitis, cystic fibrosis, pneumonia, interstitial lung disease, wound healing, arthritis, parkinson or Alzheimer; Or be used to promote described patient's wound healing.
2. the described method of claim 1, wherein said disease is emphysema.
3. the described method of claim 1, wherein said disease is a bronchitis.
4. the described method of claim 1, wherein said disease is a cystic fibrosis.
5. the described method of claim 1, wherein said disease is a pneumonia.
The described method of 6 claim 1, wherein said disease is an interstitial lung disease.
7. the described method of claim 1, wherein said disease is an arthritis.
8. the described method of claim 1, wherein said disease is a parkinson.
9. the described method of claim 1, wherein said disease is an Alzheimer.
10. the described method of claim 1, wherein said CO (carbon monoxide converter) gas are used to prepare the medicine of the wound healing that is used to promote described patient.
11. CO (carbon monoxide converter) gas is used for the treatment of purposes in patient's the medicine in preparation, this patient suffers from or easily suffers from and be positioned at the inflammation that is selected from following at least a organ: kidney, spleen or skin.
12. the described method of claim 11, wherein said organ is a kidney.
13. the described method of claim 11, wherein said organ is a spleen.
14. the described method of claim 11, wherein said organ is a skin.
15. improve the method for the storage stability of organ in medium, it comprises:
The medium that comprises carbon monoxide is provided; And
Described organ is stored in the described medium, and the CO content that exists in the wherein said medium is enough to improve the storage stability of described organ.
Easily suffer from the method for sepsis or septic shock 16. determine whether patient, it comprises: measure the carbon monoxide in the patient expired breathing, the amount of carbon monoxide shows that at least about 1ppm this patient easily suffers from sepsis or septic shock in the wherein said breathing.
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2002
- 2002-05-09 WO PCT/US2002/014836 patent/WO2003094932A1/en active Application Filing
- 2002-05-09 MX MXPA04011113A patent/MXPA04011113A/en active IP Right Grant
- 2002-05-09 CN CNA028292995A patent/CN1638781A/en active Pending
- 2002-05-09 AU AU2002308676A patent/AU2002308676B2/en not_active Ceased
- 2002-05-09 KR KR10-2004-7018082A patent/KR20040106515A/en not_active Application Discontinuation
- 2002-05-09 UA UA20041210106A patent/UA84402C2/en unknown
- 2002-05-09 CA CA002484770A patent/CA2484770A1/en not_active Abandoned
- 2002-05-09 EP EP02807413A patent/EP1501523A4/en not_active Withdrawn
- 2002-05-09 EA EA200401478A patent/EA200401478A1/en unknown
- 2002-05-09 JP JP2004503016A patent/JP2005532314A/en active Pending
- 2002-05-09 RS YUP-969/04A patent/RS96904A/en unknown
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2004
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103491783A (en) * | 2011-01-14 | 2014-01-01 | 洛杉矶儿童医院 | Solution of carbon monoxide for treatment of disease, including sickle cell disease |
| CN112272559A (en) * | 2018-06-08 | 2021-01-26 | 住友精化株式会社 | Composition for skin wound |
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA04011113A (en) | 2005-02-14 |
| AU2002308676A1 (en) | 2003-11-11 |
| KR20040106515A (en) | 2004-12-17 |
| EA200401478A1 (en) | 2005-12-29 |
| WO2003094932A1 (en) | 2003-11-20 |
| EP1501523A4 (en) | 2006-12-13 |
| UA84402C2 (en) | 2008-10-27 |
| AU2002308676B2 (en) | 2009-06-11 |
| BR0215717A (en) | 2005-02-22 |
| EP1501523A1 (en) | 2005-02-02 |
| CA2484770A1 (en) | 2003-11-20 |
| NO20044865L (en) | 2004-12-07 |
| JP2005532314A (en) | 2005-10-27 |
| RS96904A (en) | 2007-02-05 |
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