CN102802643A - Treatment of inflammatory disorders, cardiovascular diseases and acute ischemic brain stroke with ozone - Google Patents

Abstract

Methods of treating mammalian subjects suffering from, or believed to be suffering from, acute ischemic brain stroke, cardiovascular disease, inflammatory disease or any of the conditions or symptoms related to those diseases, are disclosed in which a biological fluid withdrawn from the subject is processed through an ozone delivery system to deliver a measured amount of ozone to the biological fluid to produce a treated fluid that has a quantifiable absorbed-dose of ozone which, upon re-introduction of the treated fluid containing the quantifiable absorbed-dose of ozone to the subject, effectively treats any number of described disease conditions and symptoms. Methods for manufacturing medicaments for treatment of acute ischemic brain stroke, cardiovascular disease, inflammatory disease or any of the conditions or symptoms related to those diseases, are also disclosed.

Description

Utilize ozone therapy inflammatory disease, cardiovascular disease and acute ischemic apoplexy

Background

Invention field

The present invention relates to inflammatory disease in the mammal, cardiovascular disease, acute ischemic apoplexy and the medical condition of being correlated with and the therapeutic treatment of symptom; And being specifically related to utilize provides the method for biological fluid therapeutic treatment such disease; Said biological fluid is taken from mammalian subject; The biological fluid that has had ozone that can quantitative absorbed dose with the ozonization of the amount of measuring with generation; When introducing mammalian subject again, the biological fluid with ozone that can quantitative absorbed dose provides the therapeutic treatment of disease or related conditions and symptom.

The statement of association area

Provide list of references that this paper discusses just to describing about the field of the invention.Any content of this paper should not be interpreted as admits that the inventor haves no right because of before inventing prior to disclosure.And; It is not to admit that this document is a prior art that this paper quotes any file; Or to the consideration material of the patentability of any claim of this paper, and be based on when proposing applicant's information available and do not constitute statement about any statement on interior perhaps date of any file and be correct affirmation or admit.

The disease patient's condition (such as inflammatory diseases, cardiovascular disease and ischemia apoplexy and the relevant symptom and the patient's condition) presents challenge to human subject with similar animal subject, and is some dead main causes in a lot of countries in the world.For example, apoplexy is that dead second main cause and annual accounts for sum 5,050 4,400 ten thousand (9%) in the dying of dieing ten thousand deaths all over the world.In the U.S., apoplexy is No. three cause of the death after heart disease (apoplexy and heart disease are closely connected) and the cancer.The U.S. in every year wind effect greater than 800,000, wherein 600,000th, first outbreak and 200,000th, recurrence.By current trend, annual rise 1,000,000 when estimating this numeral to the year two thousand fifty.Represent disabled main cause in U.S.'s apoplexy, follow the life of outbreak sequela greater than the 4 million people people.

The apoplexy characteristic is the circulation that loses the brain zone suddenly, causes correspondingly losing nervous function.Apoplexy also is called cerebrovascular accident or cerebrovascular accident, is the non-specific term that comprises one group of different pathological physiological reason, comprises thrombosis, thromboembolism and hemorrhage.Current be categorized as apoplexy hemorrhagic or ischemic.Acute ischemic stroke refers to the apoplexy that caused by thrombosis or thromboembolism, and accounts for about 87% of whole apoplexy.

Cerebral infarction is caused by blood vessel blockage, the oxygen that it stops blood flow and captures surrouding brain tissue.Under the situation that does not have oxygen, directly the brain cell in the zone begins dead and discharges a series of toxic chemical substance that threatens the cerebral tissue in the peripheral region.This phenomenon is called as ischemic penumbra.

Current statistics shows 7.6% death in 30 days of outbreak of the individuality of suffering from cerebral infarction.And all individual about 25% is dead in a year of apoplexy first at it.Paralytic's 14% will be recurred by apoplexy in 1 year, and relapse rate is increased to 25% in 5 years.50% experience of the stroke victim of survival needs the medium to major injury of special nursing, and said special nursing comprises sanitarium nursing or the treatment of other long-term care facility.When the direct cost of considering apoplexy simultaneously (nursing and treatment) during with indirect cost (losing the productivity), estimation is Mei Nian $650 hundred million in the totle drilling cost of the apoplexy of the U.S. in 2008, and wherein 87% owing to cerebral infarction.

On macroscopic scale, cerebral infarction is caused by outer thromboembolism of cranium or intracranial thrombosis the most usually.On cellular level, interrupt blood flow and start the ischemic cascade to any process of a part of brain, cause neuronic death and cerebral infarction.

Thrombotic apoplexy is caused by the thrombosis that in the tremulous pulse of cerebral blood supply, forms (clot).This is normally because fatty deposits, calcium and thrombin such as the Fibrinogen that delivers in the blood and the multiple accumulation of cholesterol.Health is regarded as accumulation to react to the damage of blood vessel wall and through forming clot.These clots fall on the speckle on the blood vessel wall, stop blood flow at last.

Based on blood vessel diameter, there is two types thrombotic apoplexy.Trunk thrombosis (the modal form of thrombotic apoplexy) occurs in the bigger tremulous pulse of brain.Because all less blood vessels that tremulous pulse is supplied with lose blood, so influence and damage trend enlarge.In most of the cases, trunk thrombosis is with uniting of forming of clot causes fast subsequently by long-term speckle accumulation (atherosclerosis).Little angiopathy (being also referred to as lacunar infarction) takes place during to minimum arteries when blood flow is blocked.It has connected and has been the indication of atheromatosis with vascular hypertension (hypertension).Thrombotic disease accounts for about 60% of acute ischemic stroke.In those thrombotic diseases, about 70% is trunk thrombosis.In embolic stroke, clot forms beyond brain, and is common in the large artery trunks of heart or top chest and cervical region, and is transported to brain through blood flow.There, it arrives the enough little blood vessel that gets to stop up its passage at last.Embolus can be the piece (being the lipid fragment) of Oil globule, bubble or the modal atheromatous plaque that breaks away from from arterial wall.A lot of emboluses cause by the heart patient's condition that is called atrial fibrillation, and said atrial fibrillation causes that blood converges and forms and can parade to the clot of brain and cause apoplexy.Heart source property thromboembolism accounts for 80% of thromboembolism cerebral infarction.

Lose beginning ischemic cascade within dabbling several seconds to a few minutes to a part of brain.Allow its development will cause by the zone of potential reversible ischemic penumbra around the irreversible infraction of central area.

On cellular level, along with ATP exhausts, the ischemic neuron becomes unpolarized, and film ion transport thrashing.The inflow of the calcium that obtains causes the release of many neurotransmitteies, and said neurotransmitter comprises a large amount of glutamic acid, then activates other irritability receptor on N-methyl-D-aspartate (NMDA) and other neuron.These neurons become unpolarizedly then, cause that further calcium current goes into, and further glutamic acid discharges and the part of initial stage ischemia injury enlarges.This a large amount of calcium current goes into also to activate multiple digestive enzyme, causes the destruction of cell membrane and other important neuronal structure.The not normal generation of this metabolism causes the cell inside gradient of accumulating (cytotoxic edema) in the cell of water.

In several hours to several days after the apoplexy, special gene is activated, and causes the formation of cytokine and other factor, and said cytokine is transferred further to cause inflammation impaired with microcirculation with other factor.Brain endothelial cell more has resistance than neuronal cell to ischemia.Ischemia morbidity back about 2-4 hour, the integrity of blood brain barrier is impaired, and plasma protein can get into ECS.Endovascular water following (angioedema) when taking place to pour into again.It is reported that 6 hour beginning and apoplexy morbidity after 2-4 days of this process after apoplexy morbidity reach maximum.Perfusion also can follow the hemorrhagic of infraction to transform again, and it is relevant with the volume and the site of infraction usually.

This vascular inflammation possibly be owing to by related by the proinflammatory cytokine (for example interferon-, TNF-γ, IL-6 and IL-12) of immunomodulating T cell release and the imbalance between the anti-inflammatory cytokines (for example interleukin-4 and IL-10) in infraction site and the ischemic penumbra.In addition, evidence suggests that blood vessel endothelium plays main effect in regulating blood flow and be important about cardiovascular disorder (comprising the acute ischemic apoplexy).Having proposed the dysfunction endothelium is that contribution factor also can work in the death at ischemic penumbra in a lot of ischemic conditions.At last, within several hours of apoplexy morbidity, ischemic penumbra is by these progressive damage consumption, with the nuclear fusion of infraction usually.

The focus target of treatment acute ischemic stroke is the protection ischemic penumbra.This can be through the restriction ischemia injury seriousness (being neuro-protective) or reduce the ischemic persistent period (promptly recovering the blood flow of affected area) realize.The time limit of recovering big cerebral blood flow in the protection ischemic penumbra seemingly key factor and provable also be crucial in neuro-protective.

In addition, cause a large amount of death in most of industrialized countries central vessel disease.A kind of such disease is an atherosclerosis, the accumulation of cell debris in the inner membrance that is endothelial function disturbance, vascular inflammation and lipid, cholesterol, calcium and blood vessel wall for the disease and the characteristic of large-scale and medium-sized muscular artery.This accumulation causes speckle to form, blood vessel is reinvented, acute and chronic chamber is blocked and blood flow anomalies, and also causes the ischemia (reduce the oxygen of organ and tissue is supplied with) of Target organ such as heart, brain and other vitals.Long-time ischemia or unexpected ischemia can cause clinical heart attack or apoplexy, and therefrom the patient possibly recover or maybe not can recover.

If not impossible, be difficult to accurately measure atherosclerotic real frequency, because it mainly is the asymptomatic patient's condition.Atherosclerotic process begin along with the formation of fatty streak during one's childhood and in whole adult life along with the more complicated pathological changes that increases day by day forms and develops.

In the U.S., about 7,800,000 myocardial infarctions take place in every year, and suffer from chronic coronary artery disease greater than 1,320 ten thousand Americans.Some signs that age has carotid disease greater than 50 years old philtrum 30%, and cause more than annual 160,000 examples dead at U.S.'s cerebrovascular disease.In the U.S. are diet and/or the candidates of Drug therapy that improve certain form of its lipid profile greater than 5,000 ten thousand people.

Between the key cell component (cellular element) of atherosclerotic lesion, exist complicated and interaction that do not understand fully.These cell component comprise endotheliocyte, smooth muscle cell, platelet and leukocyte.The state of activation, fibrinolytic system, smooth muscle cell migration and the hypertrophy of the thrombogenicity of vasomotoricity, blood vessel wall (thrombogenicity), coagulation cascade, and cellular inflammation is complicated and is to facilitate atheroma to form and the bioprocess that is mutually related of atherosclerotic clinical manifestation.

The mechanism that atheroma forms is still uncertain.Think that at present early stage incident comprises endothelial injury, it causes that vascular inflammation and fibroplasia reaction come one after another.

Atherosclerotic pathology pathological changes the earliest is fatty streak and in the aorta of most of individualities and coronary artery, is observed during by 20 years old.Fatty streak is the result of the local accumulation of the serum lipoprotein in the blood vessel wall inner membrance.Fatty streak can develop the formation fibrous plaque, and is that carrying out property lipid gathers migration and the outgrowth result with smooth muscle cell.Fissional activator is produced by activatory platelet, macrophage and dysfunction endotheliocyte, it is characterized in that endothelium destroys early stage atheroma formation, vascular inflammation and the plateletrich thrombosis of site.

Vascular inflammation (thinking that Atheromatosis is because of important composition in learning) can be owing to proinflammatory cytokine (for example interferon-, TNF-γ, IL-6, IL-8 and IL-12) that is discharged by the relevant immunomodulating T cell of atherosclerotic lesion and the imbalance between the anti-inflammatory cytokines (for example interleukin-4 and IL-10).In other autoimmune disease such as psoriasis, rheumatic arthritis, scleroderma, lupus, diabetes, organ rejection, miscarriage, multiple sclerosis, inflammatory bowel and graft versus host disease, related to similar imbalance.

Also have emerging document part, it shows that blood vessel endothelium plays a major role and is important about cardiovascular disorder in the adjusting of the blood flow through cardiovascular system.Having proposed the dysfunction endothelium is contribution factor in observed a lot of other circulatory disturbance in a lot of cardiovascular disease such as atherosclerosiss, PAOD and mammalian subject.Recent evidence shows that the relative shortage of the nitric oxide (a kind of vasodilation) in endothelium source also strengthened the sophisticated propagation phase of speckle.

The growth of fibrous plaque causes that blood vessel is reinvented, carrying out property chamber dwindles, blood flow anomalies, and has weakened the oxygen of Target organ is supplied with.Only occupy the human coronary expansion that can take place in response to speckle forms and the chamber is narrow at 40% o'clock greater than the area that limits by internal elastic membrane at speckle.

The thrombosis inclusions of the nuclear that the breaking of the peelling off or removing of the endothelium of last covering (promptly stripping off) or protection fibrous cap can cause speckle is exposed to circulation blood.Plaque rupture can cause thrombosis, the part or all of obstruction of blood vessel and owing to the machineization of thrombosis and the development of incorporating the atherosclerotic lesion in the speckle into.

Atherosclerotic somatization provides extracellular lipid deposition, the narrow or expansion of muscular artery, or the objective evidence of Target organ ischemia or infraction greatly, and comprises the somatization that hereinafter is discussed.

Limping is defined as reproducible ischemic myalgia, is one of modal performance of the PAOD that caused by atherosclerosis.Limping takes place in the body movement process and after of short duration rest, alleviates.Because insufficient blood flow generation shank, thigh or pain of buttock.The most frightened consequence of walking lamely is the ischemia that causes the severe of amputation to threaten limbs.Yet it is uncommon that vast limping patient crowd's research discloses amputation.Intermittent claudication can be followed the pale and paraesthesia (unusual sensation is such as the tingling that does not have stimulus object or the sense of touch of burning) of limbs.Intermittent claudication causes the pain that takes place along with body movement usually.Confirm that it is important before the pain outbreak, needing how many body movemenies.Normally, the vascular surgery doctor is according to block the outbreak and the specific walking distance of pain linked together (for example walk lamely in two blocks).This helps the patient to quantize to treat before and the several criteria measurement of walking distance afterwards.Other important aspects of limping pain are that pain is reproducible and stops after time of rest 2-5 minute in identical muscle group.Confirm the position of pain through the anatomy location of arterial disease.

The blood flow of the minimizing that can be caused by cholesterol thromboembolism or stricture of artery is relevant with the limbs of thromboembolism or vasoconstriction far-end or the muscle sign in the muscle group often.But numbness and tingling, muscle spasm, forfeiture unable and motion are common reporting events.The blood flow (ischemia) of the minimizing that causes the oxygen of organ or tissue is deprived is relevant with stricture of artery with atheroembolism (cholesterol thromboembolism) usually.This descends relevant with measurable temperature of the limbs of thromboembolism or angiostenosis site far-end often.

Under the situation of atheroembolism and stricture of artery since the minimizing of the pulse that blood flow caused that reduces or forfeiture be can quantitative parameter and often with limbs in pale minimizing relevant.Hypertensive primary factor is that the Peripheral resistance that the peripheral vascular vasoconstriction by the stricture of artery secondary causes increases.Another principal element that constitutes the basis of weight increase is the lipidosis of gathering of too much triglyceride or the inhibition institute secondary that triglyceride is removed.

Clinical events about cardiovascular disease comprises because the carrying out property lumen of artery that the expansion of fibrous plaque causes is narrow, when the intracavity diameter greater than 50-70% gets clogged, causes stream to reduce.This stream minimizing causes the symptom to the insufficient blood supply of Target organ under the situation that metabolic activity increases and therefore oxygen demand increases.Stable angina pectoris, intermittent claudication and mesenteric angina are the instances of the clinical effectiveness of this patient's condition.

The breaking or overlay on the exposure that can cause highly thrombosed subendothelium and lipid core of stripping off of endothelium above the fibrous plaque of speckle.This exposure can cause thrombosis, and it can partially or even wholly block the stream in the relevant tremulous pulse.Unstable angina pectoris, myocardial infarction, transient ischemic attack and apoplexy are the instances of the clinical manifestation of part or all of tremulous pulse acute occlusion.

Atheroembolism (claiming the cholesterol thromboembolism again) refers to that little caliber and medium caliber tremulous pulse (100-200 μ m diameter) are blocked by cholesterol crystal.It can present the symptom of finger necrosis, hypertension, gastrointestinal hemorrhage, myocardial infarction, retinal ischemia, cerebral infarction and renal failure.Sign comprises livedo reticularis (owing to the net formula variable color of the persistency purple of the skin that is caused by capillary tube and venular expansion that smoulders or change in the potential blood vessel), gangrene, cyanosis and ulcer.There is pedal pulses hint microvascular disease in the peripheral ischemic environment.

The angina pectoris characteristic is that the breastbone metathorax is uncomfortable, and its common radiation to left arm also can be with dyspnea.Angina pectoris increases the weight of and can alleviate through rest or nitrate treatment because of tired.Pain when unstable angina pectoris has been described the type that frequency or the intensity of angina pectoris attacks increases and has been included in rest.Can be the hint of myocardial infarction with the anginal prolongation outbreak of diaphoresis.

The brain that cerebrovascular disease indication is caused by the pathological process of blood vessel any unusual, for example the inner chamber because of thrombosis or embolus blocks, the permeability of any pathological changes of the breaking of blood vessel, blood vessel wall or change and viscosity that blood increases or other change of blood properties.The disease of cerebral circulation comprises any disease of vascular system of the hematostaxis of the ischemia that causes brain or infraction or brain or subarachnoid space.

Cerebrovascular accident (CVA) or apoplexy are the sudden death that causes the brain cell of abnormal brain function owing to impaired blood flow.The blood flow that flows to brain can be because of interrupting arteriocerebral obstruction (obstruction of brain medium-sized artery, carotid artery occlusion, thromboembolism) or arteriocerebral breaking (cerebral hemorrhage or subarachnoid hemorrhage).Transient ischemic attack (TIA) is the of short duration outbreak (less than 24 hours) of the temporary transient damage of the brain that causes of the forfeiture by blood supply.TIA causes the afunction in the body region that is divided control by influenced brain.

The risk factor that cerebrovascular disease relates to comprises cerebral infarction and cerebral ischemia, and its unexpected obturation by the tremulous pulse of supplying with brain causes, or is caused by the lazy flow of inaccessible or highly narrow arterial distal infrequently.Inaccessible or narrow can be arterial wall or from the result of the disease of the thromboembolism of heart.Infraction is derived from and stops normal dabbling result, and it is caused by the thrombosis of atherosclerosis and coexistence usually.Atheroembolism (atheroma), the thrombosis particle that is derived near end source (tremulous pulse source, cardiac origin or careful source) takes place when passing vascular system and cause far-end inaccessible.

The inference of cerebrovascular disease and other factor are the generations of the little angiopathy of intracranial (arteriole gruel type).The little infiltration tremulous pulse of brain is not supplied with by good side Zhi Xunhuan and one of them inaccessible of these tremulous pulsies quite possibly cause infraction usually in the zone little, that limit of brain.

The inflammation angiopathy of tremulous pulse (or vein) wall can order about enough cell proliferation, necrosis and fibrosis with inaccessible inner chamber, deposition thrombosis and thromboembolism then, or promotes aneurysm to form, separate and even the breaking of blood vessel.These vasculitis diseases in its course of disease process, can appear or concurrent cerebral infarction, intracranial hemorrhage, intracranial venous thrombosis and modal broad sense ischemic encephalopathy.

The sign of cerebrovascular disease comprises carotid pulsation, carotid artery noise and the focus property neurologic impairment of minimizing.PAOD (PAOD) shows as intermittent claudication, sexual impotence and non-healing ulcer usually and limbs infect.PAOD is most commonly in the femoral artery,superficial (being positioned on the knee joint just) of far-end, and it is corresponding to the limping in the Calf muscle zone (muscle group of the far-end of arterial disease just).When atherosclerosis is distributed in whole AI when zone, limping accounts for main flow to thigh with buttocks muscles.Sign comprises the peripheral pulse, Peripheral arteries noise (noise of hearing on the unexpected swish sound of hearing or tremulous pulse or the blood vessel access, it shows usually the turbulent flow of the increase that is caused by partial obstruction) of decline, pale, property cyanosis, gangrene, ulcer on every side.The symptom that lost efficacy at Target organ and sign before the internal organs ischemia can be shelter or sign property.

The mesenteric angina characteristic be epigastrium or umbilicus around food after pain and can and lose weight relevant with hematemesis, melena, diarrhoea, malnutrition.The aortic aneurysm of abdominal part is normally asymptomatic before violent and fatal usually break symptom and sign, though the patient possibly describe the pulsation abdominal mass.Sign comprises pulsation abdominal mass, periphery thromboembolism and circulatory failure.

Dyslipidemia is the disease of lipoprotein metabolism, comprises lipoprotein overproduction or deficiency.Dyslipidemia can be shown as the raising of T-CHOL in the blood, low density lipoprotein, LDL (LDL) cholesterol and triglyceride concentration, and the decline of high density lipoprotein (HDL) cholesterol concentration.

Congestive heart failure (CHF) is caused by coronary artery disease or hypertension the most frequently, and when heart no longer can satisfy the metabolic demand of health under standard physiology venous pressure, takes place.Along with the demand of heart surpasses the critical field of physiology's compensatory mechanism, the sign of CHF appears.These signs comprise tachycardia, venous congestion, higher catecholamine levels and, at last, insufficient cardiac output.Chronic inflammatory disease is considered to facilitate the development of chronic heart failure and the potential pathology of process.

Raynaud disease is meant that finger or toe (toes) experience the sanguimotor disease that reduces suddenly.Raynaud disease can be categorized as former (or idiopathic) and (also the claiming Raynaud's phenomenon) of secondary.The constitutional Raynaud disease is lighter, and causes less complication.The Secondary cases Raynaud disease is more complicated, serious, and more possibly develop.Many medical condition make the patient bring out the Secondary cases Raynaud disease, comprise scleroderma, and said scleroderma is the severe disease of connective tissue, and wherein the tissue of skin, heart, esophagus, kidney and lung becomes that thicken, hard and hangs and contracts.Form sclerodermatous patient's about 30% and will at first form Raynaud disease.Other medical condition that makes the patient bring out the Secondary cases Raynaud disease comprises connective tissue disease, such as systemic lupus erythematosus, rheumatic arthritis, dermatomyositis and polymyositis, and the disease that causes the obstruction (being atherosclerosis) of tremulous pulse.Think that the constitutional and the Secondary cases type of Raynaud's phenomenon Raynaud's syndrome are owing to over-reactive small artery (small-sized tremulous pulse).Although the cold muscle contraction of forming arterial wall that causes usually, degree is extremely in Raynaud disease, and to flow to this regional blood be strict limited.

Be familiar with the relation between diet lipid, serum cholesterol and the medicated porridge appearance arteriosclerosis already.In many epidemiological studies, shown that the single measurement of serum cholesterol has proved the important indication that coronary heart disease takes place.Therefore diet is the fundamental of all treatments of hyperlipemia (excess fats in the blood plasma).Yet, utilize diet to need part doctor, nutritionist, dietician and other fitness guru to do great effort as the primary pattern of treatment.If metatrophia is unsuccessful, Drug therapy is alternate selection.It is feasible using or be used in combination some medicines separately.Yet, but do not reduce the positive evidence that the medicine long-term safety is used about any cholesterol.

The combination that possibly need medicine and diet is to reduce the concentration of blood plasma lipide.Therefore blood lipid-lowering medicine is as the fill-in of diet control.A lot of medicines are effectively to blood fat reducing, but neither one works in all types of hyperlipidemias, and it all has undesirable side effect.There is not blood lipid-lowering medicine can cause atherosclerotic restorative final evidence.Therefore, although get along with aspect the heart disease to stop realizing reducing plasma cholesterol through diet, Drug therapy, surgery vascular reconstruction algorithm and angioplasty, in the atherosis main causes of death that remain of western countries' medium-sized artery.

Consider above-mentionedly, just seeking new method is secondary to the various disease and the disease that with the cardiovascular disease are characteristic widely with reduction the frequency of clinical sequela.

Except the disease patient's condition (comprising the inflammatory patient's condition that the acute ischemic apoplexy is relevant with cardiovascular disease) of above description, there is serious medical predicament in other inflammatory diseases with the relevant symptom and the patient's condition.For example, autoimmune disease is considered between the tissue (self) of body, distinguished inefficacy in it and cause with originating from invading the exogenous antigen of organism (non-self) by immune system usually.When self and the non-this inefficacy generation of distinguishing between self and immune system are reacted autoantigen, possibly produce autoimmune disorder.Autoimmune disease or the disease with autoimmune composition comprise rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), scleroderma, diabetes, inflammatory bowel, psoriasis, pemphigus, atherosclerosis (wherein vascular system is regarded as specific organ) and chronic heart failure.

Rheumatic arthritis is the instance of common mankind itself's immunological diseases, influences about 1% population.This genius morbi is the chronic inflammatory disease of synovial joints, and it can cause the carrying out property destruction of cartilage and bone.Pemphigus is to be characterized as the one group of autoimmune disease that on skin, forms the water sample blister.It is a disease of sending out bleb in a kind of epidermis, and Clinical symptoms is the corrosion of surperficial vesicle and skin and/or mucosa, particularly oral cavity.Often utilize antiinflammatory such as corticosteroid to produce the inflammation-inhibiting process through suppressing specific cytokine.Systemic lupus erythematosus (SLE) is the inflammation of connective tissue and can torments each tract.90% patient experience is similar to the arthritis of rheumatic arthritis.Treatment comprises the anti-inflammatory drug of controlling arthritic symptom and the topical corticosteroid that is used for skin.Oral steroid such as prednisone is used to treat General Symptoms.Scleroderma relates to the symptom of excrescent one group of disease of connective tissue, and said connective tissue is supported skin and internal.Sclerodermatous rheumatic composition characteristics is inflammation and/or the pain in muscle, joint or the fibrous tissue.

Diabetes have been thought to have the disease of rudimentary systemic inflammatorome day by day.This slight inflammatory states is closely related with obesity and insulin resistance, and wherein adipose cell (especially in the overweight people) is secreted many proinflammatory cytokines.Psoriasis is the result of the early stage cellular inflammation of high response.Psoriasis has speed and the blood vessel and the fibroblast proliferation of quickening of destruction and the reparation of the epidermis of fast breeding, strong acute inflammatory response, skin simultaneously.Inflammatory bowel has been described two kinds of autoimmune disorders of small intestinal; Crohn disease and ulcerative colitis.Treatment comprises the use anti-inflammatory drug, comprises the corticosteroid of the acute attack that is used for these diseases.

Like above record, atherosclerosis relates to carrying out property inflammatory reaction, and it has important effect during whole stages of the disease of mediation from initial to progress and last atherosclerotic thrombus complication.The rising indication patient of marker of inflammation suffers from the result of acute coronary syndrome.Rudimentary chronic inflammatory disease (as represented through the level of Inflammatory Mediators C-reactive protein) expectedly defines the danger of atherosclerosis complication.Chronic heart failure is the weak patient's condition, and the ability that its cardiac plays pump is compromised, the most frequently as coronary artery disease or hypertensive result.Think that chronic inflammatory disease facilitates the development and the progress of heart failure.

The alloimmunity disease is meant that disease such as graft versus host disease and tissue transplantation repel among this paper, and wherein can to cause severe complications maybe possibly be fatal in the immunoreation of antagonism or the tissue transplanted by external source.In these treatment of conditions, hope to stop health that non-autoantigen is reacted.Often use corticosteroid to reduce inflammation through migration that suppresses polymorphonuclear leukocyte and the capillary permeability that reverses increase.

The disease that inflammatory cytokine is relevant with the inflammation of brain is relevant; Be neural inflammatory, neurodegenerative and neurological's disease such as Alzheimer, alzheimer disease, multiple sclerosis, depression, mongolism, Huntington Chorea, peripheral neuropathy, myelopathy, neuroarthropathy, chronic inflammatory demyelinating disease (CIPD); Neuropathy comprises mononeuropathy, polyneuropathy, far-end symmetry sensory nerve pathological changes, cystic fibrosis, neuromuscular junction disease, myasthenia and parkinson disease.

Understand some neurological's encephalopathy diseases such as mongolism, epilepsy, cerebral trauma and Huntington Chorea (chorea) at present and relate to the potential pathological important component of the inflammation of brain cell as disease.Other neurological's disease with important inflammatory component comprises that guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy become (CIDP), myasthenia gravis (MG), dermatomyositis, polymyositis, inclusion body myositis, cerebral infarction, neurosarcoidosis, vascular dementia, vasospasm, subarachnoid hemorrhage, adrenal gland's leukocyte nutritional disorder (thesaurismosis), inclusion body dermatomycosis, Min. cognitive impairment and Duchenne muscular dystrophy.

It is neurological's disease that the chronic inflammatory demyelinating polyneuropathy becomes (CIDP), is characterised in that the unable and sensory disturbance of slowly carrying out property of lower limb and arm.This disease is sometimes referred to as the chronic recurrent polyneuropathy, is caused by the infringement of peripheroneural myelin.The main symptoms comprises slow progressive muscular weakness and the sensory disturbance that influences upper limb and lower limb.CIDP becomes closely related with the more common acute demyelinating neuropathy that is called as guillain-Barre syndrome (GBS).CIPD is considered to the chronic copy of acute illness GBS.The difference of CIPD and GBS mainly is clinical disease course and prognosis.Guillain-Barre syndrome (GBS) is that the acute leading motor polyneuropathy that nature recovers becomes, and it can cause serious quadriparesis and need artificial ventilation in the patient of 20-30%.The modal disease that becomes this syndromic basis has been categorized as acute inflammation demyelination polyneuropathy (AIDP).

Autoimmune myasthenia gravis (MG) is to cause changing the disease that weak (fluctuating weakness) and unusual tired neuromuscular transmit.Weak owing at neuromuscular soleplate place through the circulation autoantibody, the destruction of partial subsequently complement activation and acetylcholinergic receptor and to the blocking-up of acetylcholinergic receptor.The reason of inflammatory myopathy dermatomyositis, polymyositis and inclusion body myositis (IBM) is unknown, but involves immunologic mechanism consumingly.Although clinically with immunopathology on different, these diseases are shared three leading histologic characteristicses: inflammation, fibrosis and muscle fiber reduce.

Sarcoidosis is unknown cause and multisystem chronic disease that the whole world distributes.Neurosarcoidosis is the complication that relates to the sarcoidosis of inflammation and abnormal deposition thing in the neural tissue.Burst, of short duration facial paralysis generally relates to cranial nerve VII.Other performance comprises aseptic meningitis, hydrocephalus, central nervous system's parenchyma disease, peripheral nervous pathological changes and myopathy.Based on the neuroradiology imaging, the intracranial sarcoid can be imitated meningitic various ways, comprises carcinoma property and intracranial lump pathological changes such as meningioma, lymphoma and glioma.

Vascular dementia (VaD) is to become the blanket of the dementia that causes by the organic disease in blood vessel source, such as the ischemic change of cerebral infarction, ICH or subcortical white.Vascular dementia is the modal reason of the dementia after Alzheimer, accounts for about 20% and 50% among the curee more than 80 years old of case.Inflammatory component has been illustrated under the protection of VaD in multiple potential disease.

Cerebral vasospasm is to narrow down in response to the arteriae cerebri that the postponement of the residual clot in the subarachnoid space is fallen ill afterwards at spontaneous aneurysm subarachnoid hemorrhage (SAH).Angiography narrows down its persistent chamber that is characterized by main extraparenchymal arteriae cerebri and influences big brain microcirculation and cause the cerebral blood flow (CBF) of decline and the neural shortage of the ischemic of postponing.In cerebrospinal fluid, produce proinflammatory cytokine after also having proved SAH.

Duchenne's muscular dystrophy (DMD) is one of mortality disease of modal heredity in the childhood.It is the chain neuromuscular disease of X, and it influences 1 in 3500 male.Progressive muscular weakness is in beginning between 2 to 5 years old and at last in the process in two teens mid-term to latter stages, cause premature death through respiratory failure or heart failure.DMD patient lacks the protein dystrophin, and said protein dystrophin is essential being connected in connecting the proteinic complex of cytoskeleton and extracellular matrix.Evidence show these patients showed with inflammatory diseases such as the similar immunocyte of finding in the polymyositis of those immunocytes.Current research shows that also the T cell can work in the pathology of dystrophin defective and in the autoimmune composition.

Multiple sclerosis (a kind of central nervous system's autoimmune disease) is expressed with corticosteroid treatment to reduce the inflammatory component of inflammation.

As before institute's record, cerebral infarction causes by the obstruction in the blood vessel, the oxygen that it stops to flow of blood and deprives surrouding brain tissue.Within dabbling several seconds to a few minutes of losing to a part of brain, the cascade of beginning ischemic.Allow its development will cause the central area of the irreversible infraction of being surrounded by the zone of potential reversible ischemic penumbra.The cell inside gradient (cytotoxic edema) that the not normal generation of metabolism is gathered about water in the cell.After this form proinflammatory cytokine and other factor, the said factor is transferred further to cause and is caused angioedematous inflammation and microcirculation to endanger.In addition, evidence suggests that blood vessel endothelium plays an important role in regulating blood flow and be important for cardiovascular disorder (comprising inflammatory diseases).Handicapped endothelium possibly be the contribution factor of the death of ischemic penumbra.

Edema is to be characterized as the part that can cause health or the more part of slight patient's condition of the unusual big amount of liquid of (interstitial space) between the soma to the blood circulation of serious swelling or in the tissue.The balance that can upset liquid in the health comprises with the factor that causes edema: fixing, the medicament (steroid, hormone replacement, NSAID (NSAID)) of lower limb, absorption, menstruation and the pregnancy of salt.The medical patient's condition that can cause edema comprises: heart failure, kidney disease, thyroid or hepatic disease, malnutrition, thrombosis, infection, lymphedema and solid tumor.Symptom is according to the former of edema thereby variation.Usually, the swelling of the eyelid of weight increase, edema and lower limb can be used as the result of excessive amount of liquid and produces.Pulse rate and blood pressure possibly raise.The patient's condition that edema is relevant comprises traumatic brain injury, and its permeability, gangrene and motion and memory dysfunction with the increase of multiple physiological phenomenon and cell phenomenon such as ischemia, blood brain barrier is relevant.Ischemia by the initial stage brain injury causes is brought out a succession of secondary incident that causes cell death at last.The experimental model of closed head injury has been explained and has been induced proinflammatory cytokine to discharge the destruction that causes the blood brain barrier integrity together with the infringement to endotheliocyte.

Initial a succession of biochemistry incident and the cell incident that comprises the inflammation immune system response of spinal cord injury.Take place immediately after the damage to descend greatly to the blood flow in site.The cell of arranging along blood vessel not impaired yet in the spinal cord begins swelling, and it continues to be reduced to the blood flow of injured area.The inflow of liquid and immunocyte (neutrophilic granulocyte, T cell, macrophage and mononuclear cell) causes inflammation through the blood brain barrier of irresistance, and it discharges the impaired spinal cord of the further destruction of proinflammatory cytokine through multiple neurogliocyte and astrocyte and aggravates.

Soft tissue injury is a kind of acute connective tissue damage that relates to muscle, ligament, tendon, capsule and cartilage structure.Sprain, pull, in contusion or the crush injury, the local area network columnar structure of blood vessel is destroyed, and Oxygenated blood can not arrive affected tissue again, causes cytoclasis.The characteristic that temperature increases, rubescent, pain and swelling (local edema) have showed the initial stage inflammatory stage.Inflammatory swelling began to form and sustainable several days or a few week in impaired back in about two hours.Instant treatment comprises the control acute inflammatory response.

Multiple imaging technique capable of using is with the degree of estimating the edema around the infraction site among the ischemia apoplexy patient with to the blood flow of ischemic penumbra.Instance comprises: computerized axial tomography (CT scan), doppler sonography, and NMR-imaging.At present, the vasodilative modal method of assessment endothelium mediation is brachial artery (BA) imaging, and it related in arterial occlusive a few minutes takes a picture the high-resolution ultrasonoscopy before and afterwards to confirm the diameter of BA.The variation of artery diameter is the measuring of vasodilation (FMVR) of blood flow mediation.

Other method that vasodilation is measured comprises through linear actuators induces artificial pulse on surperficial radial artery.The ultrasonic doppler stethoscope detects the pulse from initial pulse upper reaches 10-20cm.Delay between pulse is used and detected provides pulse conduction time (PTT).Before inaccessible with reactive hyperemia five minutes of BA and measure PTT afterwards.Along with blood flow after the obturation increases, the endotheliocyte of arranging along the tremulous pulse inwall is felt the chemical constituent of the frictional force that increases and blood and relaxant is discharged in the arterial smooth muscle.Vascular system is more healthy, the endodermis function good more and inaccessible before and the difference between the measurement result of inaccessible back will be big more.

The measurement of patient's inflammation can comprise the physique evaluation of pain of temperature and the report of ankylosis, rising.The laboratory measurement of inflammation can comprise raising numeration of leukocyte (blood coagulation system that comprises difference is measured), inflammatory cytokine (comprising IL-6 and IL-8) improves and increase C proteins C reactive (comprising hypersensitivity CRP) and procalcitonin level.

Apoptosis

Apoptosis refers to the process of the asynchronous Gene Handling that energy relies on particularly, when apoptogene is activated unnecessary or destructive unicellular through said process self-destruction (Martin, SJ 1993; Earnshaw, WC 1995).There are three different apoptosis stages.At first, cell shrinkage and separate with contiguous cell.Nucleus comprises the cohesion (pyknosis) of chain interruption (nucleorhexis) and nuclear chromatin because of the variation of DNA damages.In second stage, nuclear fragmentation and organelle cohesion and being wrapped at last in the membrane-bound folliculus, exocytosis is also absorbed by peripheral cell.In stage in the end, finally lose film integrality and produce permeability dyestuff (being trypan blue).When being engulfed by macrophage and epithelial cell the disappearance of inflammation distinguish apoptosis with downright bad (Kam, PCA2000).

In contrast, non-viable non-apoptotic cell death is the pathological process (Lennon, SV 1991) that is caused by irresistible noxious stimulation.In cell multiplex, take place simultaneously, it is characterized in that cellular swelling or " oncosis ", cause losing of Cytoplasm and nucleus swelling and early stage film integrality.Plasma membrane forms blister (structure of phlyctenoid liquid filling), wherein possibly take place finally to break, and causes neutrophil cell and the inflow of macrophage in the surrounding tissue, and cause whole body inflammation (Majno, G1995).

Four main group stimulus object of apoptosis have been reported: cause destructive ionizing radiation of DNA and alkylation cancer therapy drug; Receptor mechanism is regulated (being glucocorticoid, tumor necrosis factor-alpha, nerve growth factor or interleukin-3); The enhancer of apoptosis pathway (being phosphatase and inhibitors of kinases); Cause that directly cell membrane destroys and comprise the agent (Kam, PCA 2000) of temperature, ultraviolet light and oxidant (being superoxide anion, hydroxyl and hydrogen peroxide).

Except oxidant, a lot of chemotherapies that can be apoptosis-induced and naturopathy be also known to cause oxidative stress (Buttke, M 1994, Chandra, J 2000).Ionizing radiation and ultraviolet radiation all produce reactive oxygen intermediate such as hydrogen peroxide and hydroxyl radical free radical.The hydrogen peroxide of low dosage (10-100 μ M) is apoptosis-induced in the cell type of the medium that many direct establishment oxidative stresss are apoptosis.Yet this oxidant of high dose is necrosis induced, the notion of the form of the cell death (the apoptosis contrast is downright bad) that the severity that meets damage is confirmed to be taken place.Free radical is not apoptosis-induced essential condition; The lipid that amycin, cisplatin and ether are connected is apoptosis-induced and the destructive antitumor agent of oxidation.

Selectively, oxidative stress can cell be removed or the ability of elimination reactive oxygen intermediate (ROI) is induced (Buttke, M 1994) through reducing.The medicine (fourth methyllanthionine-sulphoxide imine) that reduces glutathion inside cell (GSH) makes cell more responsive to the inductive apoptosis of oxidative stress.Cell research has been reported extracellular hydrogen peroxide enzyme level and to the direct relation between the sensitivity of the apoptosis of hydrogen peroxide-induced.Having proved through tumor necrosis factor-alpha stimulates inductive apoptosis relevant with the increase of ROI in the cell.Yet, suppressed this apoptosis through adding many antioxidants; Thioredoxin (a kind of free radical scavenger), and N-acetylcystein (a kind of antioxidant and GSH precursor).

The evidence that exist to increase shows that the neutrophil cell of being engulfed the back apoptosis by macrophage and dendritic cell plays a part positive in adjusting and resolution.Through macrophage phagocytic remove downright bad neutrophil cell sign be to comprise the inflammatory reaction that discharges proinflammatory cytokine (Beutler, B 1988, Moss, ST 2000, Fadok VA, 2001 for Vignola, AM1998).In contrast, inflammatory reaction is not followed in the removing of the neutrophil cell of apoptosis; The inhibition macrophage of engulfing that has shown these apoptotic cells produces the activation (Fadok that proinflammatory cytokine (GM-CSF, IL-1 β, IL-8, TNF-α, TxB2 and LTC4) is followed anti-inflammatory cytokines (TGF-β 1, PGE2 and PAF); VA 1988; Cvetanovic, M 2004).This phenomenon that suppresses macrophage generation proinflammatory cytokine has extended to lymphocytic the engulfing (Fadok, VA 2001) that comprises apoptosis.

Except macrophage; Also proved downward adjusting (Fadok in response to the proinflammatory cytokine release of apoptotic cell through non-phagocytic cell (comprising HF, smooth muscle, blood vessel endothelium, neuron and breast epithelial cell); VA 1988,2000; McDonald, PP 1999, Cvetanovic M, 2006).The neutrophil cell of the apoptosis that contacts with activatory mononuclear cell is drawn the reaction of the immunosuppressant cell factor, strengthens IL-10 and TGF-β and produces and only produce atomic TNF-α and IL-1 β cytokine (Byrne, A 2002).People such as Byrne infer that the interaction between the neutrophil cell of activatory mononuclear cell and apoptosis can produce unique reaction, and it becomes activatory mononuclear cell the cell of prepare to deactivate self and other cell target from the promotion factor of inflammatory cascade.

Identification and quantitative apoptosis and distinguish this incident and downright bad technology can comprise with the nuclear stain (promptly with Hoeschst 33258 acridine oranges) that allows the video picture of nuclear chromatin clumping dye (Earnshaw, WC1995).With the accurate identification of the method realization apoptosis of the peculiar dna cleavage of targeting specifically.The agarose gel electrophoresis of the dna fragmentation that extracts produces distinctive ' ladder ' shape, and it can be used as the mark (Bortner, CD 1995) of apoptosis.The lesser extent of dna degradation produces the six aggressiveness structures that are called ' rosette (rosette) ', and wherein non-viable non-apoptotic cell stays inenarrable hangover (Pritchard, DM 1996).The terminal transferase BrdU breach end labelling (TUNEL method) of the dna break point of the uridnine residue of labelling nuclear dna fragmentation also capable of using comes quantitative apoptosis (Gavrieli, Y 1992).

Also can come some characteristic events in the quantitative apoptotic process through flow cytometry.These characteristic events are included as the consumption of the mitochondrial membrane potential of early apoptosis incident; Alienation through the Phosphatidylserine of catching with annexin V; Losing and the activation (the commitment characteristic of apoptosis) (technical bulletin-InVitrogen 2004) of nuclear chromatin cohesion (distinguishing survival, apoptosis and cell necrosis) and caspase of membrane integrity.

Known vascular endothelial cell (comprising Human umbilical vein endothelial cells (HUVEC)) discharges effective vasodilation, comprises nitric oxide (NO) and prostacyclin.Handling HUVEC with ozonisation serum (oxidative stress thing) causes significant and stable NO output to increase.In addition, be reported in and utilized ozonisation serum to hatch in 24 (24) hours processes of HUVEC, suppressed E-and selected proteic release (pro-inflammatory mediator) and the generation of endothelin-1 (effectively vasoconstrictor) is not had influence (Valacchi, G 2000).People such as Valacchi have proposed through the release of enhancing NO ozonisation blood to be infused into the vasodilation that can induce the ischemia zone among the patient again and to reduce anoxia.

C proteins C reactive (CRP)

CRP is the product of inflammation, stimulates the synthetic CRP of liver through the cytokine in response to the inflammatory stimulus thing.The complement pathway that the CRP activation is classical also participates in the conditioning of part is engulfed being used to.Originally strong indication thing as unique biomarker and cardiovascular danger is proposed, the medium of CRP atheroma formation seemingly now.CRP has direct effect to promoting Atherosclerosis and activated endothelial cell.CRP effectively regulates endothelial nitric oxide synthase (eNOS) downwards and transcribes and make eNOS mRNA unstable, and it has reduced the basis and nitric oxide (NO) irriate discharges.

In synchronous pattern, CRP has shown that the stimulating endothelial angiogenic peptide-1 (effectively vasoconstrictor) that contracts discharges (proinflammatory cytokine) with interleukin-6, raises adhesion molecule, and stimulates monocyte chemotaxis albumen-1 to promote macrophage LDL to absorb simultaneously.Early, shown that CRP promotes endothelial cell apoptosis and suppress blood vessel to take place, and raised nuclear factor κ-B (promoting the crucial nuclear factor of the atherosis genetic transcription of many prerolandic artery Rolandos) potentially.

CRP directly before activate that the effect of arteries and veins gruel type is prolonged and beyond the endothelium to vascular smooth muscle, CRP directly raises the hypertensin 1 receptor and stimulates vascular smooth muscle migration, propagation, new intima to form and produce reactive oxygen species in smooth muscle.CRP (for example has some deleterious effects to endothelial progenitor cells; Survival, differentiation, function, apoptosis and the endothelial progenitor cells that descends-eNOS mRNA expresses); Said endothelial progenitor cells is important in new vessels forms, and said new vessels forms to be included in induces restoration of blood flow and infraction back to increase myocardium viability in the ischemic extremity.

Multiple imaging technique capable of using is estimated among the ischemia apoplexy patient degree of infraction site peripheral edema and to the blood flow of ischemic penumbra.The instance of such imaging technique below has been discussed.

Urgent non-contrast Cranial Computed Tomography scanning is compulsory to quick differentiation ischemia and red infarct and the anatomy distribution that limits apoplexy.Originally the Most patients of completed stroke cerebral infarction symptom will have normal discovery on the inherent CT scan in 6 hours.After 6-12 hour, competent edema adds in the apoplexy zone on CT scan, to produce regional low-density.The bigger density regions that appears on the preceding 3 hours inherent CT scan of paresthesia epilepsy should be about the careful in time inquiry again of the time of apoplexy paresthesia epilepsy.

In transcranial doppler TCD, probe placement on head zone to detect blood speed and the pressure in some tremulous pulse of different depth place in the brain.In the preceding several hrs after inaccessible apoplexy, TCD allow to judge obturation or the position and the degree of atheromatous plaque in cranium arteria carotis externa and the bigger intracranial vessel (comprising middle part arteriae cerebri and basilar artery).

Although distinguishing cerebral infarction and hemorrhagic apoplexy, MRI has proved the bigger prediction accuracy of degree of the lesion volume of the bigger degree of accuracy of distinguishing acute infarct and ischemic penumbra through the initial screening of CT.Method-the diffusion-weighted imaging (DWI) that MRI analyzes has reflected the microcosmic random motion of hydrone and extremely sensitive to early stage change instant after the apoplectic seizure.

For example, in the ultra acute phase of cerebral infarction (0-24 hour), MRI can detect ischemic within a few minutes of outbreak changes.After the apoplectic seizure several hours, MRI analyzes can detect the early stage flag event owing to cytotoxic edema.After 8 hours, the MRI signal is interpreted as the variation of distinguishing relevant with cytotoxic edema and angioedema.Cause it to increase through MRI to the enhanced sensitivity of the fine variation in the acute phase (1-7 days) of cerebral infarction process, subacute stage (7-21 days) and the chronic phase (＞21 days) in the diagnosis of acute ischemic stroke and the use in the treatment.

Perfusion weighted imaging (PWI) is the MRI technology of generation about the information of the perfusion state of brain.It can be used to estimate cerebral blood volume.Combine with tremulous pulse input and can calculate relative cerebral blood flow.Shown that DWI and PWI are extremely sensitive to the postictal commitment of apoplexy (up to 48 hours) together.Coordinate mutually, they provide about the position of blocking within a few minutes of showing effect and the information of degree; When carrying out continuously, they can provide the information about the evolution of ischemia pathological changes.

The somatization of acute ischemic stroke provides the objective evidence owing to the cerebral ischemia of blood flow obturation or that reduce, comprises the edema of initial infraction and generation.Contribution factor can comprise the endothelium of vascular inflammation and functional defect.The more common symptom of some of apoplexy comprises a side sensory deprivation (or unusual) of arm, lower limb or health; One side of arm or lower limb or health unable or paralysis (comprising asymmetric facial expression-facial paralysis), the part forfeiture of vision [watching paresis (slight or partial paralysis) or hemianopsia (VHF of eye or eyes is blind) attentively] is lost with the part of audition.Other somatization comprises double vision (diplopia), dizzy (comprise and fainting), babble (dysarthria-clearly tell dyslalia; The damage of the muscle that is used by speech causes); Thinking or the problem (ability of aphasia-clearly tell idea or understanding spoken language or written word is partly or entirely lost) of appropriate speech is described; Part that can not cognitive health (is not partly noted; Decay or anesthesia-can not cognitive benumb), and uneven and fall (Disability that comprises limbs ataxia-coordination muscular movement).

Designed the evaluation that many reference instruments are used for patient's apoplexy.Outcome measurement usually based on its reliability, to the familiarity of nervous system group (neurologic community), and the adaptability that in the patient who has suffered stroke, uses is selected.The instance that satisfies four kinds of apoplexy appraisal tools of these standards comprises the method for following description.Barthel index (deformity of daily life/active measurement) is the measuring reliably and effectively of active ability of carrying out daily life, the activity of said daily life such as diet, have a bath, walking and use lavatory.Can carry out all active patients fully independently and give 100 fens.The Rankin scale of improvement (overall disability scale) is the simple overall assessment of function, and wherein expression in 0 fen does not exist symptom and 5 fens expression handicaps.Glasgow scale (the horizontal scale of consciousness) as a result is the overall assessment of function, wherein the good recovery of expression in 1 fen; Represented medium deformity in 2 minutes; 3 fens expression handicaps; Expression survival in 4 fens still is in vegetative state; And expression in 5 fens is dead.

Airflow meter (NIHSS in the NIH; The damaged scale of apoplexy), (a series of measurements of neurologic defect) are quantitatively to be 42 point scales of 11 kinds with neurologic defect.For example, slight facial paralysis gives 1 fen, and with aphemic complete right paralysis, watch deviation, defect of visual field, dysarthria and anesthesia attentively and give 25 fens.Not having the normal function marking of neurologic defect is zero.

Other scale that is used to assess the paralytic can comprise: the apoplexy appraisal tool [promptly before the institute The Cincinnati Middle airflow meterWith Apoplexy examination (LAPSS) before the institute of Los Angeles]; Acute evaluation scale [promptly Canada is refreshing Study of Confucian classics scale (CNS), Glasgow stupor scale (GCS), Airflow meter (Hempispheric in the hemisphere Stroke Scale), Hunt & The Hess scale, Airflow meter among the Mathew, Simple and easy mental status examination (MMSE), Airflow meter among the Orgogozo, Oxfordshire community apoplexy classification of the items (Bamford)With Airflow meter in the Scandinavia]; The functional evaluation instrument [promptly Cypress Ge Shi balance scale, Middle wind effect amount Table (SIS), The quality of life measurement (SS-QOL) that apoplexy is specific]; With the evaluation of result instrument [promptly Beautiful State heart association apoplexy result classify (AHASOC), Function independent measurement (FIM)And The healthy accent Look into SF-36 & SF-12].

There are many processing that are used to alleviate the influence of apoplexy and stop the apoplexy in future at present, comprise treatment.At present, tissue plasminogen activator (tPA) is the unique thrombolytic agent that is used to treat acute ischemic stroke (claiming fibrinolysis or ' clot dissolution ' medicine again) by FDA (Food and Drug Adminstration) (FDA) approval.Have two kinds of methods with tPA intravenous ground or intra-arterial be applied directly to the clot site.Although the incidence rate of intracerebral hemorrhage increases, clinical effectiveness improves when finding at three months among the patient who in acute ischemic stroke showed effect three hours, treats with intravenous injection t-PA.

Except that the ischemic paralytic only can accept the strictness restriction of tPA in four and a half hours windows of the strictness that incident takes place; The patient who accepts vitamin-K antagonist for treating (being warfarin) shows serious elevated blood pressure or blood glucose; Show the low platelet counting; Suffer liver or kidney disease in late period, or stood recent surgical operation, be prevented from the thrombolytic agent treatment.At present, the tPA treatment is suitable for about paralytic of 5% to 10%.

Widen treatment window that tPA uses and proved not benefit clearly of tPA treatment up to 6 hours trial; The period that has assessment as a large amount of patients.The treatment failure possibly take place, because some patients of 4.5 to 6 hours of treatment have continued spontaneous the leading to again that serious irreversible brain injury and other patient have experienced its inaccessible tremulous pulse behind the paresthesia epilepsy.These patients' treatment unlikely produces useful effect and can cause being secondary to the infringement of cerebral hemorrhage.

Most patients arrives hospital and has consequently limited the intervention of tPA or had some other contraindications of the use that suppresses this medicine effectively too late.Relate to the blood vessel internal program that uses spiral device and be the machinery of the first FDA approval that is used to treat cerebral infarction.This device is used on the end of conduit physically to pull out all or part of clot.The major limitation of retrieval device is that clot must be visible and be accessible so that the position of doctor's guide catheter to clot.Penumbra System ^TM(comprise the suction platform that contains multiple arrangement, said multiple arrangement and specific neural blood vessel structure size coupling are so that clot sucking-off from intracranial vessel leniently) be reconstructing blood vessel after being used for apoplexy by the FDA approval in 2008.The cerebral arteries size, advanced surgical operation and imaging technique, and vascular puncture has limited the application of these mechanical clot destroy technologies significantly.

Use anticoagulant and can work to stop cerebral infarction and recurrence thereof.Anticoagulant is the medicine that is used to stop clot formation or stops established clot expansion.Yet anticoagulant can not dissolve established clot.Anticoagulant medicaments is divided into three types: the inhibitor of the synthetic inhibitor of thrombin (being warfarin), thrombin, and antiplatelet drug (being aspirin, clopidogrel, eptifibatide, dipyridamole and ticlopidine).

Consider the restriction of the treatment existence of present practice, just seeking frequency and the severity of new method with the clinical sequela of reduction acute ischemic apoplexy secondary.

In history, ozone has been used as disinfectant or biocide in wide variety of applications.These application comprise based on fluidic technology, such as the sterilization of fluidic sterilization in the purification of drinking water, the semi-conductor industry, black water, and the deactivation of pathogen in the biological fluid.Ozone also is used as partial medical care in the past, as the treatment of whole body with as the follow-up processing that is used to treat the multiple fluid of multiple disease.Particularly, exist and to utilize multiple technology to treat a lot of trials of multiple medical condition based on ozone, comprise described herein those.

Previous technology not energy measurement is also distinguished the amount of the ozone of sending and the amount of the ozone that actual absorption is also used.This means the not amount of amount and the ozone of any material actual absorption that is processed of the ozone sent of energy measurement, report or differentiation of the previous medical skill used in the patient treatment.This problem makes the registration approval impossible for therapeutic agent becomes.

In the treatment of the disease patient's condition, the amount that the ozone of sending can not be measured, reports or distinguished to previous technology with by the amount fluid actual absorption and that utilized by the patient.The amount of the ozone that impotentia measure to absorb can cause excessive absorption, thereby causes the unacceptable level of necrocytosis of the leukocyte composition of treating blood disorders liquid of living in, and it can cause the promotion of inflammatory reaction when infusion again.And, think and utilize any technology of the stripped haemodialysis disease patient's condition must be able to keep fluidic biological integrity to be used for the therapeutic use of its follow-up intention with ozone.

In addition, mix ozone and fluidic early stage method using gases-fluid contacting apparatus, said gas-fluid contacting apparatus is designed has gas to fluidic relatively poor mass-transfer efficiency.Therefore recently, developed more effective gas-fluid contacting apparatus, but these devices utilize the inert building material of non-ozone and with ozone reaction and absorb ozone.Thereby causing being configured absorbed ozone, this make it can not measure the amount that is delivered to fluidic ozone and by the amount of the ozone of absorption of fluids.In addition, be configured pollutant or the follow-up fluid that discharges into of deleterious by-product that absorbed ozone causes oxidation and oxidation probably.

Experimentation has confirmed to be configured the problem of absorbed ozone.Ozone/oxygen mixture is through commercially available membrane oxygenator under 1200ppmv.Surpass two hours time, the most of ozone that is delivered to device is configured absorbed.These data point out commercially available membrane type gas-fluid contacting apparatus to be processed by the ozone reaction material forcefully, can not use with ozone, and support the necessity of ozone-inert gasses-fluid contacting apparatus that exploitation is novel.

In addition, the amount of the existing method ozone that not have to quantize not to react with biological fluid.Impotentia is measured remaining ozone and has been caused reality by inaccurate and coarse mensuration of the amount of the ozone of absorption of fluids and utilization.

Prior art also comprises mixes ozone and fluidic inefficient method, produces irregular exposure.For example, a large amount of relatively ozone can be exposed to some in the fluid and expose less to other part.The blended result of this poor efficiency causes that the amount that is exposed to fluidic ozone changes widely.This variation widely of ozone exposure can cause all biochemistry incidents, comprises the unacceptable level of necrocytosis in the multiple part of the fluid that causes disadvantageous and irreproducible result.

Prior art fails also to recognize that the different fluids of forming have shown the differing absorption phenomenon.Extracellular antioxidant in the blood (comprises ascorbic acid (0.4-1.5mg/dL); Uric acid (2.1-8.5mg/dL); Bilirubin (0-1.0mg/dL) and Vitamin A (30-65 μ g/dL)) and other oxidable substrate (such as cholesterol (140-240mg/dL); LDL-cholesterol (100-159mg/dL); HDL-cholesterol (33-83mg/dL) and triglyceride (45-200mg/dL)) can change being delivered to fluid and being absorbed and utilizing amount subsequently with the needed ozone of clinical effectiveness that reaches hope.

The invention summary

According to the present invention, provide method to be used for the multiple disease patient's condition of therapeutic treatment, comprise acute ischemic apoplexy, cardiovascular disease, inflammatory diseases, and the relevant symptoms and the patient's condition of these diseases.Method of the present invention generally includes the extracorporeal treatment of blood, blood constituent or other biological fluid of taking from mammalian subject or patient and such fluid exposure is had the biological fluid of the processing of ozone that can quantitative absorbed dose in the ozone of the amount of accurate measurement with generation.Method of the present invention also comprises the fluid with quantitatively processing of the ozone of absorbed dose is infused in the mammalian subject to provide and to draw the patient's condition or symptom and other treatment of diseases effect of treatment disease, disclosed disease again.

Method of the present invention also provides the material useful in the therapeutic treatment of the multiple disease patient's condition or the manufacturing of compositions, and the said multiple disease patient's condition comprises the relevant symptom and the patient's condition of acute ischemic apoplexy, cardiovascular disease, inflammatory diseases and these diseases.Method of the present invention also provides the medicament of such material and compositions be used for the multiple disease patient's condition in manufacturing therapeutic treatment or the purposes of other material that can use, and the said multiple disease patient's condition comprises the relevant symptom and the patient's condition of acute ischemic apoplexy, cardiovascular disease, inflammatory diseases and these diseases.

Standing or received the patient's of acute ischemic apoplexy treatment to produce other therapeutical effect; The patient who comprises measurement is from following aspect or improvement in the following areas: paralysis, motion are unable, the reentrying of the severity of the apoplexy of sensory deprivation, vision and auditory function, the existence of no apoplexy, recurrence, cognitive function, communication, independence, and the improvement in integral body existence.

The present invention relates to provide the method that does not have excessive necrosis with ozone extracorporeal treatment blood to produce the leukocyte apoptosis; This method at the blood of handling by behind the infusion again; Be enough to reduce the edema relevant with ischemic penumbra; Increase the blood (said infraction peripheral region can comprise ischemic tissue and ischemic penumbra) that flows to the infraction peripheral region, promote the diastole of blood vessel endothelium and reduce inflammation.

The invention still further relates to the method with ozone extracorporeal treatment blood, this processing blood is by behind the infusion again, causes the minimizing of the CRP that is enough to draw clinical benefit.

The invention still further relates to processing blood, blood constituent or other the fluidic method of being provided for, and blood, blood constituent or other fluid purposes in the acute ischemic apoplexy in through blood from such processing to the patient, blood constituent or other fluid therapies mammalian subject of using of this processing.

The present invention also comprises the ozone of the amount that the external ground warp of aliquot sample of mixture (comprising platelet) of isolated cell composition or the isolated cell of the blood that makes mammalian subject or blood is measured, so that the ozone that absorption of fluids can quantitative absorbed dose.When this aliquot sample from body is introduced into patient's body again, blood, blood constituent or other fluid with ozone that can quantitative absorbed dose can influence by in the improvement of wind-induced any patient's condition.

The invention still further relates to the method that is used to treat the acute ischemic apoplexy, comprise external amount of sending measurement through the blood or derivatives thereof ozone and with post-absorption can quantitative absorbed dose ozone when being infused among the patient again, to cause or to promote to introduce the method for the required competent leukocyte apoptosis of clinical benefit from body ground.

The invention still further relates to the apoptosis of the leukocyte composition of inducing the blood that absorbs ozone that can quantitative absorbed dose or blood derivatives, thereby when being infused among the patient who suffers apoplexy again, reduce the method for inflammation from body ground.

The invention still further relates to the apoptosis of the leukocyte composition of inducing the blood that absorbs ozone that can quantitative absorbed dose or blood derivatives and do not cause excessive necrosis, thereby when being infused among the patient who suffers apoplexy again, reduce inflammation from body ground.

The invention still further relates to when being infused among the patient again from body ground, through utilizing blood or the blood derivatives treatment acute ischemic stroke absorbed ozone that can quantitative absorbed dose, stops excessive necrosis, excessive necrosis can be short inflammation.

The present invention relates to provide the method for treatment; The method of said treatment reduces the patient's who suffers from acute ischemic stroke inflammation through comprising following method: connect curee and the device that is used to take out blood; The ozone of the amount of taking out blood and not having inducing competent leukocyte apoptosis will to measure under the condition of excessive necrosis is delivered to blood, and wherein the blood of processing is infused among this curee subsequently again.

Method of the present invention is induced competent leukocyte apoptosis and is not had excessive necrosis; It can be assessed through many diagnostic methods, and said diagnostic method comprises that the optical microscopy, the electrophoretic analysis of dna break, the TUNEL that utilize nuclear stain analyze and the multiparameter flow cytometry.

Method of the present invention is induced the apoptosis of the leukocyte composition of the blood that absorbs ozone that can quantitative absorbed dose or blood derivatives, thus the edema in the ischemic penumbra that reduces the paralytic from body ground again during infusion.

This method relates to the apoptosis of the leukocyte composition of inducing the blood that absorbs ozone that can quantitative absorbed dose or blood derivatives; Thereby the edema in the zone around body ground reduces infraction again during infusion, the zone around the said infraction can comprise paralytic's ischemic tissue and ischemic penumbra.

Method of the present invention relates to through following method and reduces the edema in the zone around the patient's that edema and/or reduction in the patient's who suffers from acute ischemic stroke the ischemic penumbra suffer from acute ischemic stroke the infraction; Zone around the said infraction can comprise ischemic tissue and ischemic penumbra; Said method comprises the device that connects the curee and be used to take out blood; The ozone of the amount of taking out blood and not having inducing competent leukocyte apoptosis will to measure under the condition of excessive necrosis is delivered to blood, and wherein the blood of processing is infused among the curee subsequently again.

The invention still further relates to the apoptosis of the leukocyte composition of inducing the blood that absorbs ozone that can quantitative absorbed dose or blood derivatives; Thereby the blood flow in the zone when be improved to infraction again during infusion from body ground around, the zone around the said infraction can comprise paralytic's ischemic tissue and ischemic penumbra.

The invention still further relates to the apoptosis of the leukocyte composition of inducing the blood that absorbs ozone that can quantitative absorbed dose or blood derivatives and do not cause excessive necrosis; Thereby the blood flow in the zone when be improved to infraction again during infusion from body ground around, the zone around the said infraction can comprise paralytic's ischemic tissue and ischemic penumbra.

Method of the present invention also relates to through following method to be improved among the patient who suffers from acute ischemic stroke to the blood flow that blocks zone on every side; Zone around the said infraction can comprise ischemic tissue and ischemic penumbra; Said method comprises the device that connects the curee and be used to take out blood; The ozone of the amount of taking out blood and not having inducing competent leukocyte apoptosis will to measure under the condition of excessive necrosis is delivered to blood, and wherein the blood of processing is infused among the curee subsequently again.

Method of the present invention relates to the apoptosis of the leukocyte composition of inducing the blood that absorbs ozone that can quantitative absorbed dose or blood derivatives and does not cause excessive necrosis, thereby when diastole paralytic's blood vessel endothelium during infusion again from body ground.

Method of the present invention relates to the blood vessel endothelium of suffering from the patient of acute ischemic stroke through following method diastole; And/or the edema in minimizing acute ischemic apoplexy patient's the ischemic penumbra; And/or the edema in the zone around the minimizing infraction; Zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra; Said method comprises and connects curee and the device that is used to take out blood, take out blood and do not have under the condition of excessive necrosis inducing competent leukocyte apoptosis and can keep blood biology integrity condition under the ozone of the amount that will measure be delivered to blood.The blood of handling is infused among the curee subsequently again.

The present invention includes the edema in the ischemic penumbra that reduces acute ischemic apoplexy patient; And/or the method for the edema in the zone around the minimizing infraction (zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra), like what assessed through multiple diagnostic tool (comprising MRI and doppler imaging technology).

The present invention relates to reduce the decline of inflammation with the edema in the ischemic penumbra that causes acute ischemic apoplexy patient; Thereby cause the decline of blocking the edema in the zone on every side with the minimizing inflammation, the zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra.

When in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the effect that reduces inflammation.

The minimizing of inflammation can take place through the minimizing of the proinflammatory cytokine (for example interferon-, TNF-γ, IL-6 and IL-12) that discharged by immunomodulating T cell and/or the increase of anti-inflammatory cytokines (for example interleukin-4 and IL-10).The effect that reduces inflammation can produce many clinical benefits, comprises and improve endothelial function that said endothelial function comprises endotheliocyte reparation or replacement.These results can cause the decline of edema in the ischemic penumbra.

The minimizing of inflammation can take place through the minimizing of the proinflammatory cytokine (for example interferon-, TNF-γ, IL-6 and IL-12) that discharged by immunomodulating T cell and/or the increase of anti-inflammatory cytokines (for example interleukin-4 and IL-10).The effect that reduces inflammation can produce many clinical benefits, comprises and improve endothelial function that said endothelial function comprises endotheliocyte reparation or replacement.The decline of edema in the zone around these results can cause blocking, the zone around the said infraction can comprise ischemic tissue and ischemic penumbra.

Method of the present invention provides the treatment of acute ischemic apoplexy; Comprise through the blood or derivatives thereof send externally measurement amount ozone and with post-absorption can quantitative absorbed dose the method for ozone; Said blood or derivatives thereof can cause the decline of CRP when being infused among the patient again from body ground.

Method of the present invention provides the treatment of acute ischemic apoplexy; Comprise through the blood or derivatives thereof send externally measurement amount ozone and with post-absorption can quantitative absorbed dose the method for ozone; Said blood or derivatives thereof can cause the decline of the CRP that is enough to draw clinical benefit when being infused among the patient again from body ground.Clinical benefit can comprise the minimizing inflammation, forms increasing blood flow through the vasodilation increasing blood flow with through new vessels.

Method of the present invention relates to the blood flow that increases to infraction zone on every side; Zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra; Said method comprises and connects curee and the device that is used to take out blood, takes out blood and the ozone of the amount that under the condition that can keep blood integrity biology, will measure is delivered to blood.The blood of handling is infused among the curee subsequently again.

Method of the present invention relates to the blood flow that increases to infraction zone on every side; Zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra, like what assessed through multiple diagnostic tool (comprising MRI and doppler imaging technology).

Thereby method of the present invention also relates to the minimizing inflammation causes the blood flow increase to infraction zone on every side, and the zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra.

Method of the present invention also provides blood, blood constituent or other fluidic processing, and the fluid of in the treatment of acute ischemic apoplexy, using this processing is for the vasodilator endothelium.

The ozone of the amount that this method is measured based on the external ground warp of aliquot sample of the mixture (comprising platelet) of the isolated cell composition of blood that makes mammalian subject or blood or isolated cell so that its absorption can quantitative absorbed dose ozone.When this aliquot sample from body was introduced into patient's body again, blood, blood constituent or other fluid with ozone that can quantitative absorbed dose can have some useful effect.One of these effects are the diastole endotheliums.This diastole can result from vasodilative increase (promptly promote vasodilation or suppress vasoconstrictor), comprises the endothelial function of endotheliocyte reparation or replacement and improves blood flow and produce enhanced oxygenation thereby improve.Therefore, method of the present invention also relates to the diastole that promotes blood vessel endothelium, thereby causes the decline of the edema in acute ischemic apoplexy patient's the ischemic penumbra.The diastole of blood vessel endothelium can result from the decline of edema in the zone around the infraction, and the zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra.

When in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the vasodilator endothelium.These effects can cause vasodilative increase (promptly promote vasodilation or suppress vasoconstrictor), thereby improve the endothelial function that comprises endotheliocyte reparation or replacement.These results can cause suffering from patient's the ischemic penumbra of acute ischemic apoplexy and the decline of the edema in the zone around the infraction, and the zone around the said infraction can comprise the patient's who suffers from the acute ischemic apoplexy ischemic tissue and ischemic penumbra.

Thereby the edema that method of the present invention also relates in the ischemic penumbra that the vasodilator endothelium causes acute ischemic apoplexy patient descends; And/or thereby the vasodilator endothelium causes that the edema in the infraction zone on every side descends; Zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra, like what assessed through multiple diagnostic tool (comprising MRI and doppler imaging technology).

Method of the present invention also relates to the vasodilator endothelium to cause the blood flow increase to infraction zone on every side, and the zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra.

When in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the vasodilator endothelium.These effects can cause vasodilative increase (promptly promote vasodilation or suppress vasoconstrictor), thereby improve the endothelial function that comprises endotheliocyte reparation or replacement.The blood flow in the zone around these results can cause blocking increases, and the zone around the said infraction can comprise the patient's who suffers from the acute ischemic apoplexy ischemic tissue and ischemic penumbra.

Therefore increase thereby method of the present invention relates to the blood flow that the vasodilator endothelium causes the zone around the infraction; Zone around the said infraction can comprise acute ischemic apoplexy patient's ischemic tissue and ischemic penumbra, like what assessed through multiple diagnostic tool (comprising MRI and doppler imaging technology).

Method of the present invention relate to can through number of ways (comprise intravenous, intramuscular with subcutaneous, or its any combination) introduce blood, blood constituent or other fluidic aliquot sample of the mammalian subject absorbed ozone that can quantitative absorbed dose again from body.

Method of the present invention provides through treating the acute ischemic apoplexy in the mammalian subject with discontinuous mobile method (discontinuous flow method) processing blood.This method comprises and connects curee and the device that is used to take out blood, take out blood and can keep blood biology integrity condition under the ozone of the amount that will measure be delivered to blood, wherein the blood of processing is infused among the patient subsequently again.

Method of the present invention also provides through treating the acute ischemic apoplexy in the mammalian subject with discontinuous mobile method processing blood or its composition (comprising blood plasma or serum).This method comprises the device that connects the curee and be used to take out blood; From the curee, take out the blood contain hemocyte, from blood, separate the acellular composition and can keep blood constituent biology integrity condition under the ozone of the amount that will measure be delivered to this composition.The composition of handling combines with hemocyte subsequently again and is infused among the curee.

The paralysis that the paralysis that method of the present invention provides the paralysis that causes the patient who suffers from the acute ischemic apoplexy to improve, cause the patient who suffers from the acute ischemic apoplexy through middle airflow meter appraisal tool assessment improves, cause the patient who suffers from the acute ischemic apoplexy through middle airflow meter appraisal tool assessment is improved and the wherein treatment of clinical efficacy through measuring with untreated paralytic's statistical comparisons.

Method of the present invention also provides and has caused as can be through unable improvement of the patient moving of suffering from the acute ischemic apoplexy of middle airflow meter appraisal tool assessment and/or the wherein treatment of clinical efficacy through measuring with untreated paralytic's statistical comparisons.

The anesthetic improvement that causes the patient who suffers from the acute ischemic apoplexy that can be through the assessment of middle airflow meter appraisal tool also is provided method of the present invention and wherein clinical efficacy can be through the treatment of measuring with untreated paralytic's statistical comparisons.

The improvement of the vision that causes the patient who suffers from the acute ischemic apoplexy that can be through the assessment of middle airflow meter appraisal tool and auditory function is provided method of the present invention and wherein clinical efficacy can be through the treatment of measuring with untreated paralytic's statistical comparisons.

Method of the present invention provides the severity of the recurrence apoplexy that causes the patient who suffers from the acute ischemic apoplexy that can be through the assessment of middle airflow meter appraisal tool to descend and wherein clinical efficacy can be through the treatment of measuring with untreated paralytic's statistical comparisons.

Method of the present invention also provides the improvement of the cognitive function that causes the patient who suffers from the acute ischemic apoplexy that can be through the assessment of middle airflow meter appraisal tool and the wherein treatment of clinical efficacy through measuring with untreated paralytic's statistical comparisons.

The improvement of the communication that causes the patient who suffers from the acute ischemic apoplexy that can be through the assessment of middle airflow meter appraisal tool is provided method of the present invention and wherein clinical efficacy can be through the treatment of measuring with untreated paralytic's statistical comparisons.

Method of the present invention also can provide and cause can reentry through the patient who suffers from the acute ischemic apoplexy of middle airflow meter appraisal tool assessment independence and the wherein treatment of clinical efficacy through measuring with untreated paralytic's statistical comparisons.

Method of the present invention also can provide the treatment of improvement of breaking away from speed and/or total survival rate of apoplexy through the patient who suffers from the acute ischemic apoplexy with the assessment of untreated paralytic's statistical comparisons as causing, as can be through with untreated paralytic's statistical comparisons assessment.

Method of the present invention also can provide and wherein have the treatment of blood vessel endothelium from the acute ischemic apoplexy of short scorching state-transition to antiinflammatory state.

Method of the present invention also can provide through discharging anti-inflammatory cytokines (comprising interleukin-4 and IL-10 INTERLEUKIN-10 and TGF-γ) vasodilator endothelium.Method of the present invention also can provide through suppressing proinflammatory cytokine (comprising interferon-, TNF-γ, IL-1, IL-6 and IL-12) vasodilator endothelium.

Method of the present invention also can provide through suppressing the vasoconstriction therapy acute ischemic apoplexy of blood vessel endothelium.Method of the present invention also can provide through promoting the vasodilation treatment acute ischemic apoplexy of blood vessel endothelium.

Method of the present invention also can provide through causing the release treatment acute ischemic apoplexy of endothelium source relaxing factor, nitric oxide, prostacyclin or other relevant vasodilation chemical compound.

Method of the present invention can provide the treatment of the acute ischemic apoplexy that wherein has the oxygen increase that is delivered to ischemic area.Method of the present invention also can provide through promoting the angiogenesis in the ischemic area to treat the acute ischemic apoplexy.

The accompanying drawing summary

In order further to illustrate the present invention, the therapy system of the present invention of utilizing the ozone delivery system has been described in the accompanying drawing, it has schematically explained the current best pattern of the present invention of thinking to carry out;

In sketch map, Fig. 1 has explained the fluidic optional method of handling from the patient, comprises successive loop type and selectable discontinuous mobile method.

The embodiment of invention definition details

As used herein; " comprise ", " comprising ", " containing ", " being characterised in that " and grammer equivalents thereof be not get rid of the element other, not narration or the pardon term or the open-ended term of method step, and comprise more restrictive term " by ... form " with " basically by ... composition ".

As used in this paper and the appended claims, singulative, for example " one (a) ", " one (an) " and " being somebody's turn to do (the) " comprise plural number, only if the indication in addition of clear from context ground.For example, mention " a gas-fluid contacting apparatus " and comprise a plurality of such gas-fluid contacting apparatus, and for example mention a kind of " protein " and just mention a plurality of similar protein and equivalents thereof.

" ozone/oxygen mixture " refers to the concentration of the ozone in the oxygen carrier gas.The multiple concentration unit that those skilled in the art use comprises every milliliter of oxygen of microgram ozone, part (ozone) per 1,000,000 parts (oxygen) (' ppm ') and part per 1,000,000 parts (' ppmv ') by weight by volume.As the concentration unit of ozone in the oxygen, ppmv is restricted to the mol ratio between ozone and the oxygen.One ppmv ozone equals every milliliter of oxygen of 0.00214 microgram ozone.In addition, a ppm ozone equals every milliliter of oxygen of 0.00143 microgram ozone.According to percentage ratio ozone by weight, 1% ozone equals every milliliter of oxygen of 14.3 microgram ozone.All concentration units and equivalents thereof are calculated at (promptly under 1 atmospheric pressure 25 ℃) under standard temperature and the normal pressure.

" ozone of sending " is the amount that is delivered to the ozone that contains in the volume of fluidic ozone/oxygen mixture, and with the ozone of the amount of sending measurement be synonym.

" ozone of absorption " is actual in the amount of a certain amount of absorption of fluids and the ozone of sending that utilizes, and with ozone that can quantitative absorbed dose be synonym.

The amount of " remaining ozone " unabsorbed ozone of sending, promptly

The ozone of the ozone-absorbed dose of remaining ozone=send

" contact " is restricted to the contact between fluid and the ozone/oxygen mixture.

" time of contact " is restricted to and is present in gas-fluid contacting apparatus and the time that contacts with ozone/oxygen mixture.

" contact surface long-pending " is restricted to the size that fluid in gas-fluid contacting apparatus flows through and contact the surface of ozone/oxygen mixture.

" elapsed time " be fluid in the whole ozone delivery system circulation time, the ozone delivery system comprises through one or more gas-fluid contacting apparatus, connection tube and optional memorizer.

" ozone inert material " is restricted to not with the building material of the mode of the pollutant of the oxidation of in fluid, introducing building material or harmful side product and ozone reaction and do not absorb the ozone material.

" not reactive " is restricted to and is difficult for interacting to form new chemical compound with other element or chemical compound.

" measurement data " is restricted to the information of collecting from the multiple measurement assembly that runs through system (such as inlet ozone concentration monitor, outlet ozone concentration monitor, gas flowmeter, fluid pump, data acquisition unit, humidity sensor, temperature sensor, pressure transducer, absorption oxygen sensor).

" calculating data " is restricted to the digital processing of data acquisition unit to measurement data.

" biological fluid absorption ozone " is restricted to following phenomenon: wherein ozone is through number of mechanisms (comprising oxidation) and pending fluid reaction.No matter related mechanism why, reaction immediately takes place, and the product of this reaction comprises oxidation product, and wherein MDA is an instance.

" biological fluid " is restricted to the organic component biology that is derived from any kind.The instance of biological fluid comprises blood, blood products and other fluid, such as saliva, urine, feces, seminal fluid, breast, tissue, tissue sample, homogenization tissue sample, animal glue and any other material of having its origin in the organism in biology.Biological fluid also can comprise and add the synthetic material have the material of its origin biology in the organism, such as the vaccine product, cell culture medium, cell culture, the viral cultures that contain Alumen and virus (said virus is the material that has its origin in biology in the organism) be derived from organic other culture biology.

" blood products " is restricted to and comprises and contain proteinic blood constituent and the therapeutic protein compositions that is derived from blood.Containing also can be through this method processing except that the fluid of those biologically active proteins protein that are derived from blood.

" in the body " of material or chemical compound uses to be restricted to material or chemical compound is incorporated in the lived mankind, mammal or the vertebrates.

" external " of material or chemical compound used and is restricted to materials used or chemical compound outside the lived mankind, mammal or vertebrates, and wherein material or chemical compound are not intended to be incorporated in the lived mankind, mammal or the vertebrates again.The instance of external use is for utilizing the component of laboratory equlpment analyzing blood sample.

" exsomatizing " of process used to be restricted to and outside the lived mankind, mammal or vertebrates, used the process of handling biologic material such as blood products.For example, the method that shifts out blood and make this blood stand to treat cardiovascular disease from philtrum is restricted to the stripped use of said method, as long as the blood intention is introduced this people or another person again.Human blood is introduced into this people or another person again uses, completely contradict with the stripped use of method in the body of blood.

" external " is restricted to following state, wherein blood or the blood constituent processing of outside health, (exsomatizing), for example, in the sending of the ozone of the amount of measuring to patient's blood sample.

" synthetic medium " is restricted to aqueous dextran or blood products storage medium.

" pharmaceutically acceptable carrier " or " pharmaceutically acceptable vehicle " is restricted to any liquid that comprises water, saline, gel, ointment, solvent, diluent, fluid ointment base, liposome, micelle or giant micelle; Said liquid is suitable for contacting with lived animal or human's class tissue and not causing disadvantageous physiological reaction, and not with other component interaction of deleterious mode and compositions.

" BA " is restricted to the variation that can cause lived organism or its component.

" integrity biology of biological fluid " is after the method for treatment cardiovascular disease described herein, when being infused in the mammalian subject again, keeps the fluidic quality or the state of its function fully.

" cardiovascular disease " is restricted to those diseases that can comprise atherosclerosis, arteriosclerosis, PAOD, cerebrovascular disease, hypertension, Raynaud disease, dyslipidemia and congestive heart failure.

" edema " be restricted in blood circulation or in tissue between somatic cell the patient's condition of (interstitial space) unusual big Fluid Volume.

" inflammatory diseases " is restricted to immune system and is activated to the disease that abnormal level is a characteristic, and said abnormal level is characterized as the tissue of inflammation, and the tissue signature of said inflammation is pain, swelling, rubescent and heating.

" neurodegenerative disease " is restricted to by causing the neurocyte dysfunction, finally causing the disease that the degeneration of some neurocytes that it is dead causes.

" autoimmune disease " is restricted to and thinks by immune system at the exogenous antigen of biological invasion body (non-self) with originate from and between the tissue (self) of itself, distinguish the disease that lost efficacy and cause.

" alloimmunity disease " is restricted to and results from the immunoreation of antagonism external source transplanted tissue or the disease that is caused by external source transplanted tissue.

" C proteins C reactive " is restricted to the synthetic acute phase reactive protein of liver, and it is considered to can activation classical complement pathway (classical compliment pathway) and nurses one's health the acutely inflamed mark of part to be used to engulf.

The invention provides the patient's condition and the method for symptom of therapeutic treatment acute ischemic apoplexy, cardiovascular disease, inflammatory diseases and those disease associations that is delivered to patient's blood, blood constituent or other fluidic sample mediation through the ozone that utilizes the amount that the ozone delivery system will measure externally.Absorption of fluids can quantitative absorbed dose ozone be infused into again among the same patient subsequently.Contain can quantitative absorbed dose ozone this from the blood sample of body disappearing of can influencing that improvement, the minimizing of atheromatous plaque, the atheromatous plaque of the minimizing of edema, impaired blood flow form, the minimizing of ischemic penumbra, the diastole of blood vessel endothelium, the minimizing of inflammation and the minimizing of lipid and lipid deposits.Therefore this method possibly be useful in the cardiovascular disease that comprises atherosclerosis, PAOD, congestive heart failure, hypertension, cerebrovascular disease, dyslipidemia and vasospasm disease (comprising Raynaud disease) of treatment mammalian subject.The positive treatment result can measure through multiple quantification or quantitative methods; And comprise cholesterol, triglyceride and the measurable minimizing of other lipid; The minimizing of the seizure frequency of intermittent claudication, severity and persistent period; The minimizing of limb paralysis, unable and LOM, limbs are pale, the improvement of temperature and pulse, elevated blood pressure and the minimizing that loses weight.

Method of the present invention also provides the effective treatment and the improvement of any patient's condition that is caused by the acute ischemic apoplexy, said effective treatment and improvement comprise the minimizing of the edema relevant, the zone around the infraction with ischemic penumbra impaired blood flow improve (zone around the said infraction can comprise ischemic tissue and ischemic penumbra), the diastole of blood vessel endothelium and the minimizing of inflammation.The positive treatment result can be measured and can be comprised the improvement of total survival rate after the survival rate of reentrying, break away from apoplexy, recurrence frequency and the severity and the apoplexy of paralysis, vision and aural skill, cognitive function, independence.

Method of the present invention also provides efficacious therapy and the improvement that reduces inflammation, vasodilator endothelium, reduces the patient's condition relevant with inflammatory diseases such as edema and increasing blood flow.Other disease as the target of the potential candidate disease through method therapeutic treatment disclosed by the invention comprises rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), scleroderma, diabetes, inflammatory bowel, psoriasis, pemphigus, atherosclerosis, chronic heart failure, comprises graft versus host disease, Alzheimer, ischemia apoplexy, alzheimer disease, depression, mongolism, Heng Yandun disease, peripheral nervous pathological changes, myelopathy, neuroarthropathy, chronic inflammatory demyelinating disease (CIPD) and neuropathy that tissue transplantation repels, comprises mononeuropathy, polyneuropathy, far-end symmetry sensory nerve pathological changes, cystic fibrosis, neuromuscular junction disease, myasthenia and parkinson disease, traumatic brain injury, spinal cord injury and soft tissue injury.

Method of the present invention relates to through the method that provides ozone with the amount of measuring to be delivered to the blood or derivatives thereof and to absorb ozone that can quantitative absorbed dose by the blood or derivatives thereof subsequently externally provides cardiovascular disease, inflammatory diseases and acute ischemic apoplexy and the relevant patient's condition and the therapeutic treatment of symptom; When this blood or derivatives thereof was infused among the patient from body ground again, can cause for drawing the necessary competent leukocyte apoptosis of clinical benefit did not have excessive necrosis.

The present invention also provides the ozone of the amount of sending measurement externally and has been absorbed the method for ozone that can quantitative absorbed dose subsequently by the blood or derivatives thereof; Wherein at the blood or derivatives thereof after body ground is infused among the patient again, can cause the decline of the CRP that is enough to draw clinical benefit.Disclosed method also can influence the diastole of blood vessel endothelium, and can relate to the release of the vasodilation that is enough to draw clinical benefit, comprises nitric oxide and prostacyclin.

In one embodiment of the invention; Method provides blood, blood constituent or other fluidic processing; With blood, blood constituent or other fluid the handled purposes in treatment disease described herein; And being used to make the purposes of the medicament of treatment disease described herein, said disease can comprise, for example the atherosclerosis disease relevant with the dysfunction endothelium; The diastole of blood vessel endothelium, and can relate to the release that is enough to draw clinical benefit or treats the vasodilation (comprising nitric oxide and prostacyclin) of benefit.Medicament also maybe be in the inflammatory diseases of the minimizing of the diastole that comprises the minimizing of inflammation, blood vessel endothelium, edema and increasing blood flow the treatment of the relevant patient's condition be effective in improving.

In some embodiments, this method can comprise the amount that the external ground warp of aliquot sample of mixture (comprising platelet) of cell component or the isolated cell of the blood that makes mammalian subject or separate blood is measured ozone in case the absorption of fluids of handling can quantitative absorbed dose ozone.When this aliquot sample from body was introduced into patient's body again, blood, blood constituent or other fluid with ozone that can quantitative absorbed dose provided the effect of some useful effect and treatment.These effects can cause minimizing and/or the active stimulation of inhibition, deposit or plaque rupture and functional defect endothelium, the minimizing of inflammation and the blood flow of increase of for example atheromatous plaque formation.

When in the health that is infused into mammalian subject again, blood, blood constituent or other the fluidic effect that has absorbed ozone that can quantitative absorbed dose can comprise the variation of lipid metabolism and spread all over leukocyte (being cell-cell interaction or release of cytokines) the enhance immunity system of patient's peripheral blood through stimulation.This for example can cause, and atheromatous plaque forms and the minimizing of sedimentary minimizing, lipid and lipid deposits, the diastole of blood vessel endothelium, the minimizing of edema and the minimizing of inflammation.These effects can cause the narrow reverse of carrying out property lumen of artery, the minimizing of breaking or stripping off of speckle; With vasodilative increase (promptly promote vasodilation or suppress vasoconstrictor); Thereby reduce the incidence rate of atheroembolism (cholesterol thromboembolism); Improve and to comprise the endothelial function of endotheliocyte reparation or replacement, and improve blood flow and produce enhanced oxygenation.

The clinical sign of these effects can comprise minimizing, the normalization of limb temperature and the pale improvement of decline, limb adynamia and pain of minimizing, the elevated blood pressure of minimizing, the ischemic penumbra of outbreak and the severity of intermittent claudication.In addition, losing weight possibly be the result of this Therapeutic Method.

About relating to the disease of atheromatous plaque formation, deposition and plaque rupture; This method provides therapeutic treatment and the prevention to much such mammal disease, and said mammal disease comprises cardiovascular disease (such as atherosclerosis, PAOD), cerebrovascular disease (apoplexy and transient ischemic attack), myocardial infarction, angina pectoris, hypertension, retinal ischemia, renal failure, abdominal aortic aneurysm and hyperlipidemia.

For those diseases that relate to endothelial function disturbance; This method provides therapeutic treatment and the prevention to much such mammal disease, and said mammal disease comprises cardiovascular disease (such as atherosclerosis, PAOD, congestive heart failure), cerebrovascular disease (apoplexy), myocardial infarction, angina pectoris, hypertension, vasospasm disease such as Raynaud disease, heart X syndrome and migraine.

The therapeutical effect that has absorbed the blood or derivatives thereof of ozone that can quantitative absorbed dose possibly be when being infused among the patient again from body ground, induces to draw the needed competent leukocyte apoptosis of anti-inflammatory response and do not have excessive necrosis.Can be evaluated at the apoptosis induced that does not have excessive necrosis in the leukocyte composition of the blood of having handled through many diagnostic methods, said diagnostic method comprises that the optical microscopy, the electrophoretic analysis of dna break, the TUNEL that utilize nuclear stain analyze and the multiparameter flow cytometry.

When being infused among the patient again from body ground, the effect that has absorbed the blood or derivatives thereof of ozone that can quantitative absorbed dose can cause the minimizing of CRP and can draw clinical benefit, comprises that anti-inflammatory response, new vessels form and vasodilation.

When in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the effect that reduces edema.

In addition, when in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the effect of the blood flow that is increased to ischemic tissue.This minimizing can be through multiple diagnostic tool (comprising MRI and doppler imaging technology) assessment.

And when in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the effect that reduces inflammation that comprises.The minimizing of inflammation can take place through the minimizing of the proinflammatory cytokine (for example interferon-, TNF-γ, IL-6, IL-8 and IL-12) that discharged by immunomodulating T cell and/or the increase of anti-inflammatory cytokines (for example interleukin-4 and IL-10).The effect that reduces inflammation can cause a lot of clinical benefits, comprises that the improvement of blood flow produces enhanced oxygenation.

When in the health that is infused into mammalian subject again, come apoptosis-induced leukocyte not have blood or the effect of its blood derivatives of the usefulness ozonization of excessive necrosis can comprise the effect that reduces inflammation that comprises through this method.The minimizing of inflammation can take place through the minimizing of the proinflammatory cytokine (for example interferon-, TNF-γ, IL-6, IL-8 and IL-12) that discharged by immunity regulatory cell and/or the increase of anti-inflammatory cytokines (for example interleukin-4 and IL-10).The effect that in the treatment of cardiovascular disease, reduces inflammation can cause a lot of clinical benefits, comprises that the improvement of blood flow produces enhanced oxygenation.

The other embodiment of method of the present invention comprise the amount that the external ground warp of aliquot sample of mixture (comprising platelet) of cell component or the isolated cell of the blood that makes mammalian subject or separate blood is measured ozone in case its absorption can quantitative absorbed dose ozone.When this aliquot sample from body is introduced into patient's body again; Blood, blood constituent or other fluid with ozone that can quantitative absorbed dose to treatment by in wind-induced any patient's condition can have therapeutical effect, said therapeutical effect comprise the minimizing of the edema of ischemic penumbra, the zone around the infraction impaired blood flow improve (zone around the said infraction can comprise ischemic tissue and ischemic penumbra), the diastole of blood vessel endothelium and the minimizing of inflammation.

In addition, when being infused among the patient again from body ground, the effect that has absorbed blood or its blood derivatives of ozone that can quantitative absorbed dose can be to induce to draw the needed competent leukocyte apoptosis of anti-inflammatory response and do not have excessive necrosis.According to method of the present invention; In the leukocyte composition of the blood of handling, induce the apoptosis that does not have excessive necrosis to assess through many diagnostic methods, said diagnostic method comprises that the optical microscopy, the electrophoretic analysis of dna break, the TUNEL that utilize nuclear stain analyze and the multiparameter flow cytometry.

When being infused among the patient again from body ground, absorb the blood of ozone that can quantitative absorbed dose or the effect of its blood derivatives and can cause the minimizing of CRP, and drawn clinical benefit, comprise that anti-inflammatory response, new vessels form and vasodilation.When in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the effect of the edema in the ischemic penumbra that reduces acute ischemic apoplexy patient.This minimizing can be through multiple diagnostic tool (comprising MRI and doppler imaging technology) assessment.In addition; When in the health that is infused into mammalian subject again; Blood, blood constituent or other the fluidic effect that has absorbed ozone that can quantitative absorbed dose can comprise the effect of the blood flow that increases to the zone around the infraction, and the zone around the said infraction can comprise the patient's who suffers from acute ischemic stroke ischemic tissue and ischemic penumbra.This minimizing can be through multiple diagnostic tool (comprising MRI and doppler imaging technology) assessment.

And when in the health that is infused into mammalian subject again, blood, blood constituent or other the fluidic effect that has absorbed ozone that can quantitative absorbed dose can comprise that diastole suffers from the patient's of acute ischemic stroke the effect of blood vessel endothelium.This diastole can result from and improve the endothelial function that comprises endotheliocyte reparation or replacement and improve the vasodilative increase (promptly promote vasodilation or suppress vasoconstrictor) that blood flow produces enhanced oxygenation.When in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the effect that reduces inflammation that comprises.The minimizing of inflammation can take place through the minimizing of the proinflammatory cytokine (for example interferon-, TNF-γ, IL-6 and IL-12) that discharged by immunomodulating T cell and/or the increase of anti-inflammatory cytokines (for example interleukin-4 and IL-10).The effect that reduces inflammation can cause a lot of clinical benefits, comprises that the improvement of blood flow produces enhanced oxygenation.

When in the health that is infused into mammalian subject again, come apoptosis-induced leukocyte not have blood or the effect of its blood derivatives of the usefulness ozonization of excessive necrosis can comprise the effect that reduces inflammation that comprises through this method.The minimizing of inflammation can take place through the minimizing of the proinflammatory cytokine (for example interferon-, TNF-γ, IL-6 and IL-12) that discharged by immunity regulatory cell and/or the increase of anti-inflammatory cytokines (for example interleukin-4 and IL-10).The effect that in the treatment of acute ischemic stroke, reduces inflammation can cause a lot of clinical benefits, comprises that the improvement of blood flow produces enhanced oxygenation.

Comprise the amount that the external ground warp of aliquot sample of mixture (comprising platelet) of cell component or the isolated cell of the blood that makes mammalian subject or separate blood is measured ozone in case its absorption can quantitative absorbed dose the method for the present invention of ozone can be used for treating by in wind-induced any patient's condition or be used for making the medicament of treatment by wind-induced any patient's condition, the said patient's condition comprises that paralysis, motion are unable, the survival rate of reentrying, break away from apoplexy, recurrence frequency and severity and total survival rate of vision and aural skill, cognitive function, independence.The therapeutical effect of this method also can influence by in the improvement of wind-induced any patient's condition; Comprise the survival rate of reentrying, break away from apoplexy, recurrence frequency and the severity of paralysis, unable, the vision of motion and aural skill, cognitive function, independence and the improvement of total survival rate, it can be through middle airflow meter appraisal tool assessment.

According to method as herein described, through method of the present invention mediation by in the improvement of wind-induced any patient's condition can be through middle airflow meter appraisal tool assessment, and clinical efficacy can be through measuring with the patient's who does not treat apoplexy statistical comparisons.

The other embodiment of method of the present invention can comprise the amount that the aliquot sample of mixture (comprising platelet) of cell component or the isolated cell of the blood that makes mammalian subject or separate blood stands to measure ozone in case absorption of fluids can quantitative absorbed dose ozone; And when blood, blood constituent or other biological fluid that will have ozone that can quantitative absorbed dose are introduced into patient's body again; Therapeutical effect and beneficial effect cause the improvement of the relevant patient's condition of inflammatory diseases, comprise the minimizing of inflammation, the diastole of blood vessel endothelium, the minimizing of edema and the blood flow of increase.

When being infused among the patient again from body ground, the therapeutical effect that has absorbed blood, blood constituent or other biological fluid of ozone that can quantitative absorbed dose can be to induce to draw the needed competent leukocyte apoptosis of anti-inflammatory response and do not have excessive necrosis.In the leukocyte composition of blood, blood constituent or other biological fluid handled according to method as herein described, induce the apoptosis that does not have excessive necrosis to assess through many diagnostic methods, said diagnostic method comprises that the optical microscopy, the electrophoretic analysis of dna break, the TUNEL that utilize nuclear stain analyze and the multiparameter flow cytometry.

When being infused among the patient again from body ground; The therapeutical effect that has absorbed blood, blood constituent or other biological fluid of ozone that can quantitative absorbed dose can cause the minimizing of CRP; And draw clinical benefit, comprise that anti-inflammatory response, new vessels form and vasodilation.When in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the effect that reduces edema.In addition, when in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the effect to ischemic tissue's increasing blood flow.

According to method of the present invention, effective promotion of the minimizing edema that causes among the inflammatory diseases patient can be assessed through multiple diagnostic tool, comprises CT, MRI and doppler imaging technology.In addition, be the other key element of this method through the effect that utilizes multiple diagnostic tool to assess (comprising MRI and doppler imaging technology) blood flow of the increase that causes by method described herein.

When in the health that is infused into mammalian subject again, the blood, blood constituent or other the fluidic effect that have absorbed ozone that can quantitative absorbed dose can comprise the effect that reduces inflammation that comprises.The minimizing of inflammation can take place through the minimizing of the proinflammatory cytokine (for example interferon-, TNF-γ, IL-6, IL-8 and IL-12) that discharged by immunomodulating T cell and/or the increase of anti-inflammatory cytokines (for example interleukin-4 and IL-10).The effect that reduces inflammation can cause a lot of clinical benefits, comprises that the improvement of blood flow produces enhanced oxygenation.

When in the health that is infused into mammalian subject again, come apoptosis-induced leukocyte not have blood or the effect of its blood derivatives of the usefulness ozonization of excessive necrosis can comprise the effect that reduces inflammation that comprises through this method.The minimizing of inflammation can take place through the minimizing of the proinflammatory cytokine (for example interferon-, TNF-γ, IL-6, IL-8 and IL-12) that discharged by immunity regulatory cell and/or the increase of anti-inflammatory cytokines (for example interleukin-4 and IL-10).The minimizing of inflammation can cause a lot of clinical benefits, comprises that the improvement of blood flow produces enhanced oxygenation.The diagnosis marker of measuring the minimizing of inflammation can comprise the minimizing, normalization, blood coagulation system measurement, inflammatory cytokine, C proteins C reactive (comprising hypersensitivity CRP) and the procalcitonin level of numeration of leukocyte (comprising differential blood count) of pain of minimizing, temperature and the report of ankylosis.Comprise the diastole of blood vessel endothelium by the other therapeutical effect of method mediation of the present invention.This diastole possibly be vasodilative result and relate to nitric oxide and the release of prostacyclin, or the inhibition of vasoconstrictor, thereby causes endothelial function (comprising the reparation or the replacement of endotheliocyte) to improve.Vasodilation possibly be useful clinically in the treatment inflammatory patient's condition, comprises that the improvement of blood flow produces enhanced oxygenation.Therefore; According to method of the present invention; The vasodilative amount of being drawn by the therapeutic treatment method or the assessment of degree can be measured through multiple diagnostic method, and said diagnostic method comprises vasodilation (FMVR) and the pulse conduction time (PTT) based on the stream mediation of ultrasonography.

Treat according to several different methods of the present invention and to suffer from or think the mammalian subject of suffering from the disease patient's condition; Introducing blood, blood constituent or other fluid handled again from body ground to mammalian subject can accomplish through number of ways, comprises intravenous, intramuscular and subcutaneous approach or its combination in any.

The ozone delivery system that in the treatment of acute ischemic apoplexy, cardiovascular disease, inflammatory diseases and the patient's condition thereof and symptom, utilizes is sent between the ozone of ozone/oxygen mixture and the ozone that can measure, control, report and send and absorbed dose of amount of measurement and is distinguished.System provides the ozone of controllable, measurable, the accurate and reproducible amount of the biological fluid that is delivered to controllable, measurable, accurate and reproducible amount; And control ozone is by the speed of absorption of fluids, produce use in the treatment of cardiovascular disease can quantitative absorbed dose ozone.System can accomplish this through manufacturing assembly, Control Component, measurement assembly, reporting component and the computation module (such as ozonator, gas flowmeter, fluid pump, variable spacing platform (variable pitch platform), data acquisition unit, inlet ozone concentration monitor and outlet ozone concentration monitor) that utilize cooperation to make; And the ozone of that one or more gas-fluid contacting apparatus will be measured through using, control, accurate and reproducible amount (promptly; The ozone of sending) be delivered to fluid, said gas-fluid contacting apparatus provides contact between ozone/oxygen mixture and fluid.Utilize cooperation Control Component, measure assembly, reporting component and computation module (such as gas flowmeter, fluid pump, variable spacing platform, data acquisition unit, inlet ozone concentration monitor and outlet ozone concentration monitor), the ozone sent and the ozone of absorbed dose can immediately be distinguished by system.

(gas flowmeter, fluid pump, variable spacing platform, data acquisition unit, inlet ozone concentration monitor and outlet ozone concentration monitor) Control Component of system's utilization cooperation, measure assembly, reporting component and computation module and report data immediately, said data can comprise ozone, time of contact, the elapsed time of the ozone of sending, remaining ozone, absorbed dose and be delivered to the fluidic amount and the flow velocity of gas contact device.

The specific suitable ozone delivery system that can be used for the method for embodiment of the present invention is disclosed in U.S. Patent number 7,736,494 with common pending application serial number 12/813,371 in, its content is incorporated into integral body at this.Disclosed ozone delivery system is made especially and uniquely, makes all ozone contact surfaces of device processed by the ozone inert material, so that can accurately be measured by the amount of the ozone of the biological fluid actual absorption of handling.That is,, do not have ozone to be absorbed, and accurately reacted result for the ozone that is absorbed by any structure of device by the mensuration of the amount of the ozone of biological fluid absorption by device itself because all ozone contact surfaces make up with the ozone inert material.

Measurement assembly, reporting component and the computation module that the utilization of ozone delivery system coacts (such as inlet ozone concentration monitor, outlet ozone concentration monitor, gas flowmeter, fluid pump, data acquisition unit) measured some calculating datas, and said calculating data comprises the ozone of the ozone of sending, remaining ozone and absorbed dose.

The ozone of sending be through as multiply by the amount of the ozone that calculates by the concentration along with the measurement of ozone in the ozone/oxygen mixture that gets into gas-fluid contacting apparatus of inlet ozone concentration monitor report by the volume of the measurement of the ozone/oxygen mixture of gas flowmeter report.The volume of the measurement of ozone/oxygen mixture multiply by the elapsed time through the gas stream by the measurement of gas flowmeter report and calculates.

Remaining ozone is the amount that multiply by the ozone that is calculated by the concentration of the measurement of ozone in the ozone/oxygen mixture of leaving gas-fluid contacting apparatus of outlet ozone concentration monitor report through the volume of the measurement of the ozone/oxygen mixture of being reported by gas flowmeter.The volume of the measurement of ozone/oxygen mixture is through being calculated by the gas stream disappearance-time of multiply by of the measurement of gas flowmeter report.

Ozone that can quantitative absorbed dose is the amount that the amount through the ozone of sending deducts the ozone that the amount of remaining ozone calculates.In the method for the present invention can quantitative absorbed dose the scope of ozone can be from every milliliter of fluid to 10 of 1 microgram, every milliliter of fluid of 000,000 microgram, and can be at every milliliter of fluid to 10 of 1 μ g, between every milliliter of fluid of 000 μ g.

All measurement data (comprising the measurement data from gas flowmeter, inlet ozone concentration monitor and outlet ozone concentration monitor, fluid pump, temperature sensor, pressure transducer, absorption oxygen sensor and humidity sensor) are reported in data acquisition unit.Data acquisition unit has the ability of instant, real-time report, calculating and data storage to handle all measurement data.Any combination that data acquisition unit can use any measurement data or measurement data as variable to produce calculating data.The instance of calculating data can comprise the ozone that ozone and the time per unit per unit fluid volume of ozone, the per unit fluid volume absorbed dose of the ozone of sending, remaining ozone, absorbed dose can quantitative absorbed dose.

Be particularly suitable for ozone delivery system of the present invention and comprise and be used to make and the ozonator of the ozone/oxygen mixture of the amount of control survey, and wherein volume of mixture contains the ozone of sending.Can use can produce in the ozone/oxygen mixture ozone concentration scope at 10ppmv to 3,000, the commercially available ozonator of the ozone between the 000ppmv.The ozone/oxygen mixture concentration that gets into gas-fluid contacting apparatus absorbs as the inlet ozone concentration monitor of detection side's science of law through UV capable of using immediately and consistently to be measured in real time.Effusion meter is with the particular mixtures flow speed control and measure ozone the sending to gas-fluid contacting apparatus of sending in the ozone/oxygen mixture.The ozone/oxygen mixture flow velocity is the scope between 0.1 Liter Per Minute and 5.0 Liter Per Minutes usually.

The measurement of humidity that is delivered to the ozone/oxygen mixture of gas-fluid contacting apparatus can comprise through using humidity sensor.The humidity sensor port can be provided in the ozone/oxygen mixture connection tube; Yet it can be positioned over a plurality of positions.For example, humidity sensor can be arranged in mixture entering gas-fluid contacting apparatus connection tube before.

The measurement of the temperature during time of contact in gas-fluid contacting apparatus can provide through in gas-fluid contacting apparatus, comprising temperature sensor port, and temperature sensor can be inserted through said port.The temperature range of ozone/oxygen mixture contacting with fluid is from 4 ℃ to 100 ℃, and can be in room temperature, for example carries out under 25 ℃.The temperature that contact takes place can be controlled in the temperature-controlled environment and/or through gas-fluid contacting apparatus being added heating element heater or cooling element is controlled through gas-fluid contacting apparatus, optional memorizer and gas and fluid connection tube are positioned over.

The measurement of the pressure during time of contact in gas-fluid contacting apparatus can provide through in gas-fluid contacting apparatus, comprising pressure sensor port, and pressure transducer can be inserted through said port.The scope of the pressure of ozone/oxygen mixture contacting with fluid, and for example can be carried out between ambient pressure and 3psi to 50psi from ambient pressure.Can in each gas-fluid contacting apparatus, provide pressure sensor port with the pressure of measuring and report comes in contact.

Leave the concentration (and wherein volume of mixture contains residual ozone) of the ozone/oxygen mixture of gas-fluid contacting apparatus and immediately and consistently measure in real time through outlet ozone concentration monitor, said outlet ozone concentration monitor UV capable of using absorbs as detection side's science of law.

Fluid pump is with specific rate of flow of fluid control and measure the flow rate of fluid that is delivered to gas-fluid contacting apparatus.The scope of the rate of flow of fluid through gas-fluid contacting apparatus usually will be from 1ml per minute to 100 Liter Per Minute, and for example, can be between 1ml per minute to 10 Liter Per Minute.Fluid is contained in the closed loop design usually and can passes through gas-fluid contacting apparatus circulation primary or repeatedly.

Though in gas-fluid contacting apparatus, contact with ozone/oxygen mixture, the measurement that absorbs the amount of the oxygen in the influent stream body can provide through using the absorption oxygen sensor.When leaving gas-fluid contacting apparatus, pick off inserts the absorption oxygen sensor port that is arranged in pipe.The measurement that absorbs oxygen can comprise ppm, mg/litre or percent saturation (percent saturation) with multiple unit record.

The ozone delivery system also can comprise and is used for the fluid access interface that fluid is removed.This port be usually located at the fluid issuing of fluid through gas-fluid contacting apparatus leave after and in the duct member before optional memorizer.

Data acquisition unit (such as DAQSTATION (Yokogawa)) for example immediately and is in real time reported, is stored and Monitoring Data, and carries out multiple calculating and statistics operation according to the data that obtain.Data are sent to data acquisition unit through data wire, and said data comprise the data from ozone concentration monitor, effusion meter, humidity sensor, temperature sensor, pressure transducer, fluid pump and absorption oxygen sensor.

The calculating data of the method for embodiment of the present invention comprises the ozone of sending, remaining ozone and ozone that can quantitative absorbed dose.The data that the measurement of the volume of the ozone/oxygen mixture of sending can provide through the data acquisition unit by effusion meter and free measurement capability are calculated.The measurement that is delivered to the fluidic volume of gas-fluid contacting apparatus can be calculated through the data acquisition unit of utilization from the rate of flow of fluid data of fluid pump transmission.

Elapsed time can measure and control through data acquisition unit.Fluid can change through equipment (comprising gas-fluid contacting apparatus) circulation and elapsed time of contact with ozone/oxygen mixture, continued height to persistent period of 120 hours usually.Also can measure through the data acquisition unit of free measurement capability time of contact.Can control the time of contact between fluid and the ozone/oxygen mixture through compound control item.These control items comprise the data acquisition unit of the angle of gaseous fluid contact device, the rate of flow of fluid through fluid pump and free control ability.Can change in the persistent period of height to 720 minute time of contact, and usually in the persistent period of height to 120 minute.

The controlled variable of ozone delivery system can comprise the amount of sending and concentration, rate of flow of fluid, the mixture velocity of ozone in the ozone/oxygen mixture of entering, the time of contact between temperature, fluid and the mixture in gas-fluid contacting apparatus, with fluid can be through equipment circulation and the elapsed time that contacts with ozone/oxygen mixture.

Measurable variable can comprise the ozone/oxygen mixture flow velocity; Getting into ozone/oxygen mixture and amount and the concentration of leaving ozone in the ozone/oxygen mixture; Rate of flow of fluid in gas-contact device, temperature and pressure; To the humidity of the entering mixture of gas-fluid contacting apparatus, by the oxygen of absorption of fluids, time of contact and elapsed time.

The expression controlled variable that is obtained by equipment and the data of measurable variable provide multiple calculating, comprise the ozone that ozone that the ozone of sending, remaining ozone, ozone, per unit fluid volume that can quantitative absorbed dose can quantitative absorbed dose and time per unit per unit fluid volume can quantitative absorbed dose.

Fig. 1 has schematically explained embodiment of the present invention, and the fluid of wherein having obtained from the curee contacts with ozone/oxygen mixture externally.Usually, blood can discontinuous mode circulate, and wherein fluid (for example, the aliquot sample of blood) has shifted out from the patient and introduced in the ozone delivery system through conventional memorizer, and with closed loop form recirculation.Selectively, fluid can circulate with successive loop form by veno-venous external exchanging form.As an instance, this successive loop can pass through the venous channel of the antecubital vein of right arm and left arm and set up.Before setting up discontinuous closed loop form, from blood available citrate or any other suitable anticoagulant anticoagulant before being introduced into memorizer of patient.For external successive loop loop, the patient can be randomly with heparin or any other suitable anticoagulant anticoagulant well known by persons skilled in the art.

Flow for gas; In discontinuous form or successive cyclic system; Oxygen flows out from pressurized gas cylinder (1-1), through actuator (1-2), through particle filter (1-3) to remove microgranule; Through effusion meter (1-4), oxygen and ozone/oxygen mixture flow velocity are subsequently controlled and are measured in effusion meter.Oxygen moves ahead through pressure relief valve (1-5), through ozonator (1-6), produce and control the concentration of ozone/oxygen mixture therein, and wherein volume of mixture comprises the ozone of sending.Ozone/oxygen mixture flows through optional moisture eliminator (moisture trap) (1-7), to reduce moisture.

Mixture moves ahead through inlet ozone concentration monitor (1-8), and the inlet ozone concentration of the ozone/oxygen mixture that contains the ozone of sending is measured and reported to said inlet ozone concentration monitor.This real-time measurement can absorb characteristic as detection side's science of law based on the UV of ozone.The one group valve (1-9) of ozone/oxygen mixture through being used for separation gas-fluid contacting apparatus is with purge gas then.Ozone/oxygen mixture can be through optional humidity sensor (1-20) (can measure and write down humidity therein), and gas-fluid contacting apparatus (1-10), and ozone/oxygen mixture contacts with fluid therein.Time of contact between fluid and the ozone/oxygen mixture can be through variable spacing platform, fluid pump and free control ability the adjusting of data acquisition unit control.

Can measure through data acquisition unit (1-17) time of contact then.Temperature (1-21) and pressure (1-22) can through use to insert respectively its separately the optional temperature and pressure pick off of port measure.The ozone/oxygen mixture that contains residual ozone that produces is left gas-fluid contacting apparatus and is flowed through outlet blow down valve (1-11); Through moisture eliminator (1-7); Through measuring and the outlet ozone concentration monitor (1-12) of report outlet ozone/oxygen mixture concentration, said outlet ozone concentration monitor capable of using with the similar detection side's science of law of ozone concentration monitor (1-8) that enters the mouth.The ozone/oxygen mixture of leaving then moves ahead through gas dryer (1-13), through ozone decomposer (ozone destructor) (1-14) and effusion meter (1-19).

In the fluid stream of discontinuous form, blood is introduced in the memorizer (1-30).In successive cyclic system, venous blood flows through piezometer (1-27) from the patient through pipe, and said piezometer is kept watch on the pressure of the blood flow that leaves the patient.Normally, the scope of pressure of blood of leaving the patient and can have the maximum cutoff pressure of negative 250mm Hg between the negative pressure of 150-200mm Hg between the negative pressure of 100-200mm Hg.In any one form, blood flow is also randomly mixed with the heparin or other the suitable anticoagulant that are provided by optional heparin pump (1-16) through fluid pump (1-15).

Blood is through gas-fluid contacting apparatus (1-10) then, and blood contact therein contains the ozone/oxygen mixture of the ozone of sending.The port that is used for inserting pick off can lay respectively at the gas-fluid contacting apparatus that is used to measure temperature and pressure.After ozone/oxygen mixture contacted, fluid left and gets in the pipe, and the port that said pipe can contain optional absorption oxygen sensor (1-23) is followed by fluid passage port (1-24).Blood continues the air/embolus trap (1-25) through removing any bubble or embolus, and blood continues through fluid pump (1-26) then.

In discontinuous form, blood is directly return in the memorizer (1-30) then, and any can continuation with recirculation mode passes through when needing.In successive loop form, blood directly gets in the piezometer (1-28) of the pressure of keeping watch on blood flow before fluid being returned the patient.Normally, the scope of the pressure of entering patient's blood is the pressure from 100-200mm Hg, and can between 150-200mmHg, have the maximum cutoff pressure of 250mm Hg.Blood continues through preliminary filling fluid (priming fluid) entry port (1-29), and it allows the preliminary filling fluid from external ring, to remove.Blood directly is infused among the patient more then.

Data acquisition unit (1-17) (such as DAQSTATION (Yokogawa)) for example has the measure of time ability, immediately and in real time reports, stores and monitoring data, and carry out multiple calculating and statistics operation according to the data that obtain.All data are sent to data acquisition unit through data wire (1-18); Comprise: from ozone concentration monitor (1-8) and (1-12), effusion meter (1-4) and (1-19), humidity sensor (1-20), temperature sensor (1-21), pressure transducer (1-22), fluid pump (1-15) and (1-26), piezometer (1-27) and (1-28) and absorb the data of oxygen sensor (1-23).Can measure and control the elapsed time through data acquisition unit (1-17), the said elapsed time is time compound of time of contact and fluid other element of cycling through equipment.Other the possible structure that is used for extracorporeal blood is included within the spirit of present disclosure.

In the ozone delivery system, can comprise one or more gas-fluid contacting apparatus to increase pending fluidic surface area, make the mass transfer efficiency of ozone/oxygen mixture increase.Gas-fluid contacting apparatus can comprise following character: close and isolate with ambient air; Be used for gas access and outlet port that ozone/oxygen mixture gets into and leaves; Be used for fluid intake and outlet port that fluid gets into and leaves; Be used for measuring and reporting the assembly (temperature sensor, pressure transducer and data acquisition unit) of the temperature and pressure of gas-fluid contacting apparatus; Along with fluid flow to produce fluidic thin film and from the structure of ozone inertia building material, said ozone inertia building material comprises quartz, ceramic composite, borosilicate, rustless steel, PFA and PTFE in gas-fluid contacting apparatus.

Gas-fluid contacting apparatus comprises that containing can be horizontal direction or near the design on the surface of horizontal direction.Any other design that these surfaces can comprise ridge surface, serrated surface, contoured surface, etching surface or cause profile to change, and in addition can comprise and can destroy mobile, dispersion flows or cause turbulent regular or irregular any pattern.These surfaces can be contained or can not contain the hole that fluid passes through.The surface of structural detail can have identical or different spacings.The design of gas-fluid contacting apparatus can comprise with the mode of any combination assembles to be contained in those designs of any combination that relates to one or more identical shaped surfaces or different surfaces in the device, and said surface can comprise circular cone, bar, pipe, plane surface and half-plane surface, disk and spheroid.

Contact between ozone/oxygen mixture and the fluid can realize that device produces said gas-fluid contacting apparatus and the thin film of ozone-oxygen mixture fluid in contact along with fluid flows through through using gases-fluid contacting apparatus.Thereby it should be appreciated by those skilled in the art that to utilize to produce and increase any contact that the contact between fluid and the mixture was amassed and maximized to flow surface.Other instance comprises through atomizing or spraying generation aerosol.

Be measurable, controllable, computable and reportable time of contact in gas-fluid contacting apparatus.In addition, can be to continue the high persistent period to 720 minutes time of contact, yet, the normally high persistent period to 120 minutes.After time of contact, the fluid that contains ozone that can quantitative absorbed dose leaves gas-fluid contacting apparatus.Elapsed time also is measurable, controllable, computable and reportable, and the said elapsed time is time compound of time of contact and fluid other element of cycling through the ozone delivery system.This elapsed time is to continue the high persistent period to 120 hours.

But the pressure that contacts between fluid and the ozone/oxygen mixture in measurement gas-fluid contacting apparatus.The measurement of pressure can be accomplished through using the pressure transducer that inserts at the pressure port place of gas-fluid contacting apparatus in the device.The pressure that ozone/oxygen mixture contacts with fluid also can be at ambient pressure to carrying out between the 3psi from ambient pressure variations to 50psi.

Temperature in gas-fluid contacting apparatus can be controlled so that contain gas and fluidic connection tube and optional memory maintenance in controlled temperature environment through covering this device.It is the instance of controlled temperature environment that thermoregulator stream cover (flow hood) is provided.Selectively, to gas-fluid contacting apparatus interpolation heating element heater or cooling element temperature controlling can be provided.The measurement of temperature can be accomplished through using the temperature sensor of inserting in the temperature port of gas-fluid contacting apparatus in the device.The scope of the temperature of ozone/oxygen mixture contacting with fluid is from 4 ℃ to 100 ℃, and (for example, 25 ℃) carry out at ambient temperature.

Gas-fluid contacting apparatus can be united use individually or with other such device, and no matter they are similar or dissimilar on structure, design or direction.Under the situation of using multiple arrangement (or identical design, or the combination of the different gas-fluid contacting apparatus of different designs), these devices can be arranged by adjoining land (continuously) one by one, process a device by a plurality of independently contact devices.

In the configuration of a series of devices, the fluid adjoining land that flows through different contact devices flow to Next fluid intake port from the fluid issuing port of a contact device, up to through all devices.Ozone/oxygen mixture can flow with many arrangements.In an example, the ozone/oxygen mixture adjoining land flows through different contact devices, from mixture outlet port to the Next mixture inlet port of a contact device.As selectable instance, ozone/oxygen mixture can directly flow to the ingress port of each different contact device from mix source.Another selection is the combination of the instance of front, and wherein ozone/oxygen mixture flows to the ingress port of other device from the outlet port of some devices, and in addition, directly flows to the inlet of some devices from mix source.Under the situation of using multiple arrangement, the fluid that produces from final device can be collected or be back to initial device and recirculation.

When arranging continuously with other contact device, be controllable time of contact between fluid and the ozone/oxygen mixture, and can be based upon the independent spacing adjusting that successive each device is selected, or regulate through in series, adding other device.For independent device, whole contact surfaces is long-pending will be from 0.01m ²Change, and rise based on the quantity of the device of continuous use.

Embodiment 1

Utilize fluid target as herein described to be included in the table 1 through the embodiment of the data of measurement of ozone delivery system and calculating.Utilize commercially available NBCS as the target fluid.Use like U.S. Patent number 7,736, disclosed variable spacing device with variable spacing platform is as gas-fluid contacting apparatus in 494.Utilize following initial condition: 300ppmv ozone entrance concentration, 145ml initial fluid volume, 1000ml per minute gas flow rate, with the 189ml per minute rate of flow of fluid of ozone/oxygen mixture stream adverse current.The minimizing of the fluid volume that increases is because fluid is sampled through the fluid entry port.

Table 1

Embodiment 2

Additional embodiments through systematic survey as herein described and the data calculated is in following table 2.Utilize commercially available NBCS as the target fluid.Use like U.S. Patent number 7,736, disclosed variable spacing device with variable spacing platform is as gas-fluid contacting apparatus in 494.Utilize following initial condition: 600ppmv ozone entrance concentration, 137ml initial fluid volume, 1000ml per minute gas flow rate, with the 189ml per minute rate of flow of fluid of ozone/oxygen mixture stream adverse current.The minimizing of the fluid volume that increases is because fluid is sampled through the fluid entry port.

Table 2

Embodiment 3

Another embodiment through systematic survey as herein described and the data calculated is in following table 3.Utilize commercially available NBCS as the target fluid.Use like U.S. Patent number 7,736, disclosed variable spacing device is as gas-fluid contacting apparatus in 494.Utilize following initial condition: 900ppmv ozone entrance concentration, 145ml initial fluid volume, 1000ml per minute gas flow rate, with the 189ml per minute rate of flow of fluid of ozone/oxygen mixture stream adverse current.The minimizing of the fluid volume that increases is because fluid is sampled through the fluid entry port.

Table 3

In one embodiment of the invention, the patient's condition of cardiovascular disease, inflammatory diseases, acute ischemic apoplexy and said disease association in the treatment mammal or the method for symptom are provided.As previously mentioned, method relates to and makes a certain amount of blood, blood constituent or other biological fluid stand a certain amount of ozone of being sent by the ozone delivery system externally.Method also can provide fluidic biology of keeping processing integrity.Method provides the treatment conditions with the temperature that integrity the matches biology of keeping biological fluid.

For blood products, blood plasma biology integrity can through in whole blood plasma or the functional of plasma proteins component that separates into after the plasma fraction measure.Erythrocyte and platelet product biology integrity can known by one of skill in the art method and standard measure, and be used to set up storage and handle rules adaptive that those are similar.In practice, integrity biology of biological fluid is meant that the fluid after the method for the treatment disease as herein described or the patient's condition kept its function fully when being infused in the mammalian subject again.

Contain at pending biological fluid under the situation of platelet (being whole blood, platelet concentrate), fluid contact surfaces (comprising the gas-fluid contacting apparatus by ozone inert material structure) can use human serum albumin (HSA) solution-treated to stop platelet adhesion, gathering and other relevant platelet phenomenon.Normally, can use the HSA solution of scope between the 1%-10%.The HSA solution that in biocompatible bacteriostatic buffer solution, prepares will be through gas-fluid contacting apparatus.Through after, HSA solution will be discharged from device.Therefore gas-fluid contacting apparatus and all surface that in said procedure, contacts with biological fluid are ready for and contain hematoblastic biological fluid.

This method provides with ozonization blood, blood constituent or other fluid that can quantitative absorbed dose to produce the fluid of handling, and said treatment is useful through blood from processing to the patient, blood constituent or other fluid of using in the mammiferous multiple disease as herein described of therapeutic treatment, the patient's condition or symptom then.Therefore; Fluid according to method manufacturing as herein described provides material or compositions; Said material or compositions characteristic can be the medicaments that is used to treat the disease patient's condition as herein described, or can be used for making the therapeutic medicament that is used to treat disease as herein described, the patient's condition and/or symptom.

In one or more embodiments of the present invention, make the amount that the external ground warp of aliquot sample of mixture (comprising platelet) of cell component or isolated cell of blood or the separate blood of mammalian subject measured ozone in case its absorption can quantitative absorbed dose ozone.When this aliquot sample from body is introduced into patient's body again, utilize with blood, blood constituent or other fluid of ozonization that can quantitative absorbed dose in treatment disease as herein described, to promote and to produce beneficial effect.Can introduce the part from body of this processing through number of ways again, said approach comprises intravenous, intramuscular and subcutaneous, or its any combination.

In another embodiment of the invention, method relates to and when being infused among the patient again from body ground, causes and draw the needed competent leukocyte apoptosis of clinical benefit.When being infused among the patient again from body ground, method also can cause draws the needed competent leukocyte apoptosis of clinical benefit and does not have excessive necrosis.

In some embodiments of the present invention, patient's self-blood or other body fluid provides therapeutic treatment from the infusion again of body through the minimizing that causes the CRP that is enough to draw clinical benefit.

Method of the present invention can comprise the device that connects the curee and be used to take out blood; Take out the blood that contains hemocyte from the curee; From blood, separate the acellular composition, and keep blood constituent biology integrity condition under the ozone of the amount that will measure be delivered to composition.The composition of handling combines with hemocyte subsequently again and is infused among the curee.

In another embodiment of the invention; When being infused among the patient again from body ground; Through the minimizing (for example interferon-, TNF-γ, IL-6, IL-8 and IL-12) of the proinflammatory cytokine that discharged by immunomodulating T cell and/or the increase (for example interleukin-4 and IL-10) of anti-inflammatory cytokines, the therapeutic treatment of cardiovascular disease and the vascular disorder (such as vasospasm disease) relevant with defective endothelial function can be drawn the minimizing of inflammation.

According to method as herein described be derived from the blood, blood constituent or other the fluidic processing that absorb ozone that can quantitative absorbed dose and again the therapeutical effect of infusion comprise that the leukocyte (being cell-cell interaction or release of cytokines) through stimulating the whole peripheral blood of patient changes lipid metabolism and enhance immunity system, thereby cause atheromatous plaque formation and sedimentary minimizing.These effects can cause reversing carrying out property lumen of artery narrow, reduce breaking or stripping off of speckle, reduce the incidence rate of atheroembolism (cholesterol thromboembolism), and improve blood flow and produce enhanced oxygenation.

About relating to atheromatous plaque formation, deposition and disruptive disease; This method provides the therapeutic treatment and the prevention of a lot of such mammal diseases, and said mammal disease comprises cardiovascular disease (such as atherosclerosis, PAOD), cerebrovascular disease (apoplexy and transient ischemic attack), myocardial infarction, angina pectoris, hypertension, retinal ischemia, renal failure, abdominal aortic aneurysm and hyperlipidemia.

In addition, according to the therapeutic treatment that method as herein described is handled and the infusion biological fluid provides cardiovascular disease again, said cardiovascular disease comprises the vascular disorder relevant with defective endothelial function, such as the vasospasm disease.This method provides the active treatment to the functional defect endothelium to stimulate.

As described herein, other useful effect that can come from method of the present invention comprises the minimizing of edema, and it can not have excessive necrosis to produce through inducing the leukocyte apoptosis.Other benefit comprises that the minimizing of CRP is to draw anti-inflammatory response and to promote the blood flow to ischemic tissue.The effectiveness to the blood flow of ischemic tissue by Therapeutic Method of the present invention produces can be assessed through multiple diagnostic tool (comprising that MRI, CT Perfusion Imaging and doppler imaging are technological).

According to the therapeutic treatment of the biological fluid of method as herein described and again infusion also relate to leukocyte (being cell-cell interaction or release of cytokines) enhance immunity system through the whole peripheral blood that stimulates the patient, cause the improvement and the enhanced oxygenation of the blood flow that improves, vasodilative increase (promptly promote vasodilation or suppress vasoconstrictor), endothelial function (comprising endotheliocyte reparation or replacement).This method provides the therapeutic treatment and the prevention of a lot of such mammal diseases, and said mammal disease comprises cardiovascular disease (such as atherosclerosis, PAOD, congestive heart failure), cerebrovascular disease (apoplexy), myocardial infarction, angina pectoris, hypertension, vasospasm disease such as Raynaud disease, heart X syndrome and migraine.

Method of the present invention can comprise through discontinuous mobile method handles blood or other biological fluid from mammalian subject; Wherein utilize the device be suitable for taking out blood from the patient, to take out blood; From blood, separate the acellular composition and keep blood constituent biology integrity condition under the ozone of the amount that will measure be delivered to composition, combine hemocyte and blood again and the blood of processing be infused among the patient again.In processing method of the present invention related to aspect those of discontinuous method, according to patient's size and blood volume, the scope of the volume of the blood that shifts out can be from 1ml to 5000ml.In single processing procedure, this discontinuous processing method can be carried out once or be repeatedly successive.

Method of the present invention also comprises and from the curee, directly shifts out blood and in successive loop structure, it is infused to same curee or patient again.Blood can pass through this looped cycle one or many, and said loop comprises gas-fluid contacting apparatus, wherein keep blood biology integrity condition under the ozone of the amount that will measure be delivered to blood.The blood of handling is constantly directly returned among the same patient by infusion again.

Method of the present invention the therapeutic treatment that blood and biological fluid are provided with the cholesterol, triglyceride and other lipid that reduce mammalian subject on still effectively.Such method comprises and from the curee, directly shifts out blood and in successive loop structure, it is infused to same patient again.

In processing method of the present invention related to aspect those of successive loop method, the blood volume of processing can be between the global cycle blood volume of the estimation of 10ml and treatment mammalian subject repeatedly.Normally, the scope of the blood volume of processing will between the 000ml, and preferably at 10ml to 6, change between the 000ml at 10ml to 10.

Through required time of the independent processing of using successive loop form based on many factors; Comprise the fluidic volume, fluid circulation flow velocity of needed number, processing through loop, the amount of needed time of contact and needed ozone that can quantitative absorbed dose between the amount of fluid and the ozone sent.The scope of the time of handling can be from 1 minute to 720 minutes and preferably from 1 minute to 180 minutes.

Number and the frequency handled can change according to specific patient's clinical manifestation considerably.The number of normally handling changes between can and handling for 200 times in individual processing, based on the clinical effectiveness of patient's clinical assessment and hope with every day, the next day or other scheme provide.When the many treatments of completion and after, can indicate another therapeutic process by health care doctor assessment.

The selectable application of this method relates to plasmapheresis, and wherein patient's blood plasma is optionally shifted out, and the balance of hemocyte promptly is back to the patient.Can keep blood plasma biology integrity condition under the ozone of the amount that will measure be delivered to isolating blood plasma.The blood plasma of handling is infused among the curee subsequently again.

Method of the present invention is described the treatment of the patient's condition that is used to follow cardiovascular disease, inflammatory diseases, acute ischemic apoplexy and related conditions and symptom; Comprise the method for using the ozone delivery apparatus; Said ozone delivery apparatus is configured to wherein all the ozone contact surfaces and processes or construct guaranteeing accurately to measure the amount of the fluidic ozone that is delivered to processing by the ozone inert material, and guarantees accurately to measure the amount by the ozone of absorption of fluids.Ozone delivery configuration and relevant method with ozonization blood and other biological fluid, and as those fluidic purposes that are used for therapeutic treatment disclosed herein can change so that it is adapted to certain applications according to described.Therefore, be that to be used as instance be not to be used as restriction with reference to the method for specific structure and use.

Claims (21)

1. a generation is used to treat the method that the acute ischemic apoplexy reaches the therapeutic substance of the relevant symptom or the patient's condition, comprising:

Biological fluid is provided;

The ozone of the amount of measuring is delivered to said biological fluid has ozone that can quantitative absorbed dose with generation therapeutic substance; Said therapeutic substance with ozone that can quantitative absorbed dose is when to suffering from or the curee of the acute ischemic apoplexy of being thought suffering from when using, effectively treatment symptom and the patient's condition relevant with the acute ischemic apoplexy.

2. a generation is used to treat the method for the therapeutic substance of cardiovascular disease and the relevant symptom or the patient's condition, comprising:

Biological fluid is provided;

The ozone of the amount of measuring is delivered to said biological fluid has ozone that can quantitative absorbed dose with generation therapeutic substance; Said therapeutic substance with ozone that can quantitative absorbed dose is when to suffering from or the curee of the cardiovascular disease of being thought suffering from when using, effectively treatment symptom and the patient's condition relevant with said cardiovascular disease.

3. a generation is used to treat the method that inflammatory diseases reaches the therapeutic substance of the relevant symptom or the patient's condition, comprising:

Biological fluid is provided;

The ozone of the amount of measuring is delivered to said biological fluid has ozone that can quantitative absorbed dose with generation therapeutic substance; Said therapeutic substance with ozone that can quantitative absorbed dose is when to suffering from or the curee of the inflammatory diseases of being thought suffering from when using, effectively treatment symptom and the patient's condition relevant with said inflammatory diseases.

4. according to claim 1,2 or 3 described methods, wherein said biological fluid is blood, blood derivatives or blood constituent.

5. according to claim 1,2 or 3 described methods, wherein said blood derivatives is a blood plasma.

6. according to claim 1,2 or 3 described methods, wherein said blood constituent comprises platelet.

7. according to claim 1,2 or 3 described methods, wherein said biological fluid takes out from mammalian subject.

8. according to claim 1,2 or 3 described methods, wherein said therapeutic substance with ozone that can quantitative absorbed dose is suitable for introducing from body to the donor curee again.

9. according to claim 1,2 or 3 described methods, the said therapeutic substance of preparation under the condition that keeps said fluidic biology of integrity wherein.

10. be used to prepare the purposes of therapeutic medicament according to the therapeutic substance of each manufacturing in the aforementioned claim, said therapeutic medicament can be applied to suffer from the acute ischemic apoplexy of being thought suffering from, cardiovascular disease, inflammatory diseases or with those diseases in any relevant related conditions or the mammalian subject of symptom.

11. one kind is used to treat acute ischemic apoplexy and the relevant symptom or the medicament of the patient's condition; Said medicament comprises the biological fluid that contains ozone that can quantitative absorbed dose; With to suffering from or the curee of be thought suffering from acute ischemic apoplexy and the relevant symptom or the patient's condition when using said medicament, effective therapeutical effect is provided to this curee.

12. one kind is used to treat acute ischemic apoplexy and the relevant symptom or the medicament of the patient's condition; Said medicament comprises the biological fluid that contains ozone that can quantitative absorbed dose; With to suffering from or the curee of be thought suffering from acute ischemic apoplexy and the relevant symptom or the patient's condition when using said medicament, effective therapeutical effect is provided to this curee.

13. one kind is used to treat inflammatory diseases and the relevant symptom or the medicament of the patient's condition; Said medicament comprises the biological fluid that contains ozone that can quantitative absorbed dose; With to suffering from or the curee of be thought suffering from inflammatory diseases and the relevant symptom or the patient's condition when using said medicament, effective therapeutical effect is provided to this curee.

14. according to claim 11,12 or 13 described medicaments, wherein said biological fluid is blood, blood derivatives or blood constituent.

15. according to claim 11,12 or 13 described medicaments, wherein said blood constituent is made up of platelet.

16. according to claim 11,12 or 13 described medicaments, wherein said blood derivatives is a blood plasma.

17. according to claim 11,12 or 13 described medicaments, wherein said biological fluid, blood, blood derivatives or blood constituent obtain from mammalian subject.

18. medicament according to claim 17, the wherein said fluid that contains ozone that can quantitative absorbed dose is made under the condition of keeping said fluidic biology of integrity.

19. medicament according to claim 18; The wherein said minimizing that contains the fluid of ozone that can quantitative absorbed dose in the treatment edema relevant with ischemic penumbra; Improvement to the impaired blood flow in the infraction that can comprise ischemic tissue and ischemic penumbra zone on every side; The diastole of blood vessel endothelium, it is effective following in the minimizing of inflammation, paralysis, dysopia and hearing defect and cognitive function of acute ischemic apoplexy.

20. medicament according to claim 18; The wherein said fluid that contains ozone that can quantitative absorbed dose is effective in the treatment patient's condition relevant with cardiovascular disease or symptom, and the patient's condition that said treatment is relevant with cardiovascular disease or symptom comprise the minimizing of atheromatous plaque, the disappearing of atheromatous plaque formation; The minimizing of ischemic penumbra; The diastole of blood vessel endothelium, the minimizing of inflammation, the minimizing of lipid and lipid deposits; Atherosclerosis, PAOD, congestive heart failure, hypertension, cerebrovascular disease, dyslipidemia and comprise the minimizing or the improvement of the vasospasm disease of Raynaud disease; The minimizing of cholesterol, triglyceride and other lipid, the minimizing of the frequency of the outbreak of intermittent claudication, severity and persistent period, the minimizing of numb limbs and tense tendons, unable and LOM; Limbs are pale, the improvement of temperature and pulse, the minimizing of elevated blood pressure; With lose weight.

21. medicament according to claim 18; The wherein said fluid that contains ozone that can quantitative absorbed dose is effective in the treatment patient's condition relevant with inflammatory diseases or symptom; Said inflammatory diseases comprises rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), scleroderma, diabetes, inflammatory bowel, psoriasis, pemphigus, atherosclerosis, chronic heart failure, comprises graft versus host disease, Alzheimer, ischemia apoplexy, alzheimer disease, depression, mongolism, Huntington Chorea, peripheral neuropathy, myelopathy, neuroarthropathy, chronic inflammatory demyelinating disease (CIPD) and neuropathy that tissue transplantation repels that said neuropathy comprises mononeuropathy, polyneuropathy, far-end symmetry sensory nerve pathological changes, cystic fibrosis, neuromuscular junction disease, myasthenia, parkinson disease, traumatic brain injury, spinal cord injury and soft tissue injury.