CN1370277A - Method of diagnosis - Google Patents
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- CN1370277A CN1370277A CN 00811583 CN00811583A CN1370277A CN 1370277 A CN1370277 A CN 1370277A CN 00811583 CN00811583 CN 00811583 CN 00811583 A CN00811583 A CN 00811583A CN 1370277 A CN1370277 A CN 1370277A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/32—Cardiovascular disorders
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
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Abstract
The present invention relates to a method for diagnosing or detecting a predisposition to cardiac hypertrophy comprising assaying a sample of human bodily fluid in vitro for the level of cardiotrophin-1 (CT-1) contained therein and uses thereof.
Description
Technical field
The present invention relates to a kind of method, it comprises and is used for diagnosis or detects myocardial hypertrophy susceptible person (predisposition) and the progress of monitoring myocardial hypertrophy and the kit of curative effect and described method.
Background technology
Myocardial hypertrophy is heart maybe need increase a heart blood supply or an important compensatory when resistance of blood flow increases to infringement reaction.Through after the long-term hypertension, heart is by the reaction of the common gene reinvocation (reactivation of gene) that shows in the heart of fetus growth course, and producing the loose of cardiac muscle cell and accumulating with parapeptone (sarcomeric protein) under the fissional situation of shortage is the myocardial hypertrophy of feature.
Hypertension, or systemic hypertension just are familiar with by people as a main morbidity and dead reason a long time ago in animal and human's class.It is that non-fatal and fatal illness with in the relative broad range is relevant that human long-term systematic Arterial Hypertention has been illustrated, after one's own heart obstructs (heart acute disease), cerebrovas-cularaccident (headstroke), heart failure and renal failure (kidney damage) (Perea, G, 1955, J.Chronic Dis.1:33-42).The incidence of disease that the hypertension that does not obtain medical treatment can increase cardiovascular and cerebrovascular is very clearly (MacMahon, S. etc., 1990, Lancet 335:765-74) for many years.Nearest two more than ten years have shown the Research on kinds of the medicine that can bring high blood pressure down and have reduced headstroke and cardiopathic M ﹠ M.
Some EPDML investigation, as Framingham Study (Levy, D. etc., 1990, N.Eng.J.Medicine 322:1561-6 and Kannel, W.B.1991, J.Hypertension 9 (2): 53.9) show, the existence of the myocardial hypertrophy that is caused by persistent hypertension is bad relevant with prognosis, and more at present research emphasizes that the left ventricular hypertrophy prognosis is bad.Below table 1 summed up some known facts that can cause heart stalk and dangerous distribution the thereof.
The level of significance of table 1 angiocardiopathy
| Age is revised the level of significance men and women |
| 4.7 7.4 smokings 1.7 1.2 of high cholesterol 1.7 1.4 hypertension 2.2 2.5 diabetes 2.2 3.7 left ventricular hypertrophies |
Kannel, W.B.1991 is the same
Be not that each hyperpietic the cardiovascular and cerebrovascular problem can take place.To treatment and expense ratio light, the moderate hypertension patient without any other hazards is a problem.Can be contemplated that really that Britain treatment guide (British Treatment Guideline) will be revised, thereby have only those with light, the moderate essential hypertension of other hazards or exist the patient of obvious organ injury just to receive treatment.
People recognize one or more other hazards now, can determine the hyperpietic that should treat as the existence of left ventricular hypertrophy.Finally therapeutic purposes are to reduce the M ﹠ M relevant with high blood pressure, and this can obtain by the mode that reduces some hazards pointedly.Thereby the importance of smoking cessation is controlled life style (intervention regime) as part and is obtained bigger attention, and the fact has proved that smoking is the second largest hazards of high blood pressure (hazard ratio).Moreover last decade has been seen the development of the efficient and overriding resistance agent that can lower cholesterolemia, and the prevention of main and auxiliary (the primary and secondary) of miocardial infarction be studies show that reducing serum cholesterol has important meaning in treatment.This is divided by the another kind treatment measure beyond the antihypertensive control elevation of blood pressure.
According to Kannel, W.B.1991 (the same) report, having left ventricular hypertrophy (LVH) is the most dangerous factor.Therefore, need carry out the development of regular follow-up to all mild hypertension patients with prediction and assessment left ventricular hypertrophy, thus determine treatment need be to avoid the generation of cardiovascular and cerebrovascular problem.
The other diseases relevant with myocardial hypertrophy comprises a series of heart and lung diseases as pulmonary hypertension, vesica fiberization and chronic obstructive airway disease or the like, and these diseases can cause atrium dextrum and right ventricle plumpness.When right ventricle was plump, most of patient's of above-mentioned pulmonary hypertension, vesica fiberization and chronic obstructive airway disease M ﹠ M also significantly raise thereupon.Therefore, people expect to monitor the development of right ventricle plumpness so that can assess the appropriateness of its condition that is easy to produce of control.
The method of current available detection myocardial hypertrophy comprises uses cardiogram and iconography technology such as echocardiogram (echocardiography), nuclear magnetic resonance scanning etc.These technology have its corresponding shortcoming, and cardiogram just can find when serious myocardial hypertrophy, and the relatively more expensive generaI investigation health check-up that is unsuitable for immediately all hypertensive patients of echocardiogram and nuclear magnetic resonance.
Studies show that (JAMA 1979, and 242:2562-71) cardiogram only confirms that the patient about 3-8% suffers from myocardial hypertrophy when diagnosis hypertension, and this technology can not provide effective diagnosis like this.And when diagnosis hypertension, echocardiogram and nuclear magnetic resonance scanning demonstrate the left ventricular hypertrophy incidence and account for not specially about the hypertensive patient's of selection 20-60% (Savage, D.D. etc., 1979, Circulation 59:623-32).
Yet in most of the cases, these iconography technical fees are expensive and need patient to go to hospital, and most of hypertensive patient obtains medical treatment in community.The shortcoming of another iconography technology is only can differentiate established plumpness and the plump change that whether causing that can not differentiate patient.
Summary of the invention
The purpose of this invention is to provide a kind of method, differentiate those with the patient of myocardial hypertrophy with might develop into the patient of myocardial hypertrophy, and can make these patients obtain early stage treatment.
A kind of method that first aspect of the present invention provides, this method are used for diagnosis and detect the myocardial hypertrophy susceptible person, and it is included in the level of the CARDIOTROPHIN-1 (cardiotrophin-1) that contains in the human humoral sample of external test.
The present invention is the discovery according to the inventor, raises than the level that does not have CARDIOTROPHIN-1 in the myocardial hypertrophy blood samples of patients sample the patient who utilizes traditional method as the myocardial hypertrophy as indicated in cardiogram and the echocardiogram.
CARDIOTROPHIN-1 (CT-1) is that a cytokine family comprises interleukin-6 (IL-6), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin-M (OSM) and interleukin 11 (IL-11).CT-1 is a lot, but expresses in not all ripe mouse heart, kidney and the liver organization.In vitro study shows the level that comes from the CT-1 in the mouse tissue sample owing to the reaction of cardiac muscle cell's myocardial hypertrophy raises, and it has hinted that CT-1 activates cardiac muscle cell's hypertrophy (Wollert, K.C. etc., J.Biol.Chem.Vol.271, No.16, pp9535-45,1996).Nearer research (J.Hypertension 1999 for Ishikawa, M. etc., early stage (rat) that be expressed in ventricular hypertrophy of 17:807-16) reasoning out CT-1 mRNA increase and plumpness after keep rising.To be CT-1 may not play a machinery in the progress of the LVH of rat with aspect keeping to the further conclusion of this research.
As to disease or concerning the gene or gene outcome of the mark of the neurological susceptibility of disease, importantly in the whole cycle of the beginning of disease and process, produce this gene outcome, and this gene outcome level there is not big fluctuation for suitable.Know, in myocardial hypertrophy, give expression to α-adrenaline and transmit medium (α-adrenergic transmitters) and the endothelium blood vessel element (endothelin) that contracts.Yet when changing in the corresponding whole factor range of its blood plasma level in short-term when very big, using them is infeasible as the index of myocardial hypertrophy.It is also important that the generation of the only corresponding disease of studying of label and development and increase or reduce, and with other conditional independence.For example, a kind of myocardial hypertrophy label of suggestion is atrial natriuretic peptide (atrial natiuretic) factor (ANF atrionatriuretic factor).And be that ANF also raises under many other conditions with ANF as the problem of the label of myocardial hypertrophy, as heart failure.In a word, ANF is defective as the definite label of myocardial hypertrophy.
Prior art comprises evidence that CT-1 works hardly, does not have evidence to show that CT-1 relates to people's myocardial hypertrophy in myocardial hypertrophy, if also do not have hint to exist tissue can discharge this cell factor and a suitable myocardial hypertrophy label is provided in the human body fluid sample.
Further, people's ventricular hypertrophy relate to some comprise hormone such as adrenaline and Angiotensin II interior humoral factor with the irrelevant trophic factor influence of blood pressure.These hormones not only show as the hypertensive cerebral myocardial hypertrophy but also the plump degree of performance to the mankind's influence on pathology.This and the variation such as the SHRsp (Pennica that in hypertension animal model, see, Deng, 1995, PNAS92:1142-6) opposite, and prompting is people and other animals, has different mechanism as the generation and the development of the ventricular hypertrophy between rat of the prior art and the mouse model.
Embodiment
The preferred embodiments of the present invention are by not being subjected to CT-1 basic horizontal (basal level) in people's body fluid sample that myocardial hypertrophy influences and the CT-1 level in the tested individual humoral sample diagnosable or detect the people of easy trouble myocardial hypertrophy.
CT-1 remains on a basic horizontal in the people's body fluid sample that not influenced by myocardial hypertrophy.This is a basis.This basic horizontal can compare with the level of CT-1 in the tested human body fluid.When increasing than basic numerical value, the level of CT-1 shows that this individuality easily suffers from myocardial hypertrophy or myocardial hypertrophy and easily take place and develop.Then, myocardial hypertrophy can be determined by prior art such as cardiogram and iconography technology.
Method of the present invention compared with prior art, it has some advantage: this method can be used to diagnosis or detect a left side and/or right ventricle plumpness (the right ventricular hypertrophy-RVH orleft ventricular hypertrophy-LVH) patient at interior myocardial hypertrophy is taken place easily.
Before finding plumpness, the reason of ventricular hypertrophy just may be clear and definite, and perhaps ventricular hypertrophy will be found when patient has problems.
It is a high-risk factor that LVH causes cardiac problems to the hyperpietic.The diagnosis of LVH easily takes place or detect to make this class patient is carried out the danger of hypertension therapeutic with generation, development and the generation cardiac problems of prevention LVH in the hyperpietic.
RVH occurs in a series of heart and lung diseases, comprises pulmonary hypertension, vesica fiberization and chronic obstructive airway disease.Therefore, can indicate the order of severity of above-mentioned pathology to the diagnosis of RVH.
Since cause myocardial hypertrophy the expression of the beginning CT-1 that changes of biological chemistry just raise the danger that the myocardial hypertrophy that this method can be used to detect before any irreversible generation infringement as cardiac muscle is plump before producing takes place.
The detection of carrying out humoral sample is easily, does not need patient in order to check that whether suffering from myocardial hypertrophy goes to hospital to carry out the inspection of some iconographies.This detection also can be undertaken by the Senior Nurse in operation, even imagines this detection and can be produced as a kind of kit further, and this kit enough simply can make the people who suffers from myocardial hypertrophy danger detect at home.This method is to myocardial hypertrophy patient diagnosis or detect than the conventional art of using at present its low price, quick.
The major advantage of the inventive method is its accuracy.Cardiogram only is 3-8% to hypertension with myocardial hypertrophy patient's correct diagnosis, so this technology can not provide effective diagnosis.And ultrasonic and nuclear magnetic resonance scanning aroused in interest has shown that hypertension companion left ventricular hypertrophy rate is 20-60%.So think that the present invention can improve patient's diagnosis of myocardial hypertrophy even can make and clarifying a diagnosis before PD.
Method of the present invention can be used as generation and the progress that detects myocardial hypertrophy.Raise than CT-1 level with normal phase and to show and begin to produce myocardial hypertrophy.
Method of the present invention also can compare the level of CT-1 in previous and the present humoral sample to be measured in same individuality, and the progress of definite myocardial hypertrophy.The level rising of CT-1 shows that myocardial hypertrophy is in progress in the previous sample of sample now.Otherwise, indicate that then myocardial hypertrophy takes a turn for the better or treatment is effective.
Can be used to detect the result of treatment of myocardial hypertrophy according to method of the present invention.Can determine the situation of change of CT-1 as the level of repeatability mensuration CT-1.The CT-1 level reduces the susceptible of proof result of treatment gradually.
Measure the CT-1 level preferably annually with this method, more preferably six months once, more preferably per season once and most preferably per six weeks once.The annual number of times of measuring is decided by that myocardial hypertrophy degree of causing danger is decided with the result who detected in the past between individuality.
Can be according to method of the present invention to whole blood, blood plasma, serum, urine, tears, saliva, phlegm or synovia sample carry out.
According to the preferred embodiments of the present invention, described method comprises that analyzed in vitro is to detect CT-1 albumen or its special segment.Preferably, the analyzed in vitro method comprises radiommunoassay or enzyme linked immunosorbent assay (ELISA) (ELISA).Preferably, the binding partner (bonding partner) of specific CT-1 or its part can be used to the level of CT-1 in the quantitative sample.This specific binding partner more preferably has the function that produces mark or is connected with the mark that shows that the CT-1 level exists.Although other suitable particular combination parts are conspicuous concerning the insider, the example of the binding partner that CT-1 is specific comprises CT-1 acceptor and anti--CT-1 antibody.
Preferably, at whole C T-1 albumen or its specific part antibody can be in carrying out immune detection as the particular combination part of CT-1.Applied suitable antibody is the human CT-1 antibody of total length in detection: rabbit IgG.
Be determined at that other modes of CT-1 protein level are molecular wt or electric charge in the sample.On a porous carrier, carry out chromatography or SDS-PAGE (SDS PAGE) because sample contents difference of range ability on carrier can be used to show the level of the CT-1 in the sample.Owing to the electric charge of CT-1, also can be used to identify the level of CT-1 by the isoelectric focusing method.
According to an alternative embodiment of the invention, described method comprises that analyzed in vitro is used to detect CT-1 nucleic acid or its segment.Preferably, analyzed in vitro comprises hybridization (hybridisation), order-checking (sequencing) or amplification (amplification) technology such as PCR.
Owing to when the albumen of measuring CT-1 and nucleic acid, importantly show the level of CT-1, so preferably analyzed in vitro is quantitative.Kit can be provided as measures necessary reagent of CT-1 level and container.
People know that the heart that the expression of CT-1 not only is confined to mouse also can comprise kidney and liver at other tissue expressions of mouse.In order to improve degree of accuracy, further a kind of additional marking thing is carried out analyzed in vitro according to the described method of first of the present invention.
The label that is applicable to cardiac function comprises ANF, oncostatin (oncostatin)-M, ciliary neurotrophic factor and leukaemia inhibitory factor.
The importance of myocardial hypertrophy diagnosis is owing to LVH except that hypertension can cause the cardiovascular and cerebrovascular problem.
Thereby a second aspect of the present invention provides the application of a first aspect of the present invention method so that decision should be carried out the patient of hypertension therapeutic.
Hypertension companion LVH is a high-risk factor to heart, if therefore when the CT-1 level increases in the humoral sample, should treat to prevent the generation of cardiac problems hypertension.
According to third part of the present invention, can be to hypertensive result of treatment by measuring the previous and present CT-1 level of same individuality and relatively it changes and monitors.Show that when descending treatment produces effect along with time CT-1 level.
Further specify the present invention referring now to following indefiniteness example.
Example
The scheme of carrying out a first aspect of the present invention method comprises competitive ELISA.
Briefly, competitive ELISA comprises by passive absorption conjugated antigen spend the night (purifying people CT-1).Can add emulative antibody in the plasma sample, be rabbit IgG to people CT-1, or plasma sample is carried out the incubation of a period of time before adding antibody.Add a kind of enzyme target antibody then and make its colour developing (color development).
This detection using monoclonal antibody can further improve the sensitivity of mensuration and reduces step.
Step is summed up:
(i) the passive absorption of antigen-CT-1 of adding purifying places and spends the night in flat board
(ii) rinsing
(iii) add sample/standard (standards)-adding blood plasma
The antibody rabbit IgG that (iv) adds competitive antibody-interpolation people CT-1
(v) rinsing
(vi) add the IgG of enzyme target antibody-anti-rabbit coupling of interpolation
(vii) rinsing
(viii) add substrate-interpolation Color Appearance System
(ix) differentiate change in color-mensuration light absorption value
The further analysis of measuring CT-1 level in the human plasma is by Talwar, and S. etc. are at Biochem.﹠amp; Biophys.Res.Comms.261 567-571 (1999) has description.This analytical approach is disclosed behind the application's priority date.Talwar etc. have described sensitivity and the specific method that is used for CT-1, promptly based on the "dead" immunoluminescence method (non-radioactiveimmunoluminometric) of competitive part combination principle.
Chemiluminescent labeling fluosulfonic acid 4-(2-succinimide-oxygen carbonyl ethyl) phenyl-10-methyl-acridine (acridinium)-9-carboxylate is used to the peptide in zone that mark is represented the center section of CT-1.The detection in this zone of heart failure patient CT-1 (amino acid/11 05-120) has been disclosed the normal control value rising of value of CT-1.
According to Talwar, people such as S. CT-1 is analyzed is considered to can be applicable in the preferred embodiments of the present invention.
Claims (16)
1. method that is used to diagnose or detect the myocardial hypertrophy susceptible person is included in the level of CARDIOTROPHIN-1 (CT-1) contained in the analyzed in vitro human body fluid sample.
2. according to the described method of claim 1, wherein compare and diagnose or detect the myocardial hypertrophy susceptible person by level to the basic horizontal that is not subjected to the CT-1 in the individual humoral sample that myocardial hypertrophy influences and the CT-1 in the tested individual humoral sample.
3. in accordance with the method for claim 1, wherein compare and diagnose or detect the myocardial hypertrophy susceptible person by level to the CT-1 in CT-1 basic horizontal in the previous humoral sample of tested individuality and the current same tested individual humoral sample.
4. according to claim 1 or 2 described methods, wherein the rising of the level of CT-1 is the indication that myocardial hypertrophy begins or produces.
5. in accordance with the method for claim 3, the rising of the level of CT-1 is the indication of myocardial hypertrophy development.
6. according to the described method of above-mentioned each claim, wherein said human body fluid sample comprises whole blood, blood plasma, serum, urine, tears, saliva, phlegm or synovia.
7. according to the described method of above-mentioned each claim, wherein said analyzed in vitro is to be used to detect CT-1 albumen or its segment.
8. in accordance with the method for claim 7, wherein analyzed in vitro comprises radiommunoassay or Enzyme Linked Immunoadsorbent Assay.
9. according to each described method of claim 1-5, wherein said analyzed in vitro is to be used to detect CT-1 nucleic acid or its segment.
10. in accordance with the method for claim 9, its analyzed in vitro comprises hybridization, order-checking or amplification technique.
11., further comprise analyzed in vitro for the additional marking thing according to the described method of above-mentioned each claim.
12. in accordance with the method for claim 11, its additional marking thing is selected from ANF, oncostatin-M, ciliary neurotrophic factor and leukaemia inhibitory factor.
13. comprising, a kit that is used to diagnose or detect the myocardial hypertrophy susceptible person, this kit be applicable to container and the reagent of measuring CT-1 level in the human body fluid sample.
14. application in accordance with the method for claim 1, it is used for determining to carry out the patient of hypertension therapeutic.
15. application in accordance with the method for claim 3, it is used for determining the hypertensive curative effect of treatment.
16. be used to diagnose or detect myocardial hypertrophy susceptible person's method, it substantially as previously discussed.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14277599P | 1999-07-08 | 1999-07-08 | |
| GBGB9915881.8A GB9915881D0 (en) | 1999-07-08 | 1999-07-08 | Methods of diagnosis |
| US60/142,775 | 1999-07-08 | ||
| GB9915881.8 | 1999-07-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1370277A true CN1370277A (en) | 2002-09-18 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00811583 Pending CN1370277A (en) | 1999-07-08 | 2000-06-29 | Method of diagnosis |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1196781A2 (en) |
| JP (1) | JP2003504602A (en) |
| CN (1) | CN1370277A (en) |
| AU (1) | AU5693300A (en) |
| CA (1) | CA2380339A1 (en) |
| WO (1) | WO2001003573A2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006117410A1 (en) * | 2005-04-28 | 2006-11-09 | Proyecto De Biomedicina Cima, S.L. | Use of a c-terminal fragment of cardiotrophin-1 as a cardiotrophin-1 marker |
| DE102006034142A1 (en) * | 2006-07-24 | 2008-01-31 | B.R.A.H.M.S. Aktiengesellschaft | Method for controlling the therapy of heart failure patients by the in vitro determination of threshold levels of vasoactive peptides |
| CN108254576B (en) * | 2018-01-25 | 2020-08-04 | 南京医科大学 | Application of adenine nucleotide transporter 1 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5534615A (en) * | 1994-04-25 | 1996-07-09 | Genentech, Inc. | Cardiac hypertrophy factor and uses therefor |
-
2000
- 2000-06-29 AU AU56933/00A patent/AU5693300A/en not_active Abandoned
- 2000-06-29 CN CN 00811583 patent/CN1370277A/en active Pending
- 2000-06-29 EP EP00942228A patent/EP1196781A2/en not_active Withdrawn
- 2000-06-29 CA CA002380339A patent/CA2380339A1/en not_active Abandoned
- 2000-06-29 WO PCT/GB2000/002521 patent/WO2001003573A2/en not_active Application Discontinuation
- 2000-06-29 JP JP2001508865A patent/JP2003504602A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CA2380339A1 (en) | 2001-01-18 |
| AU5693300A (en) | 2001-01-30 |
| EP1196781A2 (en) | 2002-04-17 |
| JP2003504602A (en) | 2003-02-04 |
| WO2001003573A3 (en) | 2001-10-11 |
| WO2001003573A2 (en) | 2001-01-18 |
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