CN1636598A - Methods to potentiate intravenous estramustine phosphate - Google Patents
Methods to potentiate intravenous estramustine phosphate Download PDFInfo
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- CN1636598A CN1636598A CNA2004100867183A CN200410086718A CN1636598A CN 1636598 A CN1636598 A CN 1636598A CN A2004100867183 A CNA2004100867183 A CN A2004100867183A CN 200410086718 A CN200410086718 A CN 200410086718A CN 1636598 A CN1636598 A CN 1636598A
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- Prior art keywords
- estramustine
- cancer
- estramustine phosphate
- carcinoma
- phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
Estramustine phosphate is an anti-mitotic chemotherapeutic drug with proven efficacy against cancer. The invention describes methods which potentiate the therapeutic benefit of intravenous estramustine phosphate. The invention provides for intravenous estramustine phosphate to be administrated at a high dosage exceeding 1300 mg as a single dose. Efficacious enhancement of estramustine phosphate pharmacokinetics is thereby achieved. Further provided, estramustine phosphate may be intravenously administered for use in combinational regimens with other chemotherapeutic agent. The therapeutic advantages achieved using the intravenous estramustine phosphate formulation are applicable to treatment of a variety of cancers including prostate cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, melanoma, and other cancers.
Description
The application requires U.S. Provisional Application to be priority No. 60/079542, and its applying date is on March 27th, 1998.The application is the dividing an application of Chinese invention patent application of 99800823.0 same title for application number.
Technical field
The present invention relates to the purposes of estramustine phosphate as the heavy dose transfusion, estramustine phosphate is the phosphatic non-chlormethine carbamate derivatives of a kind of estradiol-17b-.The invention further relates to intravenous administration the estramustine phosphate effect method and treat method for cancer by the estramustine phosphate intravenous administration.
Background technology
Proved that cytotoxicity is by complete estramustine molecule caused (Hartley-Asp, 1982).Study on tissue culture shows that estramustine (EM) is a kind of antimitotic agent, has the retardance tumor cell differentiation of metaphase of cell division, and this retardation is decided (Hartley-Asp, 1984) on dosage.It is caused to the interference effect of micro-tubular structure by medicine stopping mid-term known, and this micro-tubular structure forms mitosis spindle.Studies show that by means of immunohistochemistry the obstructive action relevant with dosage occurs in the human prostate cell of cultivation (Mareel 1988, and Dahllof 1993) to the karyostasis microtubule.External EM handles the microtubule that has suppressed only to be made up of tubulin and forms, and this just proves that EM directly disturbs tubulin (Dahllof, 1993).The interference effect (Stearns, 1988) of in addition, verified it and microtubule proteins associated matter (MAPs).MAPs is a macro-molecular protein, it is believed that stabilize microtubules is played an important role.Confirm in the body that EM shows the mechanism of action (Ekl v, 1992) of antimitotic agent.
Therefore, estramustine phosphate is a kind of antimitotic agent, is used for the treatment of serious carcinoma of prostate at present.As single reagent, it is comparable to other several cell toxicant reagent (Murphy, 1983) of being studied by national carcinoma of prostate project to the activity of the carcinoma of prostate that hormone is not answered in a series of multimachine structures, randomized test.This medicine is normally with 10-15mg/kg/ days oral dose administration, the intravenous administration that also some state approvals arranged.But, estramustine phosphate is to carry out according to the predetermined scheme that is parallel to oral administration dosage when intravenous administration, that is to say recommended doses for every day intravenous give 300-600mg, repetitively administered in continuous several days usually.And then oral administration.
In disclosed data, can find the details for the treatment of and then carrying out about 500 routine patients of oral medication earlier with iv formulation.Typical situation is in these researchs, and elder generation uses 300-600mg every day, intravenous administration 7-21 days, then every day oral administration.Pass through the mode of intravenous injection slowly or bolus during administration, dosage is 300mg/ days, and the thrombophlebitis of injection site and local irritant effect are considered to require to establish the main limitation of the medication that maincenter intravenously administrable or treatment stop in most of patients in the peripheral vein.Under 450mg/ days dosage level, Nagel and K lln (1977) say that this dosage level causes so " therefore serious gastrointestinal problems adopts the 300mg/ days maximal doses as intravenous administration every day ".In a works by editors such as Andersson, accept administration in 300-600mg/ days 21 days, be among weekly or 2 months the patient of twice administration of same dose then in 245 examples, 20% patient shows thrombophlebitis, 17% performance gastrointestinal problems, 9% performance hepatic insufficiency.The toxic action that is caused by this repeatability dosage regimen requires to stop administration (Lundgren, 1995) usually.Maier (1990) report, with 900mg/ days intravenous administration 7-10 days, carry out among the patient of oral medication then, 11 to 18 examples (61%) are arranged though there is not phlebitis, serious liver problem occurs, and an example arranged because the death of toxicity liver failure.
Therefore, the typical case of prior art is to utilize the iv formulation of estramustine phosphate as single agents, succeeded by the therapy of long-term oral estramustine.And, because toxicity it is generally acknowledged that the intravenous administration of heavy dose of estramustine phosphate should be forbidden.Concerning prior art, estramustine phosphate is with feasible intravenous mode single dose, heavy dose of administration, neither known, neither be conspicuous.Although oral administration dosage Ceng Gaoda is 1200mg/m
2(Keren-Rosenberg, 1997), but the difference on drug metabolism and the bioavailability does not allow the iv formulation of heavy dose is inferred, because the relative bioavailability of the Estromustine behind the oral administration (estromustine) only is 44% (Gunnarsson, 1984), also because opposite with iv formulation, the phosphate moiety generation dephosphorylation in the oral formulations.And prior art does not also know that the intravenous estramustine phosphate can be used in the chemotherapy regimen of associating, comprises the use of heavy dose of intravenous estramustine phosphate.And prior art does not know that the intravenous estramustine phosphate also has clinical efficacy to many cancers except the carcinoma of prostate indication yet.
In forefathers' work, first recognizes the synergism (Mareel, 1988) of estramustine phosphate and other cell toxicant reagent co-inventor Beryl doctor Hartley-Asp of the present invention.Somely experiment showed, that accepting estramustine for a long time is that realize to improve effect necessary.Therefore, it is essential that administration every day is considered to be, and makes to use oral formulations by former vein (IV) preparation data, and hint can not reach constant higher level clinically with the IV administration.
Estramustine and other a lot of cell toxicant reagent have demonstrated the additional of external pair cell and may be the anti-microtubule effects (Mareel 1988, and Speicher 1992, and Pienta 1993, and Batra 1996) of working in coordination with.Therefore, use the estramustine phosphate oral formulations to finish the combination of estramustine phosphate and other drug to the people.Unite the II phase of using estramustine phosphate and vincaleucoblastine to carry out the carcinoma of prostate that hormone do not answer and test (Seidman 1992, and Hudes 1992, and Pienta 1994, and Hudes 1996).In these trials, 88 routine patients confirm that prostate specific antigen has reduced 50-75%.Modal toxicity also relaxes and becomes moderate and feel sick.It should be noted that especially, the incidence rate of significant Cardiovascular Toxicity is 10.5% (4/37), comprise a routine degree of depth venous thrombosis (DVT), one routine myocardial infarction, one routine congestive heart failure outbreak, with a routine reversible neuropathy, these needs of patients stop treatment, and these toxic actions are caused by estramustine phosphate.In testing in another II phase of being undertaken by (1994) such as Pienta, estramustine phosphate (oral) is united use with etoposide.52 routine patients have been estimated: comprise the 20 routine patients of soft tissue diseases, wherein observe 3 routine complete reactions (CR) (15%), 6 routine partial reactions (PR) (30%).Among the 32 routine bone metastatic tumour patients, 8 examples are improved (25%), 12 examples stable (38%).The prostate specific antigen that has 13 routine male (25%) has reduced by 75%, 28 routine male (54%) and has reduced 50%.The patients with prostate cancer that 17 routine hormones are not answered has carried out taxol (Hudes, 1992) and has studied with the I-II phase of estramustine phosphate.Six routine patients' minimizing level is measurable, and wherein the PR of 3 examples is 2+, 6 and 8 months.Prostate specific antigen (PSA) reduce 〉=50% account for 58.8%.The middle bit duration of reaction is 7 months.3-4 level granulocytopenia and mucositis take place in 2 routine patients, and 70.5% the 1-2 level takes place feels sick, and a routine patient is 3 grades.8 routine patients (47%) see edema, and 6 routine patients (35.2%) 1-3 level one property crossed liver enzyme levels are taken place raise.
In the nearest research, Petrylak etc. (1997) prove that with the docetaxel and the estramustine phosphate oral administration that progressively increase dosage total prostate specific antigen response rate is 62%.In the measurable disease patient of two dimension, 3 examples (43%) have realized the partial reaction of lymph node, and 1 example has realized ischium group's less reaction.This proof, with the therapeutic alliance of oral estramustine be effective.But, associating intravenous estramustine phosphate and these cell toxicant reagent are that this area is unknown.The difference of oral and iv formulation in metabolism of estramustine phosphate, particularly about phosphate moiety, it is non-obvious making the conjoint therapy with iv formulation.
As if different with other antimitotic agents is that the effect of estramustine phosphate depends on exist (Ekl v, 1996) of estramustine conjugated protein (EMBP).This point only is (Forsgren 1979, and Flucher 1989) found under normal operation the prostate.But, in a lot of cancerous tissue, and tumor of prostate, for example also identified in lung, mammary gland glioma, colon, the pancreas similar protein (Bj rk 1991, Bergh 1988, Ekl v 1996, Edgren 1996, Von Schoultz 1994, Bergenheim 1993).The bonded affinity of this protein and estramustine and Estromustine (EaM and EoM) is very high, be considered to be responsible for the EoM selective retention in tumor of prostate, wherein finding in the patients with prostate cancer of oral and intravenous administration treatment with estramustine phosphate respectively, the ratio of blood plasma/tumor is 1: 6 to 1: 11 (Norlen 1988, and Walz 1988).Recently, we are verified in the estramustine phosphate disposable vein to after patient's administration, mutual relation in the human prostate tumor before the prostatectomy completely between EMBP level and EaM and the EoM level illustrates that EMBP may be the reason (Walz, 1996) that medicine keeps.
As a reference, the present invention removes U.S. Provisional Application 60/079542 extra that quotes in full application on March 27th, 1998, also quotes following list of references:
1.Andersson SB, Lundgren R, Svensson L: the metabolite of four kinds of estramustine phosphates in the gas chromatographic measurement blood plasma (Gas chromatographic determination of fourmetabolites of estramustine phosphate on plasma), Acta Pharm.Suec19:1-10,1982;
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3.Bergenheim AT, Gunnarsson PO, Edman K, von Schoultz E, Hariz MIHenriksson R: the absorption of estramustine and reservation and estramustine are protein-bonded in the human malignant cerebral tumor exists (Uptake and retention of estramustine and the presence ofestramustine binding protein in malignant brain tumors in humans), Br J Cancer67:358-361,1993;
4.Bergh J, Bj rk P, Westlin J-E, Nilsson S: estramustine is in conjunction with the expression (Expression of an Estramustine-binding associated protein inhuman lung cancer cell lines) of relevant albumen in human lung carcinoma cell line, Cancer Res 48:4615-4619,1988;
5.Bj rk P, Borg A, Fem M, Nilsson S: expression and the part characterization (expression and partialcharacterization of estramustine-binding protein (EMBP) in human breast cancerand malignant melanoma) of estramustine conjugated protein (EMBP) in human breast carcinoma and malignant melanoma, Anticancer Res 11 (3): 1173-1182,1991;
6.bj rk P, Jonsson U, Andr é n-Sandberg: estramustine phosphate (Estracyt 8.) is Mus and be different from the binding site (Binding sites for the cytotoxic metabolites of Estramustine phosphate (Estracyt 8.) in rat and human pancreas that are distinct from pancreaticEstrogen-binding protein) of the cell toxicant metabolite among the human pancreas of pancreas estrogen binding protein, Pancreas 6:1:77-89,1991;
7.Dahll f B, Hartley-Asp B, Billstr m A, Cabral F: estramustine is by combining depolymerization microtubule (Estramustine depolymerizes microtubules by binding totuulin) with tubulin, Cancer Res 53:4573-4581,1993;
8.Edgren M, Westlin JE, Letocha et al: conjugated protein (EMBP) of estramustine in renal cell carcinoma immunohistochemical method, immune scintigraphy and the useful effect of external estramustine (Estramustine-binding protein (EMBP) in renal cell carcinomaimmunohistochemistry, immunoscintigraphy and in vitro estramustine effects), Acta Oncol 35 (4): 483-488,1996;
9.Ekl v S et al., the basis (Evidence for a non-estrogenic cytostatic effect of estramustine onhuman prostatic carcinoma cells in vivo) that in the estramustine body the non-estrogen of human prostate oncocyte is suppressed cytosis, The Prostate 20:43-50; 1992;
10.Ekl v S, Mahdy E, Wester K et al.: the dependency (Estramustine-binding protein (EMBP) content in four different cell lines and itscorrelation to estramustine induced metaphase arrest) that the content of estramustine conjugated protein (EMBP) and mid-term of bringing out with estramustine thereof stagnate in four kinds of different cell strains, Anticancer Res 16 (4A): 1819-1822,1996;
11.Fl ü chter S, Nelde HJ, Bj rk P et al.: the influence that treatment is expressed in the carcinoma of prostate patient estramustine conjugated protein (EMBP): the research of immunohistochemical method (Effect oftreatment on the expression of estramustine-binding protein (EMBP) in prostaticcancer patients:An immunohistochemical study), The Prostate 14:27-43,1989;
12.Forsgten B, Bj rk P, Carlstr m K, Gustafsson J, P usette A, HogbergB: in the Mus prostate with the purification and distribution (the Purification and distribution of a major protein in rat prostate that bindsestramustine of the bonded major protein of nitrogen mustard derivatives of estramustine, oestradiol-17, a nitrogen mustard derivative of estradiol-17 β), Proc.Natl.Acad.Sci USA:76:3149-3153,1979;
13.Gunnarsson PO, Andersson S-B, Johansson S-A et al.: the pharmacokinetics (Pharmacokinetics ofestramustine phosphate (Estracyt 8.) in prostatic cancer patients) of estramustine phosphate (Estracyt 8.) in the carcinoma of prostate patient, EurJ.Clin.Pharmacol, 26:113-119,1984;
14.Gunnarsson PO, Plym Forshell G, Fritjofsson A, Norl é n BJ: in the estramustine phosphate (plasma concentration (Plasma concentration of Estramustinephosphate and its major metabolites in patients with prostatic carcinoma treatedwith different doses of Estramustine phosphate (Esstracyt 8.)) of estramustine phosphate and major metabolite thereof among the prostate tumor patient of (Estracyt 8.) treatment with various dose, Scand J.UrolNephrol 15:201-206,1981;
15.Hartley-Asp B: the mitosis that estramustine brings out in two routine human prostate tumor cell strain DU 145 and PC-3 is stagnated (Estramustine induced mitotic arrest in two humanprostatic carcinoma cell lines DU 145 and PC-3), The Prostate 5:93-100,1984;
16.Hartley-Asp B, Gunnarsson PO: with growth and survivaling cell (the Growth and cell survival following treatment with estramustine after the testosterone processing of estramustine, nor-nitrogen mustard, estradiol and Human Prostate Cancer Cells strain (DU 145), nor-nitrogenmustard, estradiol and testosterone of a human prostatic cancer cell line (DU145)), J Urology 127:818-822,1982;
17.hudes G, Obasaju C, Chapman A, Gallo J, McAleer C, the I phase of Greenberg R:Paclitaxel and estramustine is studied: do not answer preliminary activity (PhaseI study of Paclitaxel and Estramustine:Preliminary activity in hormonerefractory prostate cancer) in the carcinoma of prostate at hormone, Sem Oncol, vol.22:3, Suppl 6:6-11,1995;
18.Hudes GR, GreenbergR, Krigel RL, Fox S, et al.: estramustine and vincaleucoblastine, two kinds of microtubule inhibitor, study (Phase II study ofestramustine and vinblastine, two microtubule inhibitors, in hormone-refractoryprostate cancer) in the hormone II phase in the carcinoma of prostate of not answering, J Clin Oncol 10:1754-1761,1992;
19.Keren-Rosenberg, S.Muggia, FM: estramustine phosphate and paclitaxel are in the serious intravital reaction of patient with breast cancer: the I phase is studied (Response to estramustine phosphate andpaclitaxelin patients with advanced breast cancer:A Phase I Study), Seminarsin Oncology 24:5 S3-26-S3-29,1997;
20.Lindberg B: with the treatment (Treatment ofrapidly of progressing prostatic carcinoma with Estracyt) that Estracyt takes a turn for the better prostate tumor fast, Journal of Urol108:303-305,1972;
21.Maier U, Hienert G, Simak R: estramustine phosphate is (Estramustine phosphate in secondaty hormone-resistant carcinomaofthe prostate) in the tumor of prostate Secondary cases hormone antagonist, Eur Urol 17:216-218,1990;
22.Mareel MM, Storme GA, Dragonetti CH, De Bruyne GK, Hartley-Asp B, Segers JL, Rabaey ML: estramustine is to pernicious MO
4Mus cell and external tamper resistance activity (Antiinvasive activity of estramstine on malignantMO to DU 145 human prostate tumor cells
4Mouse cells and DU 145 human prostate carcinoma cells in vitro), CancerRes., 48:1842-1849,1988;
23.Murphy GP, Slack NH, Mittleman A: use estramustine phosphate (Estracyt, Emcyt) experience (Experiences with Estramustine Phosphate (Estracyt, Emcyt) in prostate cancer), Seminars in oncology 10 (3) Suppl 3,34-42,1983;
24.Nagel R, K lln C-P: with the serious tumor of prostate (Treatment of advanced carcinoma of the prostate with estramustine phosphate) of estramustine phosphate treatment, British Journal of Urol 49:73--79,1977;
25.Norl é n, B.J., Andersson S.B., Bj rk P., Gunnarsson PO., Fritjofsson, estramustine phosphate (Estracyt) the metabolite absorption (Uptake of Estramustinephosphate (Estracyt) metabolites in prostate cancer) in carcinoma of prostate, Journal of Urology140:1058-1062,1988;
26.Petrylak DP, Shelton GB, the Mac Arthur RB et al.:Docetaxel-I phase of estramustine in the carcinoma of prostate of androgen insensitivity tested (Phase I trial of DocetaXel-Estramustinein androgen insensitive prostate cancer), Cancer Investigation 16, Supp 162,1997;
27.Pienta KJ, Lehr JE: suppress the growth of carcinoma of prostate by means of estramustine and etoposide: interactional foundation under nuclear matrix (Inhibition of prostate cancer growth byestramustine and etoposide:Evidence for interaction at the nuclear matrix), Journal of Urol 149:1622-1625,1993;
28.Pienta KJ, Redman B, Hussain M, Cummings G et al.: do not answer in the carcinoma of prostate II phase of oral estramustine and oral etoposide to estimate (Phase II evaluation of oralestramustine and oral etoposide in hormone-refractory adenocarcinoma of theprostate) at hormone, J Clin Oncol 12:2005-2012,1994;
29.Seidman AD, Scher HI, Petrylak D, Dershaw DD, Curley T: estramustine and vincaleucoblastine: prostate specific antigen is not answered the purposes (Estramustine and vinblastine:Use ofprostate specific antigen as a clinical trialend point for hormone refractory prostatic cancer) of the clinical trial terminal point of carcinoma of prostate as hormone, J Urol 147:931-934,1992;
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31.Stearns M, Tew KD: estramustine combines with MAP-2 with the vitro inhibition microtubule and forms (Estramustine binds MAP-2 to inhibit microtubule assembly in vitro), J CellScience 89:331-342,1988;
32.von Schoultz E, Carlstr m K, Henriksson R et al.: the transferring enzyme (metastases) (Estramustine binding proteinin primary tumors and metastases of malignant melanoma) of the conjugated protein and malignant melanoma of the estramustine in the primary tumor, Melanoma Res4 (6): 401-405,1994;
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Summary of the invention
The invention describes the therapeutic use of the estramustine phosphate of strengthening intravenous administration and the method for effect.This method provides dosage to surpass the intravenous administration of the estramustine phosphate of 1300mg.It also provides dosage to surpass 950mg/m
2The intravenous administration of the estramustine phosphate of (every square metre of body surface area milligram number).It further provides disposable, heavy dose of intravenous administration of estramustine phosphate, and administration can be weekly or the longer time once.The present invention has optimized pharmacokinetics, makes therapeutic effect reach maximum, and intravenous estramustine phosphate and other treatment being united use becomes possibility, comprises that other further improve the chemotherapy of therapeutic effect.The present invention can use the intravenous estramustine phosphate as the polytype tumor, comprises the therapy of prostate, mammary gland, lung, ovary, colorectum, melanoma, pancreas and the brain cancer.
Therefore, an application of the present invention provides heavy dose of estramustine phosphate intravenous therapy, and wherein dosage surpasses 950mg/m
2
Another application provides the scheme of intravenous administration, and this scheme can be optimized the pharmacokinetics and the metabolite thereof of estramustine phosphate thus, makes the toxicity minimum, and described thus optimal seeking method further makes combined treatment easily and effectively.
Therefore, an application of the present invention is to allow intravenous estramustine phosphate and other treatment system to unite use, comprises cytotoxic chemotherapy.
Another application of the invention provides a kind of method, and this method has improved estramustine phosphate or its metabolite and estramustine is conjugated protein or the bonded saturation of the conjugated protein sample protein of estramustine (EMBP), has prolonged the bonded persistent period.
Thus, the invention provides the application that has the cancer of EMBP by the intravenous administration treatment, include but not limited to prostate, mammary gland, lung, ovary, colorectum, melanoma, pancreas and the brain cancer.
Another application of the invention provides the method for quick alleviation cancer secondary symptom, includes but not limited to the pain and the urinary tract obstruction that are caused by cancer.
In addition, the present invention further makes these application be applicable to not to be subjected to the intravenous estramustine phosphate of preparation domination.Thus, the invention provides the estramustine phosphate transfusion of free drug, protein bound medicine or lipid drug disposition form.
Thus, the invention describes a kind of estramustine phosphate preparation, estramustine phosphate wherein and liposome are together with the administration of intravenous mode.
Therefore, method of the present invention is very beat all, in this method, and safety and can reach 900mg/m with the dosage of effective scheme administration
2More than (general every dose greater than 1300mg).
The present invention has provided the advantage that intravenous estramustine and other chemotherapeutics are united use.The present invention has further provided the advantage that heavy dose of intravenous estramustine and other chemotherapeutics are united use.
We provide in the present invention, and the intravenous estramustine phosphate can be used for the treatment of the tumor with high-level EMBP sample albumen (abbreviating EMBP here as).
According to pharmacokinetic data behind the estramustine phosphate oral administration relatively and the pharmacokinetic data behind heavy dose of estramustine phosphate intravenous administration, can recognize novelty of the present invention and non-obvious application.About the pharmacokinetics and the toxicity data of heavy dose of intravenous estramustine phosphate is the unknown of present technique field.Behind the estramustine phosphate oral administration in the intravital main metabolic step of people be, estramustine phosphate becomes estramustine (EM) by dephosphorylation, is oxidized into Estromustine (EoM) at 17 then, and the latter is the female keto analog of EM.When estramustine phosphate during by every day oral scheme administration, the main metabolites that finds in the blood plasma is EoM.Relative bioavailability based on Estromustine approximately is 44% (Gunnarsson, 1984).Behind the intravenous administration, what find at first in the blood plasma is estramustine phosphate, but it be hydrolyzed to rapidly with oral administration after the identical metabolite that found, main metabolites is an Estromustine.Estramustine and Estromustine decompose by carbamate and produce about 15% estradiol and estrone respectively and further metabolism (Gunnarsson, 1981,1984).We are verified, and behind heavy dose of intravenous administration, the main metabolites Estromustine unexpectedly for a long time can be for utilizing, and this can bring unexpected beneficial effect clinically.The patient data with the treatment of 300mg single dose intravenous administration in the past proves that the elimination half-life of Estromustine is 10-20 hour.Main elimination approach is that the estramustine phosphate metabolism is estramustine, Estromustine, estradiol and estrone.The estramustine phosphate efficacy data of particular importance is the half-life (Fig. 1) of estramustine phosphate and main cell toxicant metabolite Estromustine (Fig. 2).By using method of the present invention, we have confirmed this new discovery: estramustine phosphate is with 1000mg/m
2Heavy dose of disposable, intravenous administration after, the half-life of Estromustine approximately is 100 hours (Fig. 2).This discovery further makes the treatment of heavy dose of intravenous estramustine phosphate use becomes possibility.
Brief description of drawings
With reference to following detailed description, and in conjunction with the accompanying drawings, helping has a complete understanding to the present invention and lot of advantages thereof better, wherein:
After Fig. 1 was set forth in the interior administration of estramustine phosphate (Estracyt) disposable vein, (average ± SEM, N=4+4+3), dosage was 1000mg (scope 980-1070mg), 1000mg/m to the concentration of estramustine phosphate
2And 1500mg/m
2
After Fig. 2 was set forth in the interior administration of estramustine phosphate disposable vein, (average ± SEM, N=4+4+3), dosage was 1000mg (scope 980-1070mg), 1000mg/m to the concentration of Estromustine
2And 1500mg/m
2
The detailed description of preferred implementation
The present invention provides, and estramustine phosphate can be with 950mg/m
2More than the dosed administration of (promptly greater than 1300mg).
Following realization method of the present invention.In a preferred method, the disposable infusion dosage of estramustine phosphate administration surpasses 950mg/m
2Intravenous administration both can by maincenter, also can be by approach in the peripheral vein.In the process of preparation drug target, the estramustine phosphate package contents that is used for intravenous administration is a dissolved form, package contents wherein can be formed but is not limited to the freeze-dried powder of meglumine salt in bottle of estramustine phosphate by following, or similar cryodesiccated estramustine phosphate, earlier it is dissolved in sterilized water, for example every 300mg estramustine phosphate is dissolved in the 5ml sterilized water, or is dissolved in 5% D/W, is used for intravenous administration.In a preferred method, use 5% D/W as diluent.In a preferred method, in the process of preparation dissolved form medicine, should shake and should slowly put upside down and mix.Obtaining solution then, as intravenous fluids, have the preferred infusion persistent period, is 30 minutes to 3 hours, and transfusion surpasses 1-2 hour and be safety and method easily thus.Saline solution can cause drug precipitation, therefore is not the preferred of transfusion.
When estramustine phosphate by in the peripheral vein during administration, preferred longer transfusion persistent period and the bigger total transfusion volume of utilizing is so that to the stimulation minimum of blood vessel.Can be with inequalities but are preferably the 3-5% human albumin or other plasma proteins mix in probable ground, estramustine phosphate solution, comprises dextran albumen, with the protein bound of realization estramustine phosphate, thereby reduce any possible blood vessel injury.
Use other preparations or the prescription of estramustine phosphate can further realize the present invention.A kind of preparation of particularly advantageous chemotherapeutics estramustine phosphate relates to estramustine phosphate is combined transfusion (being referred to as liposomal encapsulated estramustine phosphate or liposome estramustine here) with liposome, makes the estramustine phosphate can be by periphery or maincenter vein, with heavy dose of and be lower than the dosage transfusion of 1300mg.In a kind of preferred method for preparing the liposome estramustine, prepare estramustine phosphate solution in the above described manner earlier, inject bottle then, contain the empty liposome that can obtain its freeze-dried powder form in the bottle.After liposome carries out suitable hydration, bottle is carried out vortex and sonicated, import the patient then.
When estramustine phosphate when the administration of maincenter intravenous route, described administration can be undertaken by provisional or permanent vein access to plant, includes, but are not limited to that three cavities conduit pipe, Hickman conduit, clavicle roll off the production line, jugular vein line or medi-port.Described administration can be followed anticoagulant therapy or add not commensurability but be preferably 3-5% human albumin or other plasma proteins or liposome estramustine and carry out, but dispensable, to reduce any blood vessel injury that may cause the administration patient.
The dosage of estramustine phosphate is greater than 1300mg among the present invention, but preferably to surpass 950mg/m
2Dosage treatment patient.Therefore, a kind of preferable methods is with 1000mg/m
2Administration in the dosage disposable vein.Another kind of preferable methods is with 1500mg/m
2Administration in the dosage disposable vein.And dosage can be 2000mg/m
2But, the present invention includes 950mg/m
2Other above dosage, institute's preferred dosage are not meaned restriction.
Most preferred estramustine phosphate dosage regimen is a disposable infusion among the present invention, and weekly, maximal dose reaches 4000mg or 3500mg/m
2Another kind of preferred scheme is the disposable infusion administration, whenever biweekly.Another kind of preferred scheme is the disposable infusion administration, and per three weeks once.Another kind of preferred scheme is the disposable infusion administration, whenever all around once.Consider and the scheme of other concomitant therapies that a kind of scheme can be preferable over another kind.These schemes can repeat with continuous or repeatability mode.
The inventive method described herein can prolong the high blood of estramustine phosphate metabolite and/or organize level, and metabolite comprises Estromustine, estramustine, estrone and estradiol.Therefore, can improve the mutual synergism with other therapies, wherein these other therapies include but not limited to chemotherapy, radiotherapy, monoclonal antibody and biotherapy.The present invention by prolonging estramustine phosphate and metabolite thereof high blood and organize level, maximum therapeutic effect is provided.Therefore realized maximum therapeutic effect, wherein estramustine phosphate is to surpass 950mg/m
2The dosage intravenous administration, it and other cancer therapy administering drug combinations include but not limited to radiotherapy, chemotherapy, monoclonal antibody and biotherapy.
In a preferred method, estramustine phosphate is to surpass 950mg/m
2The dosage disposable vein in administration, strengthened therapeutic effect with other cytotoxic chemotherapy agent.In a preferred method, the method that realizes described drug combination is with the estramustine phosphate intravenous administration, preferably in same day of other chemotherapeutics administrations or administration the previous day in other chemotherapeutics administrations 3 days.Realize that particularly preferred method is when other chemotherapeutics are made up of antimitotic agent or anti-microtubule agent, include but not limited to taxane (taxanes), comprise taxol and taxotere, with comprise vincaleucoblastine, vincristine, etoposide, navelbine, amycin, irinotecan (irinotecan) reagent (CPT-11), also has liposomal encapsulated chemotherapeutics, comprise liposomal encapsulated taxane, for example liposomal encapsulated paclitaxel (paclitaxel).If unite use with the monoclonal therapy, then more useful, this grouping by monoclonal reagents comprises radioactive nucleus thuja acid or the long factor reagent of antibiosis.
When estramustine phosphate surpasses 950mg/m with disposable infusion mode intravenous administration and dosage
2The time, the blood plasma or the serum levels of Estromustine are further kept.Transfusion can be chosen wantonly with continuous or repeatability mode and repeat, to keep the blood levels of higher estramustine phosphate metabolite.The estramustine phosphate and the metabolite level thereof that continue can reach lasting therapeutic effect thus.
Therefore the present invention provides a kind of method, surpasses 950mg/m by disposable infusion dosage
2The intravenous administration of estramustine phosphate, increase estramustine or its metabolite and estramustine is conjugated protein or the bonded saturation of albuminoid.Similarly, by to surpass 950mg/m
2The intravenous dosages administration, prolong estramustine phosphate or its metabolite is conjugated protein with estramustine or the conjugated protein sample protein of estramustine (EMBP) combine the persistent period.Therefore, can treat all with the intravenous estramustine phosphate and have the conjugated protein or estramustine of estramustine in conjunction with the proteinic cancer of sample.Particularly preferably be and treat carcinoma of prostate by this way.Also preferably treat breast carcinoma, melanoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer and brain cancer by this way.Particularly preferably be the estramustine phosphate intravenous administration, wherein disposable dosage surpasses 950mg/m
2, the cancer of being treated has the conjugated protein or conjugated protein sample protein of estramustine of estramustine, includes but not limited to one group of cancer, comprises carcinoma of prostate, breast carcinoma, ovarian cancer, cancer of pancreas, melanoma, pulmonary carcinoma and brain cancer.
Described cancer can be further with the treatment of liposome estramustine, and list is used or used with other chemotherapy combineds.Described medication preferably repeats with continuous or repeatability mode by the present invention program, unites or do not unite other treatment.Therefore, described scheme can comprise intravenous estramustine phosphate and other chemotherapeutics therapy therapeutic alliances, administration once in a week, whenever biweekly, per three weeks once or around every once, and variation scheme.
Particularly preferably be when being used for the treatment of carcinoma of prostate, breast carcinoma, melanoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer and brain cancer the cell toxicant reagent administering drug combinations of the estramustine phosphate of intravenous administration and other chemotherapy.Further particularly preferably be when being used for the treatment of carcinoma of prostate, breast carcinoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, brain cancer the estramustine phosphate of intravenous administration and X-ray therapy administering drug combinations.Further preferably when treatment has the conjugated protein or proteinic cancer of the conjugated protein sample of estramustine of estramustine, comprise carcinoma of prostate, breast carcinoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer and brain cancer, estramustine phosphate can surpass 950mg/m when uniting use with other cancer therapies
2The intravenous dosages administration.
The present invention can reach objective and subjective therapeutic effect.Beneficial effect relates to and reduces tumor size, improves quality of life, reduces tumor and block, for example the pain that causes of urinary tract obstruction, tumor remission, improve survival rate, reduce the sign of tumor recurrence time or other improvement.Particularly, by estramustine phosphate to surpass 950mg/m
2The dosage intravenous administration, single with or preferably and other cancer therapies unite use, can reach objective or subjective rapidly therapeutic effect.Therefore, the present invention can be alleviated the urinary tract obstruction that is caused by cancer rapidly, alleviates the pain that is caused by cancer rapidly.
By the explanation to following illustration embodiment, other features of the present invention will be significantly, and these embodiments for illustrating the present invention, are not to be used for limiting the present invention only.
Embodiment
By embodiment but unrestrictedly provide following clinical case.
1: two serious metastatic prostate cancer patient of example of embodiment treats by the maincenter intravenous administration with estramustine phosphate.The dosage that the patient accepts estramustine phosphate is 2500mg/m
2According to the scheme of infusing weekly once, estramustine phosphate is with the administration of repeatability mode.Each transfusion lasts 90 minutes.Transfusion is fully tolerance, does not have the serious toxicity effect, and two routine patients' prostate specific antigen (PSA) all confirms respond (minimizing).
2: three serious metastatic prostate cancer patients of example of embodiment treat by the maincenter intravenous administration with estramustine phosphate, and dosage is 1000mg/m
2According to the scheme of infusing weekly once, estramustine phosphate is with the administration of repeatability mode.Each transfusion lasts 30 minutes.Transfusion is fully tolerance, has several routine patients to confirm to have the PSA reaction.
3: three serious metastatic prostate cancer patients of example of embodiment treat by the maincenter intravenous administration with estramustine phosphate, and dosage is 1500mg/m
2According to the scheme of infusing weekly once, estramustine phosphate is with the administration of repeatability mode.Each transfusion lasts 30 minutes or 1 hour.Transfusion is fully tolerance, has a routine patient to confirm to have huge tumor adenopathy reaction.
4: three serious metastatic prostate cancer patients of example of embodiment treat by the maincenter intravenous administration with estramustine phosphate.The dosage that the patient accepts estramustine phosphate is 2000mg/m
2According to the scheme of infusing weekly once, estramustine phosphate is with the administration of repeatability mode.Each transfusion lasts 60 minutes.In order to prevent venous thrombosis, give antithrombotic agent in addition.The estramustine phosphate transfusion is fully tolerance, does not have serious toxicity, and PSA reaction sign is arranged.
Obviously, because above-mentioned instruction, improvement that the present invention is a large amount of and change all are possible.Therefore should understand like this, within the scope of the appended claims,, also can implement the present invention here except specifically described.
Claims (43)
1. produce the method for the high blood plasma level estramustine that prolongs, to promote the mutual synergism of estramustine and second kind of chemotherapeutics, wherein:
Estramustine is with the iv formulation administration; With
Estramustine administration in described second kind of chemotherapeutics administration same day or 3 days.
2. method according to claim 1, wherein said second kind of chemotherapeutics comprises antimitotic agent or anti-microtubule agent.
3. method according to claim 2, wherein said anti-microtubule agent is a taxane.
4. method according to claim 1, wherein iv formulation comprises estramustine phosphate.
5. method according to claim 4, wherein estramustine phosphate disposable infusion dosage surpasses 1300mg.
6. method according to claim 4, wherein estramustine phosphate disposable infusion dosage surpasses 950mg/m
2
7. method according to claim 1 is to strengthen therapeutic effect.
8. produce the method for high blood plasma level estramustine metabolite Estromustine, with the mutual synergism of accelerating oxidation estramustine and second kind of chemotherapeutics, wherein:
Estramustine is with the iv formulation administration; With
Estramustine administration in described second kind of chemotherapeutics administration same day or 3 days.
9. method according to claim 8, wherein said second kind of chemotherapeutics comprises antimitotic agent or anti-microtubule agent.
10. method according to claim 9, wherein said anti-microtubule agent is a taxane.
11. method according to claim 8, wherein iv formulation comprises estramustine phosphate.
12. method according to claim 11, wherein estramustine phosphate disposable infusion dosage surpasses 1300mg.
13. method according to claim 11, wherein estramustine phosphate disposable infusion dosage surpasses 950mg/m
2
14. method according to claim 8 is to strengthen therapeutic effect.
15. keep the method for estramustine and Estromustine blood plasma level, wherein with estramustine phosphate with the disposable infusion intravenous administration, dosage surpasses 1300mg; Repeat transfusion alternatively in a continuous manner.
16. method according to claim 15, wherein therapeutic effect is continued.
17. keep the method for estramustine and Estromustine blood plasma level, wherein with estramustine phosphate with the disposable infusion intravenous administration, dosage surpasses 950mg/m
2Repeat transfusion alternatively in a continuous manner.
18. method according to claim 17, wherein therapeutic effect is continued.
19. improve the method that estramustine or analogous protein conjugated protein with estramustine combines saturation, wherein:
Estramustine is with estramustine phosphate iv formulation form administration, and disposable infusion dosage surpasses 1300mg; With
It is protein-bonded in conjunction with saturation to improve estramustine thus.
20. method according to claim 19, wherein this method is used for the treatment of and has the conjugated protein or estramustine of estramustine in conjunction with the proteinic cancer of sample.
21. method according to claim 20, wherein said cancer are selected from the group of being made up of carcinoma of prostate, breast carcinoma, melanoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer and brain cancer.
22. improve estramustine or its metabolite is conjugated protein with estramustine or analogous protein combines the method for saturation, wherein:
Estramustine is with estramustine phosphate iv formulation form administration, and disposable infusion dosage surpasses 950mg/m
2With
It is protein-bonded in conjunction with saturation to improve estramustine thus.
23. method according to claim 22, wherein this method is used for the treatment of the cancer with the conjugated protein or analogous protein of estramustine.
24. method according to claim 23, wherein said cancer are selected from the group of being made up of carcinoma of prostate, breast carcinoma, melanoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer and brain cancer.
25. prolong estramustine or its metabolite is conjugated protein with estramustine or analogous protein combines the method for persistent period, wherein:
Estramustine is with estramustine phosphate iv formulation form administration, and disposable infusion dosage surpasses 1300mg; With
It is protein-bonded in conjunction with the persistent period to prolong estramustine thus.
26. method according to claim 25, wherein this method is used for the treatment of the cancer with the conjugated protein or analogous protein of estramustine.
27. method according to claim 26, wherein said cancer are selected from the group of being made up of carcinoma of prostate, breast carcinoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer and brain cancer.
28. prolong estramustine or its metabolite is conjugated protein with estramustine or analogous protein combines the method for persistent period, wherein:
Estramustine is with estramustine phosphate iv formulation form administration, and disposable infusion dosage surpasses 950mg/m
2With
It is protein-bonded in conjunction with the persistent period to prolong estramustine thus.
29. method according to claim 28, wherein this method is used for the treatment of the cancer with the conjugated protein or analogous protein of estramustine.
30. method according to claim 29, wherein said cancer are selected from the group of being made up of carcinoma of prostate, breast carcinoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer, melanoma and brain cancer.
31. the estramustine phosphate preparation, wherein estramustine is that to be encapsulated in lipid intravital.
32. preparation according to claim 31 is used for intravenous administration.
33. chemotherapeutics is formed by being encapsulated in the intravital estramustine phosphate of lipid.
34. product comprises estramustine phosphate and one or more chemotherapeutics of being applicable to intravenous administration, as combination formulations, is used for anti-cancer therapies simultaneously, respectively or continuously.
35. product according to claim 34, wherein said one or more chemotherapeutics are selected from the group of being made up of CPT-11, amycin, etoposide, NVB and Taxane derivative.
36. product according to claim 34, the wherein said estramustine phosphate of intravenous administration that is applicable to surpasses the disposable infusion of 1300mg as dosage.
37. product according to claim 34, the wherein said estramustine phosphate of intravenous administration that is applicable to surpasses 950mg/m as dosage
2Disposable infusion.
38., be used for the treatment of carcinoma of prostate, breast carcinoma, melanoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer or brain cancer according to any described product of claim 34 to 37.
39. the preparation that intravenous uses comprises estramustine phosphate and albuminous mixture.
40. according to the described preparation of claim 39, wherein the dosage of active component disposable infusion surpasses 1300mg.
41. according to the described preparation of claim 39, wherein the dosage of active component disposable infusion surpasses 950mg/m
2
42. according to any described preparation of claim 39-41, wherein albumin is a human albumin.
43. product comprises the estramustine phosphate of lyophilized form and contains albuminous parenteral physiological solution.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7954298P | 1998-03-27 | 1998-03-27 | |
| US60/079,542 | 1998-03-27 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99800823A Division CN1273530A (en) | 1998-03-27 | 1999-03-26 | Method to potentiate intraveneous estramustin phosphate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1636598A true CN1636598A (en) | 2005-07-13 |
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ID=22151209
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004100867183A Pending CN1636598A (en) | 1998-03-27 | 1999-03-26 | Methods to potentiate intravenous estramustine phosphate |
| CN99800823A Pending CN1273530A (en) | 1998-03-27 | 1999-03-26 | Method to potentiate intraveneous estramustin phosphate |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99800823A Pending CN1273530A (en) | 1998-03-27 | 1999-03-26 | Method to potentiate intraveneous estramustin phosphate |
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| Country | Link |
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| EP (1) | EP1003521A4 (en) |
| JP (1) | JP2001508810A (en) |
| KR (1) | KR20010021656A (en) |
| CN (2) | CN1636598A (en) |
| AU (1) | AU750010B2 (en) |
| BR (1) | BR9906425A (en) |
| CA (1) | CA2295049A1 (en) |
| EA (1) | EA004647B1 (en) |
| HU (1) | HUP0200547A3 (en) |
| ID (1) | ID24504A (en) |
| IL (1) | IL133612A0 (en) |
| NO (1) | NO20002343L (en) |
| NZ (1) | NZ501987A (en) |
| PL (1) | PL342969A1 (en) |
| WO (1) | WO1999049869A1 (en) |
| ZA (1) | ZA997821B (en) |
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|---|---|---|---|---|
| GB0003201D0 (en) * | 2000-02-11 | 2000-04-05 | Pharmacia & Upjohn Spa | Method to potentiate the therapeutic efficacy of taxane and derivatives thereof |
| US6436913B1 (en) * | 2000-07-25 | 2002-08-20 | Pharmacia & Upjohn Company | Use of estramustine phosphate in the treatment of bone metastasis |
| RU2471511C1 (en) * | 2011-05-04 | 2013-01-10 | Федеральное государственное бюджетное учреждение "Ростовский научно-исследовательский онкологический институт" Министерства здравоохранения и социального развития Российской Федерации (ФГБУ "РНИОИ" Минздравсоцразвития России) | Method of treating colonic liver metastases |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS617292A (en) * | 1984-06-20 | 1986-01-13 | Japan Atom Energy Res Inst | Method for producing estracyt compound bonded with carcinostatic agent |
| US5077056A (en) * | 1984-08-08 | 1991-12-31 | The Liposome Company, Inc. | Encapsulation of antineoplastic agents in liposomes |
| MX9203808A (en) * | 1987-03-05 | 1992-07-01 | Liposome Co Inc | HIGH DRUG CONTENT FORMULATIONS: LIPID, FROM LIPOSOMIC-ANTINEOPLASTIC AGENTS. |
| ES2148223T3 (en) * | 1992-03-23 | 2000-10-16 | Univ Georgetown | TAXOL ENCAPSULATED IN LIPOSOMES AND METHOD FOR USE. |
| FR2697752B1 (en) * | 1992-11-10 | 1995-04-14 | Rhone Poulenc Rorer Sa | Antitumor compositions containing taxane derivatives. |
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1999
- 1999-03-26 PL PL99342969A patent/PL342969A1/en unknown
- 1999-03-26 CN CNA2004100867183A patent/CN1636598A/en active Pending
- 1999-03-26 CN CN99800823A patent/CN1273530A/en active Pending
- 1999-03-26 IL IL13361299A patent/IL133612A0/en not_active IP Right Cessation
- 1999-03-26 NZ NZ501987A patent/NZ501987A/en unknown
- 1999-03-26 EA EA199901081A patent/EA004647B1/en not_active IP Right Cessation
- 1999-03-26 ID IDW20000105A patent/ID24504A/en unknown
- 1999-03-26 BR BR9906425-1A patent/BR9906425A/en not_active IP Right Cessation
- 1999-03-26 JP JP54936999A patent/JP2001508810A/en not_active Ceased
- 1999-03-26 HU HU0200547A patent/HUP0200547A3/en unknown
- 1999-03-26 CA CA002295049A patent/CA2295049A1/en not_active Abandoned
- 1999-03-26 WO PCT/US1999/004275 patent/WO1999049869A1/en not_active Application Discontinuation
- 1999-03-26 KR KR1020007000214A patent/KR20010021656A/en not_active Application Discontinuation
- 1999-03-26 AU AU33533/99A patent/AU750010B2/en not_active Ceased
- 1999-03-26 EP EP99914884A patent/EP1003521A4/en not_active Withdrawn
- 1999-12-22 ZA ZA9907821A patent/ZA997821B/en unknown
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Also Published As
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|---|---|
| WO1999049869A1 (en) | 1999-10-07 |
| HUP0200547A2 (en) | 2002-07-29 |
| JP2001508810A (en) | 2001-07-03 |
| EA004647B1 (en) | 2004-06-24 |
| ID24504A (en) | 2000-07-20 |
| KR20010021656A (en) | 2001-03-15 |
| ZA997821B (en) | 2000-08-01 |
| EP1003521A1 (en) | 2000-05-31 |
| NO20002343D0 (en) | 2000-05-04 |
| PL342969A1 (en) | 2001-07-16 |
| NZ501987A (en) | 2002-10-25 |
| EP1003521A4 (en) | 2003-07-23 |
| CA2295049A1 (en) | 1999-10-07 |
| HUP0200547A3 (en) | 2003-07-28 |
| EA199901081A1 (en) | 2000-12-25 |
| CN1273530A (en) | 2000-11-15 |
| AU750010B2 (en) | 2002-07-11 |
| NO20002343L (en) | 2000-05-04 |
| BR9906425A (en) | 2000-07-11 |
| IL133612A0 (en) | 2001-04-30 |
| AU3353399A (en) | 1999-10-18 |
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