JPH01501792A - Cancer treatment with gamma interferon - Google Patents
Cancer treatment with gamma interferonInfo
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- JPH01501792A JPH01501792A JP62501891A JP50189187A JPH01501792A JP H01501792 A JPH01501792 A JP H01501792A JP 62501891 A JP62501891 A JP 62501891A JP 50189187 A JP50189187 A JP 50189187A JP H01501792 A JPH01501792 A JP H01501792A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/00—Medicinal preparations containing peptides
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/217—IFN-gamma
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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
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 γ型インターフェロンによる癌の治療 ｌ吸些ａｔ 本発明は、ヒトにおけるある種の悪性疾患をヒトγ型インターフェロン（ｈＩＦ Ｎ−γ）で治療する方法に関する。[Detailed description of the invention] Cancer treatment with gamma interferon l suck at The present invention aims to treat certain malignant diseases in humans using human γ-type interferon (hIF). N-γ).
γ型インターフェロンはそれをα型およびβ型インターフェロンから区別するの に役立つ当分野で知られた多くの特徴を有している。これらの差異にはとりわけ 抗原特殊性および高レベルの免疫調節／抗腫瘍活性が含まれる。ヒトγ型インタ ーフェロンはマイトジェンで刺激したＴリンパ球または抗原（Ｔリンパ球が５作 される）で刺激したＴリンパ球により産生される。What distinguishes gamma-type interferon from alpha- and beta-type interferon? It has many features known in the art that make it useful. These differences include, among other things. Includes antigenic specificity and high levels of immunomodulatory/antitumor activity. human gamma type inter - Feron is a mitogen-stimulated T lymphocyte or an antigen (T lymphocytes stimulate 5 cells). produced by T lymphocytes stimulated with
それはまた当分野で今やよく知られたクローニングおよび発現技術により得るこ とができる。It can also be obtained by cloning and expression techniques now well known in the art. I can do it.
本発明で使用するヒトγ型インターフェロンの供給源は限定的でないが、この種 ′のｈＩＦＮ−γは高純度のものであり且つインターフェロン発現細胞の細胞構 成成分または細胞破片により汚染されていないことが必要である１本発明で使用 する好適なｈＩ ＦＮ−γは組換えＤＮＡ技術により生産され、そして１９８４ 年１２月１２日付の日本国特許出願公開第５９−２８１３７６号およびその対応 外国出願例えば欧州特許出願（これらはすべて参照によりここに引用される）に 教示されるように精製される。その精製法は抽出の際に１種またはそれ以上の亜 鉛塩または銅塩とポリエチレンイミンを添加することから成る。より詳細には、 それは１種またはそれ以上の亜鉛塩または銅塩、例えば塩化亜鉛、硫酸亜鉛、酢 酸亜鈴、アセチルアセトン酸亜鉛または硫酸鋼を、亜鉛塩の場合は約０．５〜５ ｍＭの範囲で、銅塩の場合は約０．０１〜３ｍＭの範囲で含有するＭ街溶液中に 組換え微生物の培養細胞を懸濁し、細胞を破壊し、次いでその遠心上清にポリエ チレンイミンを加えて例えば０．５〜１．１％の最終濃度とし、その後慣用方法 （例えばいくつかのクロマトグラフ法と透析の組合せ）で精製することから成っ ている。The source of human γ-type interferon used in the present invention is not limited, but ' hIFN-γ is of high purity and is compatible with the cell structure of interferon-expressing cells. 1 Used in the present invention must be free from contamination with components or cell debris. The preferred hI FN-γ was produced by recombinant DNA technology and was introduced in 1984. Japanese Patent Application Publication No. 59-281376 dated December 12, 2013 and its correspondence Foreign applications such as European patent applications (all of which are incorporated herein by reference) Refined as taught. The purification method uses one or more subspecies during extraction. It consists of adding lead or copper salts and polyethyleneimine. More specifically, It contains one or more zinc or copper salts, such as zinc chloride, zinc sulfate, vinegar Tin acid, zinc acetylacetonate or steel sulfate, about 0.5 to 5 in the case of zinc salt In the case of copper salts, in the M solution containing in the range of about 0.01 to 3 mM. Suspend cultured cells of recombinant microorganisms, disrupt the cells, and then add Polyester to the centrifuged supernatant. Add tyrenimine to a final concentration of e.g. 0.5-1.1% and then proceed in a conventional manner. (e.g. a combination of some chromatographic methods and dialysis). ing.
ヒトγ型インターフェロンは、例えばグレー（Ｇｒａｙ）ら、Ｎａｔｕｒｅ、２ ９５．５０３〜５０６（１９８２）およびエプスタイン（Ｅｐｓｔｅｉｎ）、Ｎ ａｔｕｒｅ、２９５．４５３〜４５４（１９８２＞に開示された方法により生産 することができる。Human γ-type interferon is described, for example, by Gray et al., Nature, 2 95.503-506 (1982) and Epstein, N. ature, 295.453-454 (1982) can do.
インターフェロンの成分はヒトに対して抗腫瘍性をもつとの推測がなされて、比 較的純度の低いインターフェロンを用いた動物実験が行われた。グレツサー（Ｇ ｒｅｓｓｅｖ） 、 Ａ ｄｖａｎ 、 ＣａｎｃｅｒＲｅｓ、１６．９７〜 ｌ ４０（１９７２＞およびグレッサー、“癌−包括的論文（Ｃａｎｃｅｒ−Ａ Ｃｏ＋＊ｐｒｅｈｅｎｓｉｖｅ Ｔｒｅａｔｉｓｅ）″、ベツカ−（Ｆ 、 Ｂ ｅｃｋｅｒ）ｉｉ集、５．５２１〜５７１ 、プレナム・プレス。It has been speculated that interferon components have antitumor properties in humans, and Animal experiments were conducted using interferon of relatively low purity. Gretzser (G ressev), A dvan, CancerRes, 16.97~ 40 (1972) and Gresser, “Cancer-A Comprehensive Treatise (Cancer-A Co+＊prehensive Treatise)'', Betska-(F, Becker) II, 5.521-571, Plenum Press.
ニューヨーク（１９７７）を参照されたい。しかしながら、患者から採取したば かりの一次ヒト癌細胞に対するｈＩＦＮ−γの効果についての決定的な研究はま だ存在しない。See New York (1977). However, if taken from a patient, Definitive studies on the effects of hIFN-γ on primary human cancer cells are still pending. It doesn't exist.
見肌Ｏ五！ 本発明は、抗腫瘍剤として有効な十分量の精製ヒトγ型インターフェロンを腫瘍 患者に投与することから成るヒトの卵巣癌、乳癌、肺癌、黒色腫、腎臓癌、ｍ臓 癌、顕部癌、結腸癌、脳腫瘍、胸膜癌および胃癌を治療する方法に間する。好適 な投与経路は非経口、ずなわち静脈内、筋肉内、皮下および腹腔内である。Looking skin O5! The present invention provides a method for administering a sufficient amount of purified human gamma interferon effective as an antitumor agent to tumors. human ovarian cancer, breast cancer, lung cancer, melanoma, kidney cancer, m. Discloses methods for treating cancer, overt cancer, colon cancer, brain cancer, pleural cancer, and gastric cancer. suitable Preferred routes of administration are parenteral, namely intravenous, intramuscular, subcutaneous and intraperitoneal.
１旦欠Ｉ肌・ ｈＩＦＮ−γの抗腫瘍活性を調べることは、ハンバーガー（Ｈａｍｂｕｒｇｅｒ ）ら、５ｃｉｅｎｃｅ、 １９７．４６１ （１９７７）およびハンバーガーら 、Ｊ、Ｃｌ１ｎ、Ｉｎｖｅｓｔ、、６０，８４６（１９７７）に記載されるよう な２層軟質寒天系（を騙ｏ−１ａｙｅｒ ５ｏｆｔ ａｇ＆ｒｓｙｓｔｅｍ）を 用いて培養ヒト腫瘍で試験宋ることにより可能である。“ヒト腫瘍クローニング 系”と初めに呼ばれたこの培養系は、個々の患者の腫瘍に最も適した抗癌剤を選 択するために使用さ１３２１（１９７８）の患者腫瘍がｉｌ ｖｉｔｒｏで薬物 に感受性である場合、患者が臨床上でその薬物に対応する可能性は８１％である ことを立証した。しかしながら、患者腫瘍がｉｎ ｖｉｔｒ。1 time missing I skin・ To investigate the antitumor activity of hIFN-γ, ) et al., 5science, 197.461 (1977) and Hamburger et al. , J. Cl1n, Invest, 60, 846 (1977). Two-layer soft agar system (O-1 ayer 5 of ag&rs system) This is possible by testing on cultured human tumors using the method. “Human tumor cloning This culture system, initially called ``system,'' selects the most appropriate anticancer drug for each patient's tumor. 1321 (1978) used to select patient tumors treated with drugs in vitro. If the patient is susceptible to the drug, there is an 81% chance that the patient will respond clinically to the drug. I have proven that. However, the patient's tumor was in vitro.
で薬物に耐性である場合は、患者がその薬物に応答しない可能性は９９％であっ た。If a patient is resistant to a drug, there is a 99% chance that the patient will not respond to the drug. Ta.
ヒト腫瘍クローニング系でヒト腫瘍に対するヒトγ型インターフェロンの抗腫瘍 活性を試験するために、既知の毛細管系が使用される。この系はフォノ・ホッフ （Ｖｏｎ Ｈｏｆｆ）ら、Ｐ ｒｏｅ 。Antitumor effect of human gamma interferon against human tumors using human tumor cloning system To test activity, the known capillary system is used. This system is Phono Hoff (Von Hoff) et al., Proe.
Ａ＋＊、 Ａｓ５ｏｃ、 Ｃａｎｃｅｒ Ｒｅｓ、 （１９８３）により開発さ れた。Developed by A+*, As5oc, Cancer Res, (1983) It was.
腫瘍コロニー形成単位のすべてを破壊する陽性対照（塩化第二水銀）の試験が組 換えヒトγ型インターフェロンの試験と並行して行われる。A positive control (mercuric chloride) test was designed to destroy all tumor colony forming units. This will be conducted in parallel with testing of recombinant human gamma interferon.
上記試験を実施する際に、以下の方法を用いる。The following method is used when conducting the above test.
Ａ、ｈ’ＩＦＮ−γの濃度が次第に増加するにつれてヒト腫瘍に対する細胞毒性 が増大するかどうかを調べるために、１００および１１０００ｎ／ｉ１の濃度が 軟質寒天にクローニングした患者腫瘍に対して試験された。これらの試験におい て、すべての対照およびｈＩＦＮ−γ処理細胞は６本の毛細管を有する。これら の試験から得られるデータは、より高い用量のｈＩＦＮ−γが抗腫瘍活性にとっ て臨床上必要であるかどうかの手がかりを与えることができる。A, Cytotoxicity against human tumors as the concentration of h'IFN-γ progressively increases. To find out whether the concentration of 100 and 11000n/i1 increases Tested on patient tumors cloned in soft agar. These test smells All control and hIFN-γ treated cells have 6 capillaries. these Data from this study showed that higher doses of hIFN-γ were associated with antitumor activity. This can give clues as to whether or not it is clinically necessary.
Ｂ、ｈＩＦＮ−γへの連続暴露が短期間の前処置よりも大きい細胞毒性をヒト腫 瘍コロニー形成単位に与えるかどうかを調べるために、１０．１００および１０ ００ｎｔｔ／ｘｉでの１時間暴露が行われ、それらの結果は同じ濃度での最高２ ０日間の連続暴露の結果として比較される。これらの濃度ｘ時間効果の結果は、 医師が患者の特定癌に対して最も有効な治療法を決定する際に役立つ。B, Continuous exposure to hIFN-γ induces greater cytotoxicity than short-term pretreatment in human tumors. 10.100 and 10 to determine whether they affect tumor colony forming units. Exposures for 1 hour at 00 ntt/xi were carried out and those results were compared to the highest 2 The results are compared for 0 days of continuous exposure. The results of these concentration x time effects are: It helps doctors determine the most effective treatment for a patient's specific cancer.
連続暴露試験の結果は以下の表■に示し、そして１時間暴露試験の結果は以下の 表■に示す。The results of the continuous exposure test are shown in the table ■ below, and the results of the 1 hour exposure test are shown below. Shown in Table ■.
宍−二Ｌ ヒトγ型インターフェロンのクローン原性検定（連続暴露） ５０ｚまたはそれ 以下のコロニー ヒトインター 生存 フェロン濃度 （Σ炙ユユニニーー」３ｊν翼１Ｊぽ ｎｌ！卵巣 ３／９ １０，１００およ び１，０００肺（非小型細胞） １／１１ １００およびｉ 、ｏｏ。Shishi-2L Clonogenic assay of human gamma interferon (continuous exposure) 50z or that The following colony human inter Survival Feron concentration (Σ Roasted Uninie" 3jν wing 1J po nl! Ovary 3/9 10,100 and and 1,000 lungs (non-small cells) 1/11 100 and i, oo.
肺（未知） １／１ １００および１，０００黒色腫 １／６ １，０００ 腎１ｉ １／１ １，０００ 膵臓 １／２ １，０００ ｆ部 １／１ １００および１，０００結腸 １／４ １，０００ 脳 １／１ １，０００ 胸膜 １／２ ｉｏ。Lung (unknown) 1/1 100 and 1,000 Melanoma 1/6 1,000 Kidney 1i 1/1 1,000 Pancreas 1/2 1,000 Part f 1/1 100 and 1,000 Colon 1/4 1,000 Brain 1/1 1,000 Pleura 1/2 io.
胃 １／３ 表Ｉのデータは、ヒトγ型インターフェロンが表示した癌に対して抗腫瘍活性を もつことを示している。Stomach 1/3 The data in Table I show that human gamma interferon exhibits antitumor activity against cancer. It shows that it has.
表−１ ヒトγ型インターフェロンのクローン原性検定（１時間暴露） ５ｏｚまたはそれ以下 ヒトインター のコロニー生存 フエロン濃度 卵巣 ２／３ １００および１０００ 膵！ｉ １／１ １０００ 上記試験は、ヒトγ型インターフェロンへの１時間暴露からの結果が連続暴露後 に得られた結果と類似していることを示している。Table-1 Clonogenic assay of human gamma interferon (1 hour exposure) 5oz or less human inter Colony survival Feron concentration Ovary 2/3 100 and 1000 Pancreas! i 1/1 1000 The above test shows that the results from 1 hour exposure to human gamma interferon are the same as after continuous exposure. This shows that the results are similar to those obtained in the previous study.
ｈＩＦＮ−γの投与量および投与方法は、患者腫瘍のｈＩ ＦＮ−γへの応答を 含めた種々の要因を考慮して、医師の判断に応じて決定される。The dosage and administration method of hIFN-γ are determined based on the response of the patient's tumor to hIFN-γ. It is decided according to the judgment of the doctor, taking into account various factors including:
ヒトγ型インターフェロンは、好ましくは非経口的に例えば静脈内（ＩＶ）、筋 肉内（ＩＭ）、皮下（Ｓ−Ｃ）または腹腔内（ＩＰ）に、慣用の剤形ですなわち 滅菌水性溶液剤または懸濁剤として投与される。これらの慣用剤形のために処方 物は活性化合物と慣用の薬学的に許容される担体、補助剤、充填剤、結合剤、崩 壊剤などを含、有する。Human gamma interferon is preferably administered parenterally, e.g. intravenously (IV), intramuscularly. Intracutaneously (IM), subcutaneously (S-C) or intraperitoneally (IP) in conventional dosage forms, i.e. Administered as a sterile aqueous solution or suspension. Formulated for these conventional dosage forms The active compound and customary pharmaceutically acceptable carriers, adjuvants, fillers, binders, disintegrators, etc. Contains or has a destructive agent.
一般に、ｈＩＦＮ−ｒは１日当たり約０．１＋ｅｆ〜１０ ｗａｇ、好ましくは 分割した用量で約０．１Ｂ〜１０ｍｆＩを非経口的に投与されるであろう。Generally, hIFN-r is administered at about 0.1+ef to 10 wag per day, preferably Approximately 0.1 B to 10 mfI will be administered parenterally in divided doses.
国際調査報告 ＡＮＮＥＸτＯＴＦｊ 工ＮＴ！ＲＮＡＴｌ０Ｎ入Ｌ ５ＥＡＲ（Ｊ ＲＥＰＯ ＲＴ ＯＮinternational search report ANNEXτOTFj Engineering NT! RNATl0N L 5EAR (J REPO RT ON
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US84030286A | 1986-03-17 | 1986-03-17 | |
| US840,302 | 1986-03-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01501792A true JPH01501792A (en) | 1989-06-22 |
Family
ID=25281977
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62501891A Pending JPH01501792A (en) | 1986-03-17 | 1987-03-13 | Cancer treatment with gamma interferon |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0302862A1 (en) |
| JP (1) | JPH01501792A (en) |
| WO (1) | WO1987005518A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005002028A (en) * | 2003-06-11 | 2005-01-06 | Univ Nihon | Method for controlling tumor formation |
| JP2012176948A (en) * | 2004-03-22 | 2012-09-13 | Osiris Therapeutics Inc | Mesenchymal stem cells and uses therefor |
| US9694035B2 (en) | 2004-03-22 | 2017-07-04 | Mesoblast International Sarl | Mesenchymal stem cells and uses therefor |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0278715A3 (en) * | 1987-02-09 | 1989-03-08 | Schering Corporation | Use of human gamma interferon for treatment of basal cell carcinoma |
| US5268169A (en) * | 1989-02-02 | 1993-12-07 | Roussel Uclaf | Treatment method of ovarian cancer using interferon gamma |
| FR2644067B1 (en) * | 1989-02-02 | 1993-02-05 | Roussel Uclaf | USE OF CERTAIN GAMMA INTERFERONS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF OVARY CANCER BY THE INTRAPERITONEAL ROUTE |
| FR2654343B1 (en) * | 1989-11-10 | 1994-08-05 | Roussel Uclaf | USE OF A POLYPEPTIDE HAVING THE ACTIVITY OF INTERFERON GAMMA FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF PRIMITIVE CANCERS OF THE FLEAVE. |
| CN111032756B (en) * | 2017-08-04 | 2023-01-24 | 巴斯夫欧洲公司 | Expandable blowing agent-containing granules based on high-temperature thermoplastics |
| CN114010791B (en) * | 2021-11-15 | 2023-11-24 | 济南市中心医院 | Application of MyD88-IFN gamma R1 dimer as target in preparation of medicine for preventing colon cancer |
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| JPS58159417A (en) * | 1982-03-01 | 1983-09-21 | エフ・ホフマン・ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト | Homogeneous human interferon and manufacture |
| JPS5951792A (en) * | 1982-02-22 | 1984-03-26 | バイオジェン インコーポレイテッド | Production of dna arrangement, rearranged dna molecule and human immune interferon-like polypeptide |
| JPS6087300A (en) * | 1983-10-18 | 1985-05-16 | Green Cross Corp:The | Interferon-gamma composition |
| JPS60172995A (en) * | 1983-10-28 | 1985-09-06 | ジ−．デイ．サ−ル アンド コンパニ− | Improvement of gamma-human interferon |
| JPS6193130A (en) * | 1984-10-05 | 1986-05-12 | ビオフエロン ビオヒエミシエ サブスタンツエン ゲゼルシヤフト ミツト ベシユレンクテル ハフツング ウント コムパニー | Gamma-interferon-containing drug for systematically treatingvarious human diseases with small dosage |
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|---|---|---|---|---|
| WO1983001198A1 (en) * | 1981-10-08 | 1983-04-14 | Kurt Frimann Berg | Method and composition for treating a patient suffering from interferon-susceptible disorder |
| IL76591A0 (en) * | 1984-10-05 | 1986-02-28 | Bioferon Biochem Substanz | Pharmaceutical compositions containing ifn-ypsilon and processes for the preparation thereof |
-
1987
- 1987-03-13 JP JP62501891A patent/JPH01501792A/en active Pending
- 1987-03-13 WO PCT/US1987/000504 patent/WO1987005518A1/en not_active Application Discontinuation
- 1987-03-13 EP EP87902004A patent/EP0302862A1/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5951792A (en) * | 1982-02-22 | 1984-03-26 | バイオジェン インコーポレイテッド | Production of dna arrangement, rearranged dna molecule and human immune interferon-like polypeptide |
| JPS58159417A (en) * | 1982-03-01 | 1983-09-21 | エフ・ホフマン・ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト | Homogeneous human interferon and manufacture |
| JPS6087300A (en) * | 1983-10-18 | 1985-05-16 | Green Cross Corp:The | Interferon-gamma composition |
| JPS60172995A (en) * | 1983-10-28 | 1985-09-06 | ジ−．デイ．サ−ル アンド コンパニ− | Improvement of gamma-human interferon |
| JPS6193130A (en) * | 1984-10-05 | 1986-05-12 | ビオフエロン ビオヒエミシエ サブスタンツエン ゲゼルシヤフト ミツト ベシユレンクテル ハフツング ウント コムパニー | Gamma-interferon-containing drug for systematically treatingvarious human diseases with small dosage |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005002028A (en) * | 2003-06-11 | 2005-01-06 | Univ Nihon | Method for controlling tumor formation |
| JP4523762B2 (en) * | 2003-06-11 | 2010-08-11 | 学校法人日本大学 | Method for inhibiting mass formation |
| JP2012176948A (en) * | 2004-03-22 | 2012-09-13 | Osiris Therapeutics Inc | Mesenchymal stem cells and uses therefor |
| US9694035B2 (en) | 2004-03-22 | 2017-07-04 | Mesoblast International Sarl | Mesenchymal stem cells and uses therefor |
| US9943547B2 (en) | 2004-03-22 | 2018-04-17 | Mesoblast International Sàrl | Mesenchymal stem cells and uses therefor |
| US10668101B2 (en) | 2004-03-22 | 2020-06-02 | Mesoblast International Sárl | Mesenchymal stem cells and uses therefor |
| US10716814B2 (en) | 2004-03-22 | 2020-07-21 | Mesoblast International Sàrl | Mesenchymal stem cells and uses therefor |
| US10729727B2 (en) | 2004-03-22 | 2020-08-04 | Mesoblast International Sárl | Mesenchymal stem cells and uses therefor |
| US10828334B1 (en) | 2004-03-22 | 2020-11-10 | Mesoblast International Sárl | Mesenchymal stem cells and uses therefor |
| US10960025B2 (en) | 2004-03-22 | 2021-03-30 | Mesoblast International Sárl | Mesenchymal stem cells and uses therefor |
| US11389484B2 (en) | 2004-03-22 | 2022-07-19 | Mesoblast International Sárl | Mesenchymal stem cells and uses therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1987005518A1 (en) | 1987-09-24 |
| EP0302862A1 (en) | 1989-02-15 |
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