JPH10509704A - Use of phosphonoacetic acid or phosphonoformic acid against human herpesvirus-7 (HHV-7) - Google Patents
Use of phosphonoacetic acid or phosphonoformic acid against human herpesvirus-7 (HHV-7)Info
- Publication number
- JPH10509704A JPH10509704A JP8515727A JP51572796A JPH10509704A JP H10509704 A JPH10509704 A JP H10509704A JP 8515727 A JP8515727 A JP 8515727A JP 51572796 A JP51572796 A JP 51572796A JP H10509704 A JPH10509704 A JP H10509704A
- Authority
- JP
- Japan
- Prior art keywords
- hhv
- acid
- infection
- treatment
- activity against
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 title claims description 14
- 241000701041 Human betaherpesvirus 7 Species 0.000 title claims description 13
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 title claims description 12
- 229960005102 foscarnet Drugs 0.000 title claims description 7
- 238000011282 treatment Methods 0.000 claims abstract description 10
- 241001529453 unidentified herpesvirus Species 0.000 claims abstract description 9
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims abstract description 8
- 208000037773 HHV-7 infectious disease Diseases 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000000694 effects Effects 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 238000011321 prophylaxis Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 241000700605 Viruses Species 0.000 claims description 3
- 241000282412 Homo Species 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 239000003981 vehicle Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000700586 Herpesviridae Species 0.000 description 1
- 241000701027 Human herpesvirus 6 Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- -1 for example Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
(57)【要約】 ＨＨＶ−７感染の治療（予防を包含）に用いる医薬の製造における、ヘルペスウイルスに対する活性を有するピロリン酸アナログの使用。 (57) [Summary] Use of a pyrophosphate analog having activity against herpes virus in the manufacture of a medicament for the treatment (including prophylaxis) of HHV-7 infection.
Description
【発明の詳細な説明】 ヒト・ヘルペスウイルス−７（ＨＨＶ−７）に対するホスホノ酢酸またはホスホ ノギ酸の使用 本発明は、ヒト・ヘルペスウイルス７（ＨＨＶ−７）により引き起こされる感 染の治療およびかかる状況の治療に用いる医薬の製造における化合物の使用に関 する。 本明細書の用語「治療」は、適宜、予防を包含する。 ホスホノ酢酸（ＰＡＡ）およびホスホノギ酸（ＰＦＡ、フォスカルネト（fosc arnet））はピロリン酸アナログであり、ヘルペスウイルスグループのメンバー を含むいくつかのウイルスの複製を阻害する（Oberg,Pharmacol.Ther.19,387-41 5,1983）。 ヒト・ヘルペスウイルス７（ＨＨＶ−７）は、ヘルペスウイルス科の最近発見 されたメンバーである。該ウイルスはＴ細胞活性化を誘導する条件下で培養され た健康個体の末梢血リンパ球（ＰＢＬ）から１９８９年に単離された。 該ウイルスＤＮＡの制限エンドヌクレアーゼプロフィールの分析により、新た な病因は既知ヒト・ヘルペスウイルスと異なっていることが示された。次いで、 ＨＨＶ−７が健康成人の７５％の唾液から単離された。正常集団の約９０％から の血清標本においてＨＨＶ−７に対する抗体を検出することができ、通常には２ 歳以降の小児期においてセロコンバージョンが起こる。 ＨＨＶ−７はヒト・免疫不全ウイルス（ＨＩＶ−１）の活性化において役割を 果たしている可能性がある。 上記化合物がＨＨＶ−７に対する潜在的活性を有することが、今回見いだされ た。 したがって、本発明は、ヒトにおけるＨＨＶ−７感染の治療方法であって、ヘ ルペスウイルスに対する活性を有する有効量のピロリン酸アナログをかかる治療 を必要とするヒトに投与することを特徴とする方法を提供する。 化合物を生物学的前駆体または医薬上許容される塩の形態として投与してもよ い。 非経口投与には、化合物および滅菌賦形剤を含有する液体の１回分の剤型を調 製する。賦形剤および濃度にもよるが、化合物を懸濁または溶解することができ る。通常には、化合物を賦形剤に溶解し、適当なバイアルまたはアンプル中に充 填する前に化合物をフィルター滅菌し、次いで、密封することにより非経口溶液 を調製する。有利には、局所麻酔剤、保存料および緩衝化剤のごときアジュバン トも賦形剤に溶解させる。安定性を向上させるために、組成物をバイアル中に充 填した後凍結し、減圧下で水分を除去することができる。 化合物を賦形剤に溶解せずに懸濁し、さらに化合物を滅菌賦形剤に懸濁する前 にエチレンオキサイドに曝露すること以外は実質的に同じ方法で非経口用懸濁液 を調製する。有利には、界面活性剤または湿潤剤を組成物に入れて本発明化合物 の均一な分散を容易にする。 化合物が十分に生体に利用される場合には、ヒトに経口投与してもよく、シロ ップ、錠剤またはカプセルの形態としてもよい。錠剤形態の場合、かかる固形組 成物の処方に適する医薬担体、例えば、ステアリン酸マグネシウム、澱粉、ラク トース、グルコース、米粉、小麦粉および胡粉を用ることができる。化合物を消 化可能カプセル、例えばゼラチンカプセルに入った形態としてもよく、あるいは シロップ、溶液または懸濁液の形態としてもよい。適当な液体医薬担体はエチル アルコール、グリセリン、セイラインおよび水を包含し、それに香料または着色 料を添加してシロップを作ってもよい。 通常の慣例であるが、普通には、医学的治療に関する使用のための手書きまた は印刷された説明書が組成物に添付されるであろう。 ウイルス感染を治療するための有効量は感染の性質および重篤度ならびに哺乳 動物の体重による。 適当な用量単位（dosage unit）は５０ｍｇないし１ｇの活性成分、例えば１ ００ないし５００ｍｇを含有する。かかる用量を１日１ないし４回、あるいはよ り通常には１日２回または３回投与することができる。一般的には、化合物の 有効量は、１日につき体重１ｋｇあたり０.２ないし４０ｍｇの範囲であろう。 サイトメガロウイルス感染に治療におけるフォスカルネトについての通常の用量 はBritish product data sheetに示されており、２０ｍｇ／ｋｇ体重の用量で３ ０分間の輸液を開始する。 また本発明は、ＨＨＶ−７感染の治療に用いる医薬の製造における、ヘルペス ウイルスに対する活性を有するピロリン酸アナログの使用を提供する。上記方法 でかかる治療を行うことができる。 さらに本発明は、ＨＨＶ−７感染の治療に用いる医薬組成物であって、ヘルペ スウイルスに対する活性を有する有効量のピロリン酸アナログおよび医薬上許容 される担体を含んでなる医薬組成物を提供する。かかる組成物を上記方法で調製 することができる。 ヒト・臍帯血細胞における細胞変性効果の阻害を包含するアッセイ方法を、０ .０１μＭ−１００μＭの用量範囲において行った。一般的方法はＨＨＶ−６に ついて記載されており、Human Herpesvirus;Epidemiology,Molecular Biology a nd Clinical Pathology-Conference Proceedings,Ablashi D.V.(Ed)の第２３章 に記載されている。 DETAILED DESCRIPTION OF THE INVENTION Use of phosphonoacetic acid or phosphonoformic acid for human herpesvirus-7 (HHV-7) The present invention relates to the treatment of infections caused by human herpesvirus-7 (HHV-7) and of such situations It relates to the use of the compounds in the manufacture of a medicament for use in therapy. As used herein, the term “treatment” includes prophylaxis, as appropriate. Phosphonoacetic acid (PAA) and phosphonoformic acid (PFA, foscarnet) are pyrophosphate analogs and inhibit the replication of several viruses, including members of the herpesvirus group (Oberg, Pharmacol. Ther. 19, 387-41). 5,1983). Human herpesvirus 7 (HHV-7) is a recently discovered member of the herpesviridae family. The virus was isolated in 1989 from peripheral blood lymphocytes (PBL) of healthy individuals cultured under conditions that induced T cell activation. Analysis of the restriction endonuclease profile of the viral DNA indicated that the new etiology was different from the known human herpes virus. HHV-7 was then isolated from the saliva of 75% of healthy adults. Antibodies to HHV-7 can be detected in serum samples from about 90% of the normal population, and seroconversion usually occurs in childhood after the age of two. HHV-7 may play a role in the activation of human immunodeficiency virus (HIV-1). It has now been found that the compounds have potential activity against HHV-7. Accordingly, the present invention provides a method of treating HHV-7 infection in a human, comprising administering to a human in need of such treatment an effective amount of a pyrophosphate analog having activity against a herpes virus. I do. The compound may be administered as a biological precursor or in the form of a pharmaceutically acceptable salt. For parenteral administration, liquid dosage forms are prepared containing the compound and sterile vehicles. The compound, depending on the excipient and concentration, can be either suspended or dissolved. Usually, parenteral solutions are prepared by dissolving the compound in an excipient and filter sterilizing the compound before filling into a suitable vial or ampoule and then sealing. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents are also dissolved in the vehicle. To improve stability, the composition can be frozen after filling into vials and the water removed under reduced pressure. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle without dissolution and the compound is exposed to ethylene oxide prior to suspension in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the present invention. When the compound is fully used in living organisms, it may be administered orally to humans and may be in the form of a syrup, tablet or capsule. In the case of tablets, pharmaceutical carriers suitable for the formulation of such solid compositions, for example, magnesium stearate, starch, lactose, glucose, rice flour, wheat flour and chalk can be used. The compound may be in a digestible capsule, for example, a gelatin capsule, or in the form of a syrup, solution or suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerin, saline and water, to which fragrances or colorings may be added to make a syrup. As is normal practice, the composition will usually be accompanied by written or printed instructions for use in medical treatment. Effective amounts for treating viral infections will depend on the nature and severity of the infection and the weight of the mammal. Suitable dosage units contain 50 mg to 1 g of the active ingredient, for example 100 to 500 mg. Such doses can be administered one to four times a day, or more usually twice or three times a day. Generally, an effective amount of the compound will range from 0.2 to 40 mg / kg body weight per day. The usual dose for foscarnet in the treatment of cytomegalovirus infection is given in the British product data sheet, initiating a 30 minute infusion at a dose of 20 mg / kg body weight. The present invention also provides the use of a pyrophosphate analog having activity against herpes virus in the manufacture of a medicament for treating HHV-7 infection. Such treatment can be performed in the manner described above. Further, the present invention provides a pharmaceutical composition for treating HHV-7 infection, which comprises an effective amount of a pyrophosphate analog having activity against herpes virus and a pharmaceutically acceptable carrier. Such compositions can be prepared in the manner described above. Assay methods involving inhibition of cytopathic effects in human cord blood cells were performed in a dose range of 0.01 μM-100 μM. The general method is described for HHV-6 and described in Chapter 23 of Human Herpesvirus; Epidemiology, Molecular Biology and Clinical Pathology-Conference Proceedings, Ablashi DV (Ed).
───────────────────────────────────────────────────── フロントページの続き (72)発明者 フェオリノ，ポール・エム アメリカ合衆国30033ジョージア州 ディ ケーター、クレアモント・ロード1670番 エモーリー・ユニバーシティ・スクール・ オブ・メディシン (72)発明者 ベレ・ホッジ，リチャード・アンソニー イギリス、アールエイチ３・７エイジェ イ、サリー、ベッチワース、ブロッカム・ パーク、スミスクライン・ビーチャム・フ ァーマシューティカルズ────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Feolino, Paul M United States 30033 Georgia Di Cater, Claremont Road 1670 Emory University School Of Medicine (72) Inventors Bere Hodge, Richard Anthony UK, RH 3.7A Lee, Sally, Betchworth, Blockham Park, SmithKline Beecham Hu Armaturicals
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9422781.6 | 1994-11-11 | ||
| GB9422781A GB9422781D0 (en) | 1994-11-11 | 1994-11-11 | Pharmaceuticals |
| PCT/EP1995/004445 WO1996014847A1 (en) | 1994-11-11 | 1995-11-10 | Use of phosphonoacetic or-formic acids against human herpes virus -7 (hhv-7) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH10509704A true JPH10509704A (en) | 1998-09-22 |
Family
ID=10764242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8515727A Pending JPH10509704A (en) | 1994-11-11 | 1995-11-10 | Use of phosphonoacetic acid or phosphonoformic acid against human herpesvirus-7 (HHV-7) |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0790828A1 (en) |
| JP (1) | JPH10509704A (en) |
| GB (1) | GB9422781D0 (en) |
| WO (1) | WO1996014847A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2177788C2 (en) * | 1998-06-10 | 2002-01-10 | Данилов Леонид Леонидович | Preparation to prevent and treat infectious diseases and correct pathological states |
| RU2542420C1 (en) * | 2014-03-13 | 2015-02-20 | Общество С Ограниченной Ответственностью "Гамаветфарм" | Drug substance of polyprenylphosphates and beta-sitosterol and method for preparing it |
-
1994
- 1994-11-11 GB GB9422781A patent/GB9422781D0/en active Pending
-
1995
- 1995-11-10 JP JP8515727A patent/JPH10509704A/en active Pending
- 1995-11-10 WO PCT/EP1995/004445 patent/WO1996014847A1/en not_active Ceased
- 1995-11-10 EP EP95937066A patent/EP0790828A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| GB9422781D0 (en) | 1995-01-04 |
| EP0790828A1 (en) | 1997-08-27 |
| WO1996014847A1 (en) | 1996-05-23 |
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