CN1089478A - 治疗剂及其用途 - Google Patents
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Abstract
本发明涉及用衍生自Mycobacterium vaceae的
抗原和/或免疫调节物质的治疗有或没有AIDS以
及与结核病有关或无关的HIV感染。
Description
本发明涉及用于治疗有AIDS（获得性免疫缺陷综合症）或没有AIDS的HIV感染的治疗剂。
人们知道，AIDS是由逆转录病毒科的一种病毒引起的，该病毒称为HIV（人类免疫缺陷病毒）。然而，感染上HIV并不立即出现明显的AIDS症状。使病毒暴露的唯一指征是，在受感染者的血液中可以存在抗体，继而称该受感染者“HIV阳性”。感染阶段可以处于休眠状态，不出现任何明显的症状。AIDS发育期前的潜伏期可以是从数月到数十年不等。AIDS发育期之前可以是AIDS相关综合征（ARC），AIDS相关综合征的特征为无缘由的发烧，体重减轻，慢性咳嗽或腹泻。
对于在感染上病毒和感染个体的免疫系统崩溃之间的可变更期限的原因了解甚少。目前未知的因素可能导致病毒的繁殖，从而破坏免疫系统。于是该病人会患有各种感染并且由于免疫系统失去作用而恶化导致死亡。
HIV感染与结核病间的联系众所周知。HIV感染的早期结果是使以前休眠的结核杆菌复能。维持对分支杆菌的抵抗力是个主动的免疫过程，该过程由于HIV感染而遭到破坏。在双重感染的病人中休眠结核杆菌的复能速度快且该复能通常发生在出现其它的HIV/AIDS相关感染之前，这强烈地暗示：HIV感染的重要结果正是破坏了可能是T-细胞传递的维持分支杆菌休眠的免疫功能。
也有证据表明，HIV感染加上活动性结核病时，CD4T细胞明显减少，从而使AIDS的明显症状非常迅速地发展。事实上似乎是，在结核病中释放的免疫递质加速了HIV前病毒的复能转化（transactivation）。
我们曾叙述了衍生自分支杆菌属Mycobacterium vaccae'用于治疗结核病的抗原和/或免疫调节物质的用途（见，例如英国专利第2156673号和美国专利第4724144号）。在我们的国际专利申请第PCT/GB90/01169号（公开号为WO91/01751）中描述了同种物质用在免疫预防治疗AIDS，即延长在感染HIV和AIDS的发育之间这一时期方面的用途。
现在我们发现该相同的治疗剂不仅能推迟HIV感染病的AIDS发育，而且能够减轻或甚至消除即使是病情严重的患者的AIDS的明显症状。在也患有结核病的患者身上发现了这些结果，而在有或没有AIDS以没与结核病无关的HIV感染的病人身上也预期能得到这些结果。
因此，本发明提供抗原和/或免疫调节物质的用途，该物质为衍生自Mycobacterium vaccae用于生产可用于治疗与结核病相关或无关的AIDS以及也治疗与结核病相关或无关的HIV阳性无症状的病人的药物。该物质可给例如HIV阳性以及表现出也有或没有结核病的明显症状的AIDS的患者使用，给药量按足以至少能阻止症状发展的剂量。
因此，本发明治疗剂含有M.vaccae的死细胞比较好，含有经高压灭菌法杀死的细胞最好。免疫治疗剂为通常每毫升稀释剂中含微生物108以上，最好是每毫升稀释剂中含杀死的M.vaccae微生物108-1011。本发明包括得自M.vaccae用于治疗有或没有AIDS和HIV感染和与结核病相关或无关的HIV感染的抗原和/或免疫调节物质。
稀释剂可以是注射用无热原盐水，或是PH9.0的硼酸盐缓冲液。稀释剂应该灭菌。适宜的硼酸盐缓冲液为：
Na2B4O7.10H2O 3.63g
H3BO35.25g
NaCl 6.19g
Tween 0.0005%
蒸馏水 至1升
优选的M.vaccae菌株是从乌干达中部Lango地区的泥浆样品中分离出来并用R877R表示的菌株（J.L.Stanford和R.C.Paul，Ann.Soc.Belge Med，Trop.1973，53，第141-389页）。该菌株是稳定的粗略变种并属于aurum亚种。可用生化和抗原的判断的标准鉴定其属于M.vaccae（R.Bonicke，S.E.Juhasz，Zentr albl.Bakteriol.Parasitenkd.Infection Skr.Hyg.Abt.1，Orig.，1964，192，第133页）。
由R877R表示的菌株被保存在National Collection of Type Cultures（NCTC）Central Public Health Laboratory，Colindale Avenue，伦敦NW9 5HT，存放日期为联合王国1984年2月13日，编号为NCTC 11659号。
就该免疫治疗剂的制备而言，微生物M.vaccae可以在适当的固体培养基中生长。优选改良的Sartor氏液体培养基（S.V.Boyden和E.Sorkin.，J.Immunol，1955，75，第15页），用琼脂固化。
固体培养基最好含1.3%琼脂。将用微生物接种后的培养基有氧培养以使该微生物能够生长，一般于32℃培养10天。获得生物体，然后称重并将其悬浮于稀释剂中。稀释剂可以是非缓冲盐水但最好是硼酸盐缓冲的并含有如上所述诸如吐温80的表面活性剂。将悬浮液稀释，得到100mg微生物/ml的悬浮液。最好用硼酸盐缓冲盐水进一步稀释，以使悬浮液成为含10mg微生物（湿重）/ml稀释剂的悬浮液。然后分装于5ml多剂小瓶中。尽管瓶中的微生物可以用辐射例如剂量为2.5兆拉德的钴60辐射或用其它任何手段例如化学方法杀死，但优选高压血菌法杀灭微生物，例如在10磅/平方英寸的压力下灭菌10分钟（115°-125℃）。现已发现高压灭菌法能生产出比辐射灭菌法更有效的制剂。
免疫治疗通常是真皮内注射给药，注射体积在0.1-0.2ml范围内，最好是0.1ml。每个单剂量一般含107-1010杀死的M.vaccae微生物。最好给病人使用含108-109杀死的M.vaccae的单剂，但可以根据病人的情况重复该剂量。
尽管免疫治疗剂通常是真皮内注射核药，但也可以使用其它给药途径，例如口服。
本发明包括治疗有或没有AIDS的HIV感染以及有或没有与结核病有关的AIDS的HIV感染的方法，它包括给有或没有AIDS的HIV感染以及与结核病有关或无关的HIV感染的患者使用衍生自Mycobacterium vaccae的抗原和/或免疫调节物质，用量按足以产生对AIDS症状有效的免疫反应的剂量。
对于20-50%HIV感染的非洲病人来说，结核病是AIDS发育期的第一个症状，在一组接受结核病治疗的病中有17人由Wellcome ELISA检查为HIVI血清反应阳性，针对他们的结核病，给所有的病人开了链霉素、异烟肼、利福平和吡嗪酰胺。缩短治疗时间，在任何情况下治疗时间都没超过3个月，17个病人中，8个接受本发明治疗剂，其余9个给予安慰剂（盐水）。跟踪调查，约1年后仅有三个只接受了抗结核药物治疗的病人活下来了，但所有三个人的结核病都加重了。8个接受本发明治疗剂中的7个人痰涂片检查变成抗酸杆菌（例如结核杆菌）阴性并且病情的综合改善情况类似于HIV外部阳性的结核病人。在诊断时，8个病人中的5个出现淋巴结病，但在跟缩调查时都消退了。在跟踪调查时，其中2个病人再进行血清学检查时发现HIVl阴性。
使用一种以上M.vaccat菌株和/或包括其它分支杆菌抗原的治疗剂是有利的并在本发明范围内，也可以包括结核菌素。
治疗剂也可含卡介面，尤其是该疫苗的冷冻干燥品以增强该治疗剂的效果。
治疗剂可以含其它成分，例如辅助剂、防腐剂、稳定剂等。可以将治疗剂制成灭菌注射液或使用前可配制的灭菌冷冻干燥产品。
可以使用M.vaccae或该有机体的提取物或分出的部分制备本发明治疗剂。
下列实施例描述用于本发明的治疗剂的制备。
实施例
M.vaccee生长在固体培养基上，该培养基为用1.3%琼脂固化的改良Sauton氏培养基。将微生物接种于该培养基并于32℃培养10天，使微生物能够生长。然后收集微生物，称重并将其悬浮于稀释剂中，得到100mg微生物/ml稀释剂的悬浮液。然后将该悬浮液进一步用缓冲盐水稀释至得到含10mg微生物（湿重）/ml稀释剂的悬浮液，并将其分装至5ml多剂小瓶中。然后将含活微生物的小瓶于10磅/平方英寸压力下高压灭菌10分钟以杀死微生物，得到本发明的免疫治疗剂，必要时可将其进一步稀释使用。
该免疫治疗剂可按已述方法皮肉注射给药。
Claims (5)
1、含有衍生自Mycobacterium vaccae的抗原和/或免疫调节物质的用于治疗有或没有AIDS以及与结核病有关或无关的HIV感染的免疫治疗剂。
2、权利要求1的治疗剂，其中源自M.Vaccae的抗原和/或免疫调节物质包括M.vaccae的死细胞。
3、按照权利要求1的治疗剂，其中M.vaccae的细胞已为高压灭菌法杀死。
4、按照权利要求1的治疗剂，其中衍生自M.vaccae的物质来自被保存在National Collection of Type Cultures（NCTC） Central Public Health Laboratory，Colindale路，伦敦NW95HT，
存放日期为联合王国1984年2月13日，编号为NCTC11659的菌株。
5、按照上述任一权利要求的治疗剂，其中衍生自M.vacea的物质被包含在每剂含有107-1010微生物的药物中。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929219425A GB9219425D0 (en) | 1992-09-14 | 1992-09-14 | Therapeutic agent and its use |
| GB9219425.7 | 1992-09-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1089478A true CN1089478A (zh) | 1994-07-20 |
| CN1060937C CN1060937C (zh) | 2001-01-24 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93117218A Expired - Fee Related CN1060937C (zh) | 1992-09-14 | 1993-09-08 | 牝牛分支杆菌在制造用于治疗受hiv感染病人的药物中的应用 |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0661998B1 (zh) |
| JP (1) | JPH06100457A (zh) |
| KR (1) | KR100272743B1 (zh) |
| CN (1) | CN1060937C (zh) |
| AP (1) | AP510A (zh) |
| AT (1) | ATE173633T1 (zh) |
| AU (1) | AU683835B2 (zh) |
| BR (1) | BR9303762A (zh) |
| CA (1) | CA2105646A1 (zh) |
| DE (1) | DE69322280T2 (zh) |
| DK (1) | DK0661998T3 (zh) |
| ES (1) | ES2125331T3 (zh) |
| GB (1) | GB9219425D0 (zh) |
| HK (1) | HK1011289A1 (zh) |
| RU (1) | RU2106878C1 (zh) |
| SG (1) | SG72610A1 (zh) |
| WO (1) | WO1994006466A1 (zh) |
| ZA (1) | ZA935575B (zh) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5985287A (en) * | 1996-08-29 | 1999-11-16 | Genesis Research And Development Corporation Limited | Compounds and methods for treatment and diagnosis of mycobacterial infections |
| US6284255B1 (en) * | 1996-08-29 | 2001-09-04 | Genesis Research & Development Corporation Limited | Compounds and methods for treatment and diagnosis of mycobacterial infections |
| US6406704B1 (en) | 1996-08-29 | 2002-06-18 | Genesis Research And Development Corporation Limited | Compounds and methods for treatment and diagnosis of mycobacterial infections |
| US6878377B2 (en) | 1996-12-18 | 2005-04-12 | Stanford Rook Limited | Mycobacterium vaccae for down-regulation of the Th2 activity of the immune system |
| ATE307600T1 (de) * | 1996-12-18 | 2005-11-15 | Stanford Rook Ltd | Verwendung von mycobacterium vaccae zur therapie des chronischen müdigkeitssyndrom |
| US5968524A (en) * | 1997-12-23 | 1999-10-19 | Genesis Research & Development Corp. | Methods and compounds for the treatment of immunologically-mediated psoriasis |
| US6328978B1 (en) | 1997-12-23 | 2001-12-11 | Genesis Research & Development Corp. Ltd. | Methods for the treatment of immunologically-mediated skin disorders |
| GB9903539D0 (en) | 1999-02-16 | 1999-04-07 | Stanford Rook Ltd | Therapy using M.Vaccae |
| US6350457B1 (en) | 1999-06-02 | 2002-02-26 | Genesis Research & Development Corporation Limited | Methods and compounds for the treatment of immunologically-mediated diseases using mycobacterium vaccae |
| UA77666C2 (en) * | 2001-01-17 | 2007-01-15 | Kabulesh Mafatlal Khamar | Use of mycobacterium w or its components in preparations for treating hiv infection |
| WO2002056898A2 (en) * | 2001-01-17 | 2002-07-25 | Mafatlal Khamar Bakulesh | Immunomodulator for the management of human immunodeficiency virus (hiv) disease/infection |
| GB2400560A (en) * | 2002-01-29 | 2004-10-20 | Rajiv Indravadan Modi | Method of providing prophylaxis for tuberculosis in hiv positive individuals |
| WO2003063896A1 (en) * | 2002-01-29 | 2003-08-07 | Modi, Rajiv, Indravadan | Process of preparing a pharmaceutical composition for immunity against tuberculosis in hiv positive individuals |
| AU2003209534A1 (en) * | 2002-03-08 | 2003-09-22 | Bakulesh Mafatlal Khamar | The method of treating tuberculosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3728367C1 (de) * | 1987-08-25 | 1988-09-01 | Burkhard Steglich | Mittel zur Immunisierung des menschlichen Koerpers bei HIV-Infektionen |
| GB8917256D0 (en) * | 1989-07-28 | 1989-09-13 | Univ London | Biological preparation and its use |
-
1992
- 1992-09-14 GB GB929219425A patent/GB9219425D0/en active Pending
-
1993
- 1993-03-05 SG SG9601341A patent/SG72610A1/en unknown
- 1993-03-05 KR KR1019950701002A patent/KR100272743B1/ko not_active IP Right Cessation
- 1993-03-05 ES ES93905520T patent/ES2125331T3/es not_active Expired - Lifetime
- 1993-03-05 EP EP93905520A patent/EP0661998B1/en not_active Expired - Lifetime
- 1993-03-05 DK DK93905520T patent/DK0661998T3/da active
- 1993-03-05 AU AU36420/93A patent/AU683835B2/en not_active Ceased
- 1993-03-05 AT AT93905520T patent/ATE173633T1/de not_active IP Right Cessation
- 1993-03-05 RU RU93004600A patent/RU2106878C1/ru not_active IP Right Cessation
- 1993-03-05 DE DE69322280T patent/DE69322280T2/de not_active Expired - Fee Related
- 1993-03-05 WO PCT/GB1993/000463 patent/WO1994006466A1/en active IP Right Grant
- 1993-03-09 JP JP5072877A patent/JPH06100457A/ja active Pending
- 1993-08-02 ZA ZA935575A patent/ZA935575B/xx unknown
- 1993-08-05 AP APAP/P/1993/000555A patent/AP510A/en active
- 1993-09-07 CA CA002105646A patent/CA2105646A1/en not_active Abandoned
- 1993-09-08 CN CN93117218A patent/CN1060937C/zh not_active Expired - Fee Related
- 1993-09-10 BR BR9303762A patent/BR9303762A/pt not_active Application Discontinuation
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1998
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Also Published As
| Publication number | Publication date |
|---|---|
| AU3642093A (en) | 1994-04-12 |
| DK0661998T3 (da) | 1999-08-09 |
| DE69322280D1 (de) | 1999-01-07 |
| AP510A (en) | 1996-07-23 |
| EP0661998A1 (en) | 1995-07-12 |
| GB9219425D0 (en) | 1992-10-28 |
| KR100272743B1 (ko) | 2000-11-15 |
| DE69322280T2 (de) | 1999-04-22 |
| SG72610A1 (en) | 2001-07-24 |
| CA2105646A1 (en) | 1994-03-15 |
| AU683835B2 (en) | 1997-11-27 |
| ZA935575B (en) | 1994-03-01 |
| RU2106878C1 (ru) | 1998-03-20 |
| JPH06100457A (ja) | 1994-04-12 |
| HK1011289A1 (en) | 1999-07-09 |
| EP0661998B1 (en) | 1998-11-25 |
| CN1060937C (zh) | 2001-01-24 |
| KR950703360A (ko) | 1995-09-20 |
| ATE173633T1 (de) | 1998-12-15 |
| AP9300555A0 (en) | 1993-10-31 |
| BR9303762A (pt) | 1994-03-22 |
| ES2125331T3 (es) | 1999-03-01 |
| WO1994006466A1 (en) | 1994-03-31 |
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