TW200522938A

TW200522938A - Pharmaceutical composition for elevating white blood cells

Info

Publication number: TW200522938A
Application number: TW93100385A
Authority: TW
Inventors: Richard L Chang; Zheng-Tao Han
Original assignee: Biosuccess Biotech Co Ltd
Priority date: 2004-01-07
Filing date: 2004-01-07
Publication date: 2005-07-16

Abstract

A pharmaceutical composition for elevating white blood cells suitable for parenteral administration to humans includes an effective amount of a compound of the formula (I) or isomers thereof and a pharmaceutically acceptable carrier. Particularly the composition mixing phorbol-12-myristate-13-acetate (TPA) as main ingredient with an aqueous carrier administrates hypodermically to elevate the number of mature white blood cells. The present invention is applicable to treating patients with neoplastic diseases such as leukemia and patients undergoing chemotherapy for the treatment of solid tumors in preventing the number of white blood cells from falling to low levels.

Description

200522938 玖、發明說明：【發明所屬之技術領域】 *人i發:s巧體tf之醫藥組成物，尤指-種可靜脈注射 D體以升问人體内成熟白血球數量之醫藥組成物 = 。’亦可治療經化學治療或放射治療之腫瘤'ί者^改“ 【先前技術】 sir1™ 液腫瘤，該病的特徵是骨髓中原始細胞數目增多 g g卜細4”Λ血病分急性和慢性，〒性白血巧㈣性自血病；紐淋巴性自血病(Aeut = 二！5產生於淋巴組織中，但最初可證實它存在於骨财，各性士的病，史’急性骨髓性白血病可分為若干白血病類型，例如白病、早幼㈣性白血病和單核細胞性白血病。慢性骨髓性 J血病（Chmuc myelogenous leukemia，CML)的特徵是不成孰骨财夕里 =增$，例如嗜中性細胞，嗜伊紅細胞，嗜驗性細胞里常增殖g錾、二巧或其他組織中。大部分慢性骨髓性白血病將發1轉變為期， Ϊ種之為”急性轉化期，，（blaSt Crisis);白血病^治病、，.田胞恢復月髄正韦的造血功能，若以上方法無效，唯有靠骨辦步二而要找到相符合的骨髓通常需花上漫長的時間與多年來致力追求能完全治癒白血病之藥物，並減少:g副=酉子界200522938 发明 Description of the invention: [Technical field to which the invention belongs] * Human i hair: a pharmaceutical composition of tf, especially a pharmaceutical composition that can be injected intravenously into the D body to raise the number of mature white blood cells in the human body =. 'Can also treat tumors treated with chemotherapy or radiation' ^ Modified "[prior art] sir1 ™ fluid tumor, the disease is characterized by an increase in the number of blasts in the bone marrow gg ^ 4" Λ blood disease points acute and chronic , Leukemia, leukemia, and leukemia; neolymphatic leukemia (Aeut = 2! 5 is produced in lymphatic tissue, but it can be initially confirmed that it exists in bone wealth, diseases of all sexes, history of 'acute myeloid Leukemia can be divided into several types of leukemia, such as white disease, early juvenile leukemia, and monocyte leukemia. Chmuc myelogenous leukemia (CML) is characterized by inability to increase the cost of bones, for example Neutrophils, eosinophils, and eosinophils often proliferate in gadolinium, diosine, or other tissues. Most chronic myelogenous leukemias will be transformed into stages 1, which is called the "acute transformation stage," (blaSt Crisis); Leukemia ^ Treatment of disease, Tian cell restores the hematopoietic function of Yuezhengzhenwei. If the above methods are not effective, it is usually necessary to find the matching bone marrow by relying on bones for step two. It usually takes a long time and years Committed to pursuit Completely cured of leukemia drugs, and reducing: g = Unitary vice sector

肉豆證酸醋-13-乙酸酯（phorbo卜 12-myristate-13-acetate，簡稱 TPA)，其 (I) 一^中可從自然界之巴豆油（Crotonoil)中提煉出一種化合物 200522938 ΤΡΑ 服後會中毒，在生物學應用上，可用，用於細胞培養中很_促細胞分裂劑；在人皮_f id續並沒有提到對白血病患者注射包含TPA之然^_文獻明人嘗試將TPA應用於血友^者病本案之發 ’时高人體_白血_^改本發明之主要目的係製造一種醫藥組成物，適於靜脈注射，球if該組成物可用於提高受過放射』之化ίί到上述之目的’本㈣可選擇包括如下舰構式⑴或同分異構物Myrtle vinegar 13-acetate (phorbo 12-myristate-13-acetate, abbreviated as TPA), a compound of which (I) can be extracted from Crotonoil in nature 200522938 ΤΡΑ service It will be poisoned later, and it can be used in biological applications for cell culture. It is a _ mitogen. It is not mentioned in the human skin that the injection of TPA in leukemia patients contains TPA. TPA is applied to the development of the case of hemophilia ^ patients with high levels of human body _ white blood _ ^ The main purpose of the present invention is to manufacture a pharmaceutical composition suitable for intravenous injection. The composition can be used to improve radiation exposure. ίί To the above purpose, the choice can include the following structures or isomers

ux\3 (I) ί何cS勿短ίΚ和不是氫’R3係選自包含下5忒i他ί (f "f it, 為了使本發明之醫藥組成物適合於人體之慈由醫學上可接收之載體製成製劑，載 ^彳’^此需藉明的水溶，溶劑有乙二醇、丙烯二^j等其^合 S；〇 SiE^EL-620 'c» el ' —B〇 (t^f ΐ 200522938 电，無論是^血病之患者’或是受過放、化療之腫瘤病 ^今得控制。以下藉實施例說明如何製作適用於本發明由貫驗室中動物實驗或細胞培養以及臨床應用之成果，效0 之醫藥組成物，並以證明本發明之成【實施方式】首先说明，適用於本發明目的且包含結構式（I)之化合物有下列數種： 2 佛，-13-丁酸自旨（ph〇rb〇i 13-Butyrate); )佛SJ-12-癸酸酉旨（ph〇rb〇i 12-Decanoate); 3) 佛醇-13-癸酸g旨（ph〇rb〇i 13-Decanoate); 4) 佛醇-12，13-二乙酸酯（phorb〇l 12,13-Diacetate); 5) 佛巧-13,2〇-癸酸酯（Ph〇rb〇l l3,2〇_Diacetate); 6) 佛巧-12，13-二苯甲酸酯（ph〇rbol 12,13-Dibenzoate); 7) 佛〒-12，13-二丁酸g旨（phorbol 12,13-Dibutyrate); 8) 佛醇-12，13-二癸酸自旨（phorbol 12，13-Didecanoate); 9) 佛醇-12，13-二己酸酯（phorbol 12,13-Dihexanoate); 10) 佛醇-12，13-二丙酸酯（phorbol 12,13-Dipropionate); 11) 佛醇-12-肉豆謹酸酯（ph〇rb〇l 12-Myristate); 12) 佛醇-13-肉豆蔻酸酯（ph〇rb〇l 13-Myristate); 13) 佛醇-12-肉豆惹酸§旨—13-乙酸g旨（Phorbol 12-Myristate-13-Acetate，簡稱ΤΡΑ); 14) 佛醇-12, 13，20-三乙酸酯（Phorbol 12,13,20-THacetate); 15) 12-脫氧佛醇—13-2-甲代丁稀酸酯（12-De〇xyph〇rbol 13-Angelate); 16) 12-脫氧佛醇一 13-2-曱代丁烯酸-20-乙酸酯（12-Deoxyphorbol 13-Angelate 20-Acetate); 17) 12-脫氧佛醇—13-異丁酸酯（12-Deoxyphorbol 13-Isobutyrate); 18) 12-脫氧佛醇-13-異丁酸-20-乙酸酯（12-Deoxyphorbol 13-Isobutyrate-20- Acetate) ϊ 19) 12-脫氧佛醇—13-苯乙酸酯（12-Deoxyphorbol 13-Phenylacetate); 20) 12-脫氧佛醇-13-苯乙酸-20-乙酸酯（12-Deoxyphorb〇l 13-Phenylacetate 20-Acetate)； 21) 12-脫氧佛醇一 13-肉豆蔻酸酯（12 - Deoxyphorbol 13-Tetradecanoate); 22) 12-脫氧佛醇-13-乙酸酯（Phorbol 12_Tigliate 13-Decanoate); 23) 佛醇-12-曱基巴豆酸-13-癸酸酯（12-De〇xyphorb〇l 13-Acetate); 24) 佛醇-12-乙酸酯（Phorbol 12-Acetate); 25) 佛醇-13-乙酸酯（Phorbol 13-Acetate)。上述之化合物皆屬於市售之產品，其中本發明之實施例將以ΤΡΑ 作為生物學實驗或臨床實驗之主要化合物。 10 200522938 收:載體製射’因此需藉由醫學上可接乙二醇、丙烯二醇、聚乙二醇、丄f等；明巧溶性溶劑有為了更適^1/藥(本體）、苯乙醇等等 >r 為了睁解 Γ8〇)或吐溫一20 配方^ ί瞭解ΤΡΑ化合物與浴劑相容之情形，因此調配了兩組包含^之 1. ΤΡΑ製劑配方A : 2⑽S水===於ί 5菌安|:: 2· ΤΡΑ 製劑配方 Β : 杉“叭 Umg々 ml，0· 5mg/2 nU。里ϊ·1〇，〇·125，〇· 25 或〇. 5mg 的 TPA 溶於〇· 2 ml 乙醇，1 2 mi ^丙醇和0.6ml 0· 9%的生理食鹽水中。在盔菌條件下，4 T二^1»1 t φ 〇· 0^/20^^ 5 : 〇· lOmg/2 ml ； 0. 125mg/2 ml ； 0. 25mg/2 mil 燃· ^分析發現，TPA製劑在避光、低溫保存一年狀態下，沒有任 ’交，至溫且避光狀態下保存兩個月，沒有任何化學改變。予文成物m分別從實驗室研究及臨床應絲分析本發明之醫藥組【實驗室研究結果】 1· TPA對人早幼粒細胞白血病細胞株(hl—6〇)的影響： 5 ΤΡ^處理，胞數量為2 X lOVmi，乙醇含量低於〇〇ι%，用τρα 理二小犄後，觀察到細胞增殖停止，並發生聚集和貼壁，48小時广月，出現型態學變化，4〜6天後，型態學和細胞生物化學研究證明，大: ίίί-60細胞誘導分化成巨噬樣細胞，且具有量效關係。 °丨刀 2·低^彳量ΤΡΑ與阿糖胞苷合用對HL-60的影響：單獨應用阿糖胞（l〇〇ng/ml)，TPA(20ng/ml)對HL-60細胞均有較弱的誘導分化作用，低劑量TPA(20ng/inl)與阿糖胞苷（100ng/ml)合用 HL-60細胞誘導分化有協同作用。、〗對 3· TPA對小鼠移植性腫瘤S18〇的影響：貫驗共分8組，每組7隻邑明種小鼠，2組做對照，6組用藥，在s明種小鼠前肢下分別接種2 X 106 Sis。細胞，24或72小時後，給小鼠腹月* 今瘤體局部$射ΤΡΑ，TPA注射劑量為50、1〇〇、200vg/kg/每天，連續^ 藥7天。停藥後24小時處死動物，秤重腫瘤，計算抑瘤率，做統計‘八 200522938 ^ Ιϊΐ，示’腹腔注射TPA5G、1GG、2GGv_/每天，連續給荜7 2_cr/l留ft別為 4i· 7%、54. 8%和 3〇·4% ;瘤體局部注射 MO : 100、 2^(^kg/母天，連縯給藥7天，抑瘤率分別為邪.5% 病理學檢查證明，TPA用藥後細胞出現分化。 ·。# 59·2/〇。 4· TPA對小鼠移植性腫瘤Bl6細胞的影響：八4組’每組7隻C57種系小鼠，1組做對照組，3組用筚TPA，隻Cs7小鼠前肢下接種0.2ml Bl6細胞1 : 6 w/v勻聚混縣液接 ΐί弟Λ天严i始用藥TPA，其劑量分別為腹腔注射50、1〇Γ2〇ί/ΐί 母天’連，給藥8天，停藥後處死動物，秤重腫瘤，其抑瘤率分Α 59. 4%^ 32. 1%，40. 0%^ 5· TPA對荷瘤小鼠外周血白血球和血紅蛋白的影響：給士 ^接種Sm細胞，第3天開始腹腔給藥ΤΡΑ5(Γ、1〇〇、2〇〇vg/i^/畚 t ^天/停藥後第2天，從小鼠尾部取血樣，做自血球和血紅蛋白刀析，TPA給樂組的白血球數量分別為16· ι± 7· 4、18· 7± 3. G和20 7 ± 3· 4 X 1〇 /L，對照組白血球數量為13· 6± 1· 8 X 1〇9/l，用藥細a έτ 別為136± 11、149± 12和142± 1()g /L，對照組血紅ί白量為 U4± 15g/L。結果顯示，腹腔注射ΤΡΑ能升高小鼠外周血的白血球數量”，且i有量效關係，而與對照組比較，TPA用藥組的血紅蛋白含量未有明顯改〇【臨床研究應用】 1·由於TPA+局部應用會引起強烈的發炎反應，因此對患者應採用靜脈滴注方式給藥。取TPA注射液，注射入200ml 0.9%的生理食鹽水中，奋公、、曰勻後供靜脈滴注。 2·臨床應用不同劑量τρα的藥性和副作用： (1) 患者每週用藥TPA lmg/每次：將含lmgTPA的注射液與200ml 0· 9%的生理食鹽水充分混勻，供靜脈滴注，靜脈滴注速度為16微克/分，約1小時滴完，Τρα靜脈^注後約1小，，患者開始寒顫，持續時間30分，繼之發燒(體溫達 37. 5〜39. 5 C，持續3〜5小時，然後降至正常），並伴有輕度到重度排汗，患者上述症狀可通過給予糖皮質激素緩解，該劑量TPA可引起個別患者出血，幾例患者出現短時間呼吸困難，尿中可測出血紅蛋白。然而這些副作用均是短暫的和可逆的，患者心、肝、腎、肺功能均為正常。 (2) 患者母週用藥TPA兩次〇. 5mg : 將〇· 5 mg TPA的注射液與200ml 〇·⑽的生理食鹽水充分混勻供靜脈滴注，靜脈滴注速度為8微克/分，約1小時滴完，TPA給藥後的反應類似lmg TPA的給藥反應，但要比lmg劑量的反應輕。患者更易受該較低的劑量，偶爾在幾例患者的尿液中測出血紅蛋白，未發生出血 200522938 ’患者心、肝、腎、肺功能均為正常。 (3)tf母週用藥TPA四次〇 25mg: 靜X商主射液與2_請的生理食鹽水充分混勻，供然也觀k到'/ϋ度為4微克/分，約1小時滴完，TPA給藥後雖中夫制ϊ Ϊ和务熱，但要比上述高劑量的反應輕的多，患者尿液 ❾S蛋白’未發生出血和呼吸困難。患者心、肝、腎、肺功 ⑷患藥TPA人次，劑量分別為四次。· 15呢及四次。.Img : 八=1將ϋ5ΐη、〇·1呢的ΤΡΑ注射液與20〇ml 〇. 9%的生理食鹽水充 5滴注，滴注時間均約為1小時’用藥後均未在患者展出、、，工蛋白，均未發現寒顫、發熱、出血和呼吸困難等副反應，卜心、肝、腎、肺功能均為正常。〜每週t 藥’認騎週四次G.1〜G.15mg織，基本上無副反應； Γ ΛΑ^Ι25呢及母週兩次〇·5呢有副反應，但患者可耐受；每週每次 1 旦^的毋性副，較大，患者不易耐受。因此建議TPA升高白血球給藥用里构u· img〜ϋ· 25mg/每次，而用於白血病治療的劑量為〇· 25〜〇· 5mg/每次。【臨床研究成果】广本發明之醫藥組成物對$例慢例轉急變白血病患者和5例呈他白血臨f療效評價分別敘述如下：（其中編號卜5號紐性白“轉急性白血病之患者，編號6〜10為其他類型的白血病） ⑴T. S，、男’ 32，病染號：28879 4PA治療前血象：血紅蛋白：289g/L， ^=求· 1. 〇 x 1〇9 /L，血小板·· l35 X 1〇9 /L。骨髓象：原始細胞+ 早幼粒細胞：30%。TPA治療：lmg/每週X 2，TPA治療後血象：血紅蛋白： 86g/L ;白血球·· 2. 8 X 1〇9 /L，血小板：283 X 1〇9 /L。骨髓象：原始細胞+早幼粒細胞：2. 5%。、 (2) C· J，男，30，病染號·· 29926。TPA治療前血象··血紅蛋白·· 94g/L，球：9.8x l〇9/L’血小板：63x 1〇9几。脾臟··肋下3公分。骨髓象：原始細胞+早幼粒細胞·· 36%。TPA治療：lmg/每週X 5，TPA治療後血象：血紅蛋白：l〇4g/L ;白血球：4. 9 X 10VL，血小板：80 x 109 /L，脾臟：肋下〇· 5公分。骨體象··原始細胞+早幼粒細胞：。 ⑶Ζ· K，男，42，病染號：18102。TPA治療前血象：血紅蛋白：70g/L，白血球：27· 5 X 109 /L，血小板：21 X 1〇9 /L。骨髓象··原始細胞+ 早幼粒細胞：90%。TPA治療：lmg/每週X 7，TPA治療後血象：血紅蛋白： 96g/L ’白血球.22 X l〇j /L，血小板：70 X 109 /L。骨骨遗象：原始細胞+早幼粒細胞：2%。 '、 ⑷W· F，男，25，病染號：21315。TPA治療前血象：血紅蛋白：87g/L，白血球：19 X 109 /L，血小板：150 X 1〇9几。骨髓象：原始細胞+早幼粒細胞：67· 5%。TPA治療：lmg/每週X 7，TPA治療後血象：血紅蛋白： 200522938 /L，血小板：21〇 x 109 /L。骨髓象：原 45g/L ;白血球：53. 5 X l〇s 始細胞+早幼粒細胞：4. 5%。 R38 5 ： 23965 ° TPA ^ : ： 84g/L ^ 早幼二於·· 4 J τΐ/血小板：29〇 X 1〇9 /L。骨趙象：原始細胞+ 4g/L ’白血球· 27· 3 x l〇 /L，血小板：i7〇 χ〗η9 /τ。骨黯奐· 原始細胞+早幼粒細胞：15%。 ⑽W X 10 /L。月如象· 利i述用=治f ?都曾接受過不同的化療，包括祕脈，馬肉Li =6胞/in5’ 例在IPA治療，有效。™ q ί，7»母天X 2 , TPA用藥後，患者再靜脈滴注阿糠胞 ίt 上述治療，患者短期内部達到骨髓象臨床緩解，另些患i臨㉟，。均未發現患者骨髓抑制，感染或出血。這ux \ 3 (I) He cS Do n’t be short and it is not hydrogen 'R3 is selected from the group consisting of the following 5 忒 i he (f " f it, in order to make the pharmaceutical composition of the present invention suitable for the human body by medical science Acceptable carriers are made into formulations containing ^ 彳 '^ which need to be water-soluble, and the solvents include ethylene glycol, propylene di ^^, etc .; SiE ^ EL-620' c »el '—B〇 (t ^ f ΐ 200522938 Electricity, whether it is a patient with blood disease 'or a tumor disease that has been treated with radiotherapy and chemotherapy ^ control can now be given. The following examples illustrate how to make animal experiments or cells suitable for use in the laboratory of the present invention. The results of the cultivation and clinical application, the efficacy of the pharmaceutical composition of 0, and to prove the achievements of the present invention. [Embodiment] First, it is explained that the compounds suitable for the purpose of the present invention and containing the structural formula (I) include the following: 2 Buddha, -13-butanoic acid (ph〇rb〇i 13-Butyrate);) Buddha SJ-12-decanoic acid (ph〇rb〇i 12-Decanoate); 3) phoranol-13-decanoic acid g (Ph〇rb〇i 13-Decanoate); 4) phorbol-12,13-diacetate; 5) phorqiao-13,2-decanoate (Ph 〇rb〇l l3,2〇_Diacetate); 6) Foqiao-1 2,13-dibenzoate (ph〇rbol 12,13-Dibenzoate); 7) phorbol-12,13-dibutyrate g (phorbol 12,13-Dibutyrate); 8) phorol-12, 13-didecanoate (phorbol 12,13-Didecanoate); 9) phorbol-12,13-dihexanoate; 10) phorbol-12,13-dipropanoic acid Phorbol 12, 13-Dipropionate; 11) phorol-12-myristate; 12) phorbol-13-myristate 13-Myristate); 13) phoritol-12-myrtoic acid § intent—13-acetic acid g intent (Phorbol 12-Myristate-13-Acetate, referred to as TPA); 14) phorin-12, 13, 20-three Acetate (Phorbol 12,13,20-THacetate); 15) 12-deoxyphorol- 13-2-methyl succinate (12-De〇xyph〇rbol 13-Angelate); 16) 12-deoxy 12-Deoxyphorbol 13-Angelate 20-Acetate; 17) 12-Deoxyphorbol 13-Isobutyrate (12-Deoxyphorbol 13- Isobutyrate); 18) 12-Deoxyphorbol-13-Isobuty-20-20 Acetate) ϊ 19) 12-deoxyphorol-13-phenylacetate ( 12-Deoxyphorbol 13-P henylacetate); 20) 12-Deoxyphorol-13-Phenylacetate-20-Acetate; 21) 12-Deoxyphorol 13-Petylacetate 20-Acetate; 12-Deoxyphorbol 13-Tetradecanoate); 22) 12-Deoxyphorbol-13-acetanoate (Phorbol 12_Tigliate 13-Decanoate); 23) phorol-12-fluorenylcrotonic acid-13-decanoate (12-De Xyxy boll 13-Acetate); 24) Phorbol 12-Acetate; 25) Phorbol 13-Acetate. The above-mentioned compounds are all commercially available products. In the embodiment of the present invention, TPA is used as the main compound for biological experiments or clinical experiments. 10 200522938 Receive: Carrier-made shots, so it needs to be medically accessible to ethylene glycol, propylene glycol, polyethylene glycol, 丄 f, etc .; it is clear that soluble solvents are more suitable for ^ 1 / medicine (bulk), benzene Ethanol, etc.> In order to dissolve Γ80) or Tween-20 formula ^ ί Understand the situation that the TPA compound is compatible with the bath, so two sets of 1. TPA formulation formula A: 2⑽S water == = 于 ί 5 Mycobacteria | :: 2 · TPA Formulation Formula B: Shan "Bom Umg々ml, 0.5mg / 2 nU. Liϊ · 10, 〇125, 〇25 or 0.5mg of TPA soluble In 0.2 ml of ethanol, 12 mi of propanol and 0.6 ml of 0.9% physiological saline. Under the condition of Helicobacter, 4 T 2 ^ 1 »1 t φ 〇 0/20 ^ 5: 〇 LOmg / 2 ml; 0. 125mg / 2 ml; 0. 25mg / 2 mil. ^ Analysis found that the TPA preparations were stored for one year in the dark and at low temperature, without any intercourse, and in a warm and dark state It was stored for two months without any chemical changes. Yuwenchengwum respectively analyzed the laboratory and clinical application of the medical group of the present invention [laboratory research results] 1. TPA on human promyelocytic leukemia cell line (hl 6〇) effects: 5 TP ^ treatment, the number of cells is 2 X lOVmi, the ethanol content is less than 0.00%, after using τρα to treat the two small pupae, cell proliferation was stopped, and aggregation and adherence occurred, 48 hours Guangyue, a morphological change, 4 to 6 days later, morphological and cellular biochemical studies proved that the large: ίί-60 cells induced differentiation into macrophage-like cells, and had a dose-effect relationship. ° 丨 2 · Effect of low-dose TPA combined with cytarabine on HL-60: Application of arabinocytosine (100 ng / ml) alone, TPA (20 ng / ml) has weaker induced differentiation on HL-60 cells Effect, low-dose TPA (20ng / inl) and cytarabine (100ng / ml) combined with HL-60 cells have a synergistic effect on the differentiation of HL-60 cells. Effect of 3. TPA on mouse transplanted tumor S18. It is divided into 8 groups, each group contains 7 mice, 2 groups are used as controls, 6 groups are treated with medicine, and 2 x 106 Sis are inoculated under the forelimbs of the mice, respectively. After 24 or 72 hours, the mice are given the mice. Abdominal month * The tumor was spotted with TPA, and the TPA injection dose was 50, 100, and 200 vg / kg / day for 7 consecutive days. The animals were sacrificed 24 hours after stopping the treatment, and the scales were swollen. Calculate the tumor inhibition rate, and do statistics 'eight 200522938 ^ Ιϊΐ, showing' intraperitoneal injection of TPA5G, 1GG, 2GGv_ / day, continuously give 荜 7 2_cr / l to leave 4i · 7%, 54.8%, and 30% 4%; local injection of MO: 100, 2 ^ (^ kg / mother day, 7 days of continuous dosing, tumor inhibition rate was 5%. Pathological examination showed that cells differentiated after TPA administration. ·. # 59 · 2 / 〇. 4. The effect of TPA on mouse transplanted tumor Bl6 cells: Eighty-four groups of seven C57 germline mice in each group, one group as a control group, three groups with TPA, and only Cs7 mice were inoculated with 0.2ml Bl6 under the forelimbs Cell 1: 6 w / v homogeneous mixed mixed solution was added to the younger brother 天 Tianyan i before taking TPA, the doses were intraperitoneal injection of 50, 1〇Γ2〇ί / ΐί mother's day, for 8 days, the drug was discontinued The animals were sacrificed and the tumors were weighed. The tumor inhibition rate was A 59.4% ^ 32.1%, 40.0% ^ 5. The effect of TPA on peripheral blood leukocytes and hemoglobin in tumor-bearing mice: ^ Sm Cells were started intraperitoneally with TAPA5 (Γ, 100, 2000 vg / i ^ / 畚 t ^ day / day 2 after discontinuation of the drug, blood samples were taken from the tails of mice, and blood cells and hemoglobin were analyzed by knife analysis. The number of white blood cells in the TPA group was 16 · ι ± 7 · 4, 18 · 7 ± 3. G and 20 7 ± 3 · 4 X 10 / L, and the number of white blood cells in the control group was 13. 6 ± 1 · 8 X 1〇9 / l, the dosage was 136 ± 11, 149 ± 12, and 142 ± 1 () g / L, and the amount of red blood in the control group was U4 ± 15g / L. The results showed that the intraperitoneal injection of TPA could Increase the number of white blood cells in peripheral blood of mice ", and i has a dose-effect relationship, and Compared with the control group, the hemoglobin content of the TPA medication group did not change significantly. [Clinical research application] 1. Because TPA + topical application can cause a strong inflammatory response, patients should be administered by intravenous drip. Take TPA injection, Injected into 200ml of 0.9% physiological saline, and then intravenously infused after Fen Gong, Jiu Jie. 2. Clinical properties and side effects of clinical application of different doses τρα: (1) Patients take TPA 1mg / time: 1mg TPA The injection was thoroughly mixed with 200ml of 0.9% physiological saline for intravenous infusion. The intravenous drip rate was 16 μg / min. The drip was completed in about 1 hour. The Tρα was about 1 hour after the intravenous injection. The patient started Shivering, lasting 30 minutes, followed by fever (body temperature reaches 37.5 to 39.5 C, lasting 3 to 5 hours, and then returns to normal), accompanied by mild to severe perspiration, the above symptoms of the patient can be given by Glucocorticoid remission, this dose of TPA can cause bleeding in individual patients, several patients have short-term dyspnea, and hemoglobin can be measured in urine. However, these side effects are transient and reversible, patients' heart, liver, kidney, lung (2) The patient was administered TPA twice a week in the mother's body. 0.5 mg: 0.5 mg of TPA injection and 200 ml of physiological saline were thoroughly mixed for intravenous drip, and the intravenous drip rate was 8 micrograms / minute, about 1 hour after the drip, the response after TPA administration is similar to the 1 mg TPA administration response, but it is lighter than the 1 mg dose response. Patients are more susceptible to this lower dose. Occasionally hemoglobin was measured in the urine of several patients and no bleeding occurred. 200522938 ′ Patients' heart, liver, kidney, and lung functions were normal. (3) Tf mother's weekly medication TPA four times 025mg: Jing X Shang main cumshot was fully mixed with 2_ physiological saline, please do n’t forget that the degree is 4 micrograms / minute, about 1 hour After the drip, although TPA was administered by the husband, the reaction was much lighter than the high dose mentioned above, and the patient's urine ❾S protein did not cause bleeding and dyspnea. The patient's heart, liver, kidney, and lung functions were affected by TPA, and the doses were four times. · 15 times and four times. .Img: Eight = 5 drops of ϋ5ΐη, 〇1? TPA injection and 20ml of 0.9% physiological saline solution for 5 drops, the infusion time is about 1 hour. No adverse reactions such as chills, fever, bleeding, and dyspnea were found in the production, engineering, and protein. Heart, liver, kidney, and lung functions were normal. ~ Drugs per week t. G.1 ~ G.15mg weaving four times a week, basically no side effects; Γ ΛΑ ^ Ι25, and twice a week maternal 0.5 side effects, but patients can tolerate; Sexual adjuvants are once a week once a week, which is large and difficult for patients to tolerate. Therefore, it is recommended that TPA be used to increase leukocyte administration img ~~ 25mg / time, and the dosage for leukemia treatment is 0.25 ~ 0.5mg / time. [Clinical research results] The efficacy of the pharmaceutical composition of the present invention in evaluating patients with slow-onset acute leukemia and 5 patients with hepatocellular leukemia was described as follows: (Numbers 6 to 10 are other types of leukemia) ⑴T.S., Male '32, disease number: 28879 4PA blood before treatment: hemoglobin: 289g / L, ^ = ask for 1. 〇x 1〇9 / L, Platelets ·· 35 × 109 / L. Bone marrow image: blasts + promyelocytic cells: 30%. TPA treatment: 1 mg / week X 2, blood image after TPA treatment: hemoglobin: 86g / L; white blood cells · 2 8 X 109 / L, platelets: 283 X 109 / L. Bone marrow image: blasts + promyelocytes: 2.5%. (2) CJ, male, 30, disease infection number · 29926. Blood image before TPA treatment ·· Hemoglobin · 94g / L, Ball: 9.8x109 / L 'Platelets: 63x 109. Spleen · 3 cm below the ribs. Bone marrow image: primitive cells + early childhood Granulocytes 36%. TPA treatment: 1 mg / week X 5, blood after TPA treatment: hemoglobin: 104 g / L; white blood cells: 4.9 X 10 VL, platelets: 80 x 109 / L, spleen: Subcostal 0.5 cm. Bone body image · Primitive cells + Promyelocytic cells: ⑶ KK · K, male, 42, disease number: 18102. Blood image before TPA treatment: hemoglobin: 70g / L, white blood cell: 27 · 5 X 109 / L, platelets: 21 X 109 / L. Bone marrow image ·· blast cells + promyelocytic cells: 90%. TPA treatment: 1 mg / week X 7, blood image after TPA treatment: hemoglobin: 96 g / L 'White blood cells. 22 X l0j / L, platelets: 70 X 109 / L. Bone and bone image: blasts + promyelocytes: 2%.', ⑷W · F, male, 25, disease number: 21315. Blood image before TPA treatment: hemoglobin: 87g / L, white blood cells: 19 X 109 / L, platelets: 150 X 109. Bone marrow image: blasts + promyelocytic cells: 67.5%. TPA treatment: 1mg / Weekly X 7, blood image after TPA treatment: hemoglobin: 200522938 / L, platelet: 210x 109 / L. Bone marrow image: original 45g / L; white blood cells: 53.5 X l0s original cells + promyelocytic cells : 4. 5%. R38 5: 23965 ° TPA ^:: 84g / L ^ 2 as early as 4 J τΐ / Platelet: 29〇 × 109 / L. Bone Zhaoxiang: Primitive cells + 4g / L 'White Blood Cells · 27 · 3 xl〇 / L , Platelet: i7〇 χ〗 η9 / τ. Bone dysfunction · Primitive cells + promyelocytic cells: 15%. ⑽W X 10 / L. Yueruxiang Liliyong = zhif? Have received different chemotherapy, including secret veins, horse meat Li = 6 cells / in5 ’cases, effective in IPA treatment. ™ q ί, 7 »mother day X 2, TPA medication, the patient then intravenously infusion of almond cell ίt the above treatment, the patient achieved clinical remission of bone marrow in the short term, and others suffered from clinical problems. No bone marrow suppression, infection, or bleeding was found in the patients. This

患者診斷為早幼粒細胞性白血病，廳*11月發病。 4nA 象典血紅蛋白：6〇g/L，白血球：〇·4 x 1〇9 /L，血小板： Ο X 10 /L。月髓象：原始細胞+早幼粒細胞：。τρα治療· img/每 ^^^/f^rD；6 χ ι〇5^^ 3° 、.工蛋白· 118g/L· ,白血球：4· 1 X 1〇9 /[，血小板·· 8〇 χ 1〇9 /L。月原始細胞+早雜細胞：3%，達職病例緩解標準。該患者已缓 (7^M. W，男，67，患者診斷為骨髓不典型增生並伴隨單核細胞串、者口服VP16四個月無效。此後患者接受如下合併治療； ^ 1用f 糖歸。ΤΡΑ缝^The patient was diagnosed with promyelocytic leukemia and the onset of the disease occurred in November. 4nA elephant hemoglobin: 60 g / L, white blood cells: 0.4 x 109 / L, platelets: 0 X 10 / L. Lunar myelogram: blasts + promyelocytes:. τρα treatment · img / per ^^^ / f ^ rD; 6 χ 〇〇5 ^^ 3 °, .in protein · 118g / L ·, white blood cells: 4 · 1 X 109 / [, platelets ·· 80 χ 109 / L. Monthly primordial cells + early heterogeneous cells: 3%, meet the standard of case remission. The patient has been delayed (7 ^ M.W, male, 67. The patient was diagnosed with atypical bone marrow hyperplasia accompanied by a mononuclear cell string, and oral VP16 was not effective for four months. After that, the patient received the following combined treatment; ^ 1 with f sugar .TPA slit ^

=9) )/、用樂週。ΤΡΑ治療前血象··血紅蛋白：36g/L，白血球：4· ο X =/L，血小板：29 χ 1〇9 /L。其中原始細胞2% ;早幼粒細胞：4% :中胞ί 3% ·;嗜中性細胞：60% ;淋巴細胞：25% ;單核細胞·· 6%。TPA 二療剷骨髓象.骨體增殖活躍，原始細胞：跳；早幼粒細胞肋下3cm。ΤΡΑ治療後脾臟：肋下〇· 5cm。ΤΡΑ治療後血象胞H醎. • 42g/L，白血球· 1〇· 2 χ 1〇9 /L，血小板·· 34 χ 1〇9 /L。其中，中性 H : 80% ;淋巴細胞]9% ;單核細胞·· 1%，外週血中未發丨見原始細 ^早幼粒細胞。骨齡：骨_殖活躍，原始細胞：4% ;早^細胞： ^ · Q，男，36 ,患者診斷為早幼粒細胞性白血病。患者用維甲 50治療無效。TPA治療：0· 5mgx 2/每週χ 3。TPA治療前血象··血 f蛋f : 45g/L，白血球：1· 〇 χ 1〇9几，血小板：35 χ 1〇9几象·月髓增殖極低下，原始細胞+早幼粒細胞：8〇· 8%。TPA治瘆德a參· 血紅蛋白：66g/L ;白血球：2· 2 χ 1〇VL，血小板：223 血f。· 骨髓象：骨體增殖活躍’原始細胞+早幼粒細胞：17%。 ⑼ζ· H，女，2卜患者診斷為慢性粒細胞性白血病化療後骨髓抑制並繼 14 200522938 發再生障礙性貧血。患者曾接受馬利蘭治療三個月。TPA治療前血象：血紅蛋白：43g/L，白血球：1. 6 X 109 /L，血小板：26 X 109 /L。骨髓象：再生障礙性貧血。TPA治療：〇· 25mgx 2。TPA治療後血象：血紅蛋白：32g/L ;白血球：1. 9 X 1〇9 /L，血小板：57 X 109 /L。因患者嚴重貧血而終止治療。 (1〇) L· N，女，26，患者診斷為慢性粒細胞性白血病。患者曾接受高三尖杉酯碱和阿糖胞苷的合併化療。TPA治療前血象··血紅蛋白：98g/L，白血球：2· 0 X 1〇9 /L，血小板：102 X 109 /L。患者靜脈輸注〇· 25mgTPA —次。TPA治療後血象：血紅蛋白：96g/L ;白血球：2. 0 X 109 /L，血小板：112 X l〇9/L°TPA給藥後的第2天，外週血中原始細胞+早幼粒細胞：4% ;中幼粒細胞：5%。TPA給藥後第5天，此類細胞在外週血中完全消失。以上之床療效總結資料如表一：表一病例編號 iM中原始細胞和早幼例細臉的百t μ μ TD A γτλτλ * .. TTPA治療前= 9)) /, use music week. Blood image before TPA treatment ·· Hemoglobin: 36 g / L, white blood cells: 4 · X = / L, platelets: 29 χ 109 / L. Among them, 2% are primordial cells; 4% are promyelocytic cells; 3% are neutrophils; 60% are neutrophils; 25% are lymphocytes; 6% are monocytes. TPA second therapy shovel bone marrow. Bone proliferation is active, primordial cells: jumping; promyelocytic cells 3cm below the ribs. Spleen after TPA treatment: 0.5cm below the ribs. Blood cells H 胞 after treatment with TPA. • 42 g / L, white blood cells · 10 · 2 χ 109 / L, platelets · 34 χ 109 / L. Among them, neutral H: 80%; lymphocytes] 9%; monocytes ... 1%, no primordial fine promyelocytic cells were found in peripheral blood. Bone age: Bone colonization is active, primitive cells: 4%; early cells: ^ · Q, male, 36, the patient was diagnosed with promyelocytic leukemia. The patient was ineffective with Vega 50. TPA treatment: 0.5 mg x 2 per week x 3. Blood image before the treatment of TPA ·· blood f egg f: 45g / L, white blood cell: 1.0 × 1.09, platelet: 35 × 109 ° · Lumens proliferation is extremely low, primordial cells + promyelocytic cells: 80.8%. TPA treatment of ginseng a. · Hemoglobin: 66 g / L; white blood cells: 2.2 x 100VL, platelets: 223 blood f. · Bone marrow image: Bone body is proliferating ’primitive cells + promyelocytic cells: 17%. ⑼ζ · H, female, 2 patients diagnosed with bone marrow suppression following chemotherapy for chronic myelogenous leukemia and subsequent aplastic anemia. The patient had been treated with Maliland for three months. Blood images before TPA treatment: hemoglobin: 43g / L, white blood cells: 1.6 X 109 / L, platelets: 26 X 109 / L. Bone marrow like: aplastic anemia. TPA treatment: 0.25 mg x 2. Blood images after TPA treatment: hemoglobin: 32g / L; white blood cells: 1.9 X 109 / L, platelets: 57 X 109 / L. Treatment discontinued because of severe anemia. (10) L · N, female, 26. The patient was diagnosed with chronic myelogenous leukemia. The patient had received chemotherapy with homoharringtonine and cytarabine. Hematology before TPA treatment ·· Hemoglobin: 98g / L, white blood cells: 2.0 × 109 / L, platelets: 102 × 109 / L. The patient was given an intravenous infusion of 0.25 mg TPA-once. Blood image after TPA treatment: hemoglobin: 96g / L; white blood cells: 2.0 X 109 / L, platelets: 112 X 10 / L ° On the 2nd day after TPA administration, blasts + promyeloblasts in peripheral blood Cells: 4%; Mesenchymal cells: 5%. On the 5th day after TPA administration, such cells completely disappeared in peripheral blood. Table 1 summarizes the curative effect of the above beds. Table 1 Case No. Hundred t of the original cells and early and young cases of fine face in iM μ μ TD A γτλτλ * .. before TTPA treatment

劑治療後個別臨床診斷如下The individual clinical diagnosis after the drug treatment is as follows

(11) L. X，女，50。诊斷為惡性淋巴瘤。患者曾接受阿霍夸激素治療。TPA治療前血象：血紅蛋白：78g/L ，、板：245 x 10VL。TPA 治療：〇· 25mgX 4，TPA 治療後L10 5 蛋白：76g/L ;白血球：6. 8 x 10VL，血小板：331 X ·血紅繼續化療5天，再給予0. 5mgTPA，患者白血球維持在3 〇。然後並繼續進行化療。 · /L以上， 15 200522938 (12) Y. G，女，45。診斷為腫瘤。化療後血象為：血紅蛋白 TPA； i〇；：L^H^3i9 人TPA用藥後血象·血紅蛋白· i23g/L，白血球·· 4 $ γ in9八，企小板·· 436 X 1〇9 /L。患者繼續進行化療。 · (13) G. F，男，60。診斷為肺癌。化療後血象為··血έ | 100I 1?l〇兩-人。TPA用樂後第2天血象：血紅蛋白：74g/L;白血球：2 5 Y in^，血小板：110 x 1〇9 /L。患者進行繼續化療。 · (1L) Z.mRfi女；ϋ診斷為乳癌。化療後白血球為：3.8 X 1〇9 /L，血小白血球：Χ8. Ο X ϋ者靜脈輸注〇. 25mg ΤΡΑ 一次。ΤΡΑ用藥後第2天 ^〇Ϋ；Τ2·4 Χ 109/L； TPA治療：0. 25呢。TPA用藥後第2天血象：白 7蛋白丨几： 6% ；： 77 X 109 /L ； χ T · 109g/L<>TPA用藥後第4天血象：白血球：4 4 X 109 (36中χ性ίΡ/T 21淋巴細胞：3% ;血小板：105 X 11)9 /L ;紅細胞：蛋白：U2g/L。TPA用藥後症狀：寒顫，局部刺激和輕微頭痛。心、肝、腎、肺功能正常。 tp! ° vpi6 ^ ^ mmt x 1〇9/l: 中木^胞：23〇/〇;血小板··101 x i〇9/l;紅細胞^ 。/Γ _114g/L。TPA用藥後第1天血象··白血球·· 5· 2 x L 中淋巴細胞··13%;血小板··60 x 109 /L;紅細 w丄血紅蛋白：122g/L°TPA用藥後第2天血象··白血 /t ： ? QQ y ： 8〇% ：： 2〇% ；： 64 X 1〇9 ΐ , f =已〇几；血紅蛋白：1〇9g/L。TPA用藥後症狀··寒 ,另員舍熱’局。卩刺激。心、肝、.腎、肺功能正常。〇7)i·^: 3°^斷為乳腺癌。手術後用環碟胺、甲氨蝶呤、5—氟 $ 匕Ϊ .。^巧樂：〇.25mgX 2(兩次給藥間隔4天）。™用藥前血 t白^ ·/Τ2· 1〇 /L ;中性細胞：85% ;淋巴細胞：15% ;血小板：欠天血工i田胞x 1〇12 /l9;血紅蛋白·· 107心 ^ : 2·9 X 10 /L ；： 83% ; Π7/Ι 1〇9/L；^&：3.36x 1〇VL；«x^^： ·β:/τρ^ί f 1給藥後第2天血象··白血球：3·8 χ i〇9 /l ;中性 r s -ri ：^ -7 · 3· -1〇： 86%；^^：14%；^fe：193x 1〇VL；m：3.49x 1〇Vl ；* 16 200522938 π 白：112g/L。。TPA用藥後症狀：寒顫持續20分，繼之發熱，體 pC，持續4小時，有局部刺激。心、肝、腎、肺功能正常。二男，56。診斷為腸癌。手術後用順翻、VP16、5—敦♦定化療。 )a樂：0· 25mgx 2(兩次給藥間隔1天）。τρα用藥前血象：白血球： 109/L;中性細胞：63%;淋巴細胞= 37%;血小板：208 x 109 /L; 胞：4· 0 X 1012 /L ;血紅蛋白：i〇4g/L。TPA第2次給藥後第1天冢/r^i血球：4. 0 X 1〇9 /L ;中性細胞·· 60% ;淋巴細胞：40% ;血小 f^L98x 1〇9/L;紅細胞：4·1χ 1〇12几；血紅蛋白：ii2s/l。™ 後f狀：寒顫、發熱，局部刺激。心、肝、腎、肺功能正常。」男，66。診斷為肺癌腎上腺轉移。手術後用絲裂霉素、長春新 ft胺化療。ΤΡΑ給藥·· 0· 25mgx 2(兩次給藥間隔1天）。ΤΡΑ用 f月;〗^象·白血球丨2·9 x 1〇9 /L ;中性細胞：76% ;淋巴細胞：24〇/0 ; TPA227 5 10 /L ;紅細胞：3· 33 x 1〇12 /L ;血紅蛋白：100g/L。 ^次給藥後第1天血象··白血球·· 5·1 x 1〇9/L;中性細胞·· 82% ; ί巴血小板:93x 1〇9几;第2天血象：白血球:5·〇χ 1〇9 ，中性細胞：80% ;淋巴細胞：20% ;血小板：ν/α ;紅細胞：3 25 X 1〇12 肝:#紅=能1if。ΤΡΑ用藥後症狀：寒顏、發熱，局部刺激。心、 (2^. nn斷為ΐ道癌肝轉移。患者接受愛紫杉化療、_、 7 Q工Τ疋等化療。丁給藥· 2mg。第1、3天分別給藥〇· 25呢，第5、 9天勿別給予〇. 5呢。TPA用藥前血象：白血球：〇. 7 χ 1〇9 /L ;中，細胞：29% ;淋巴細胞：71% ;血小板：未測；紅細胞：2 82丨12乃· =紅蛋白:87g/L。第2天血象:白血球:。· 9 χ 1〇9)L ,·中：: 淋巴細胞：34% ;血小板：82 X i〇Vl ·，紅細胞：2· 17 X i〇i2 ;T66t ^蛋白·· 72g/L。第4天血象：白血球·· u x 1〇VL ;中 j 1〇9/L；M：2.09x 1〇Vl It ，白· 58g/L。第6天血象：白血球：19 χ 1〇9 /L ;中性細、’· 淋巴細胞· 5%，血小板：43 x i〇9 /l ;紅細胞：ι· g χ ^12 0 ’ J白:70g^L。第8天血象j白血球:2·3Χ 1〇vL;紅細胞:1·71χ’ ； /L ·;血紅蛋白·· 61g/L。第13天血象：白血球：l 9 χ 1〇92〉91· x J ，· 90% 木巴細胞：10% ;血小板：32 χ 1〇9/L ;紅細胞’ 田2 /L ;血紅蛋白：57g/L。TPA用藥後症狀：第三次給藥後出^ x ^ 時間約30分。心、肝、腎、肺功能正常。雌出現承頸，持續 (21) D. Y，女，32。診斷為淋瘤骨轉移。患者接受環磷，械化，。TPA給藥··第卜2天分別給藥〇. 25mg，第素1 分別給予0· 5mg。TPA用藥前血象：白血球：i 1 / ! fj. 5、6、8天 73% ;淋巴細胞:27% ;血小板:144 x 1QVL ;紅 /L ’中'^^ : 17 200522938 3蛋，：142g/L。第2天血象：白血球：〇. 6 x 1〇Vl f f ^巴細胞:未測;血小板:69 x 1()9 /L;紅細胞:4· 15 Γ 1〇12· 91〇紅·气白：117g/L。第4天血象：白血球·· 〇· 6 X l。9 /L中二二巧，„細胞· 72% ;血小板：68 X 1〇9 /L ;紅細胞：3· 95 X ίο。$ . :气白：109g/L。第7天血象：白血球：〇· 8 χ 1〇9 /L ; x』二，，，巴細胞：12% ;血小板：6〇 χ 1〇9几；紅細胞中,,·· ^工蛋白：110g/L。第9天血象：白血球：h 5 χ 1〇9 /L ·，X =二L·， 80/〇;^木巴細胞·· 20% ;血小板·· 69 χ 1〇VL ;紅細胞·· 4· 〇2 : ^ 盔紅5白！Ji2g/L。ΤΡΑ用藥後症狀：無寒顫、無發熱，有局部刺激。心：月社肺功能與ΤΡΑ用藥前相同。由於該患者淋巴瘤已轉移到骨體， Γ22口Λ V使，，較長療程的ΤΡΑ只能升高很低水平的白二^ (222 Χ·/ίί，34^知斷為鼻咽癌頸部淋巴結轉移。患者曾接受5-氟痛阿霉素，甲氨蝶呤化療。ΤΡΑ用藥前血象：白血球：1 9 X 109/1 ·(11) L. X, female, 50. Diagnosed as malignant lymphoma. The patient had previously been treated with ajoqua hormone. Blood before TPA treatment: hemoglobin: 78g / L, plate: 245 x 10VL. TPA treatment: 0.25 mgX 4, L10 5 protein after TPA treatment: 76 g / L; white blood cells: 6.8 x 10 VL, platelets: 331 X · blood red Continue chemotherapy for 5 days, and then give 0.5 mg TPA, the patient's white blood cells were maintained at 3 〇 . Then continue with chemotherapy. Above / L, 15 200522938 (12) Y. G, female, 45. Diagnosed as a tumor. The hemogram after chemotherapy is: hemoglobin TPA; i0 ;: L ^ H ^ 3i9 blood hemoglobin after administration of human TPA · hemoglobin · 23g / L, white blood cell · 4 $ γ in9 eight, enterprise small plate · 436 X 109 / L . The patient continued chemotherapy. · (13) G. F, male, 60. Diagnosed as lung cancer. Blood image after chemotherapy was ·· 血 έ | 100I 1? L〇 Two-person. On the second day after TPA application, the hemogram: hemoglobin: 74 g / L; white blood cells: 2 5 Y in ^, platelets: 110 x 109 / L. The patient continued chemotherapy. (1L) Z.mRfi female; ϋ diagnosed with breast cancer. After chemotherapy, the white blood cells were: 3.8 × 109 / L, and the small blood white blood cells: X8. 〇 X ϋ intravenous infusion of 0.25 mg ΤΑ once. 25th。 TPA 2 days after administration ^ 〇Ϋ; T2 · 4 χ 109 / L; TPA treatment: 0.25 it. Blood image on day 2 after TPA administration: albumin 7 protein a few: 6%;: 77 X 109 / L; χ T · 109g / L < > Blood image on day 4 after TPA administration: white blood cells: 4 4 X 109 (36 medium X-type LP / T 21 lymphocytes: 3%; platelets: 105 X 11) 9 / L; red blood cells: protein: U2g / L. Symptoms after TPA administration: chills, local irritation, and mild headache. Heart, liver, kidney, and lung functions are normal. tp! ° vpi6 ^ mmt x 109 / l: medium wood cells: 23 〇 / 〇; platelets · 101 x 109 / l; red blood cells ^. / Γ _114g / L. Hematology on the 1st day after TPA administration ... White blood cells ... 5 x 2 x L lymphocytes ... 13%; platelets ... 60 x 109 / L; red blood haemoglobin: 122 g / L ° TPA on the second day after drug administration Hematology ·· white blood / t:? QQ y: 80%:: 20%;: 64 X 109 ΐ, f = several years; hemoglobin: 109 g / L. Symptoms after taking TPA ·· cold.卩 stimulation. Heart, liver, kidney and lung functions are normal. 〇7) i: 3 ° was diagnosed as breast cancer. After the operation, cyclodipamine, methotrexate, and 5-fluoro $. ^ Qiao Le: 0.25 mg X 2 (4 days between doses). ™ blood before treatment ^ · / Τ2 · 10 / L; neutrophils: 85%; lymphocytes: 15%; platelets: Hetian Xuegong i field cell x 1012 / l9; hemoglobin · 107 hearts ^: 2 · 9 X 10 / L ;: 83%; Π7 / Ι 1〇9 / L; ^ &: 3.36x 1〇VL; «x ^^: · β: / τρ ^ ί f 1 after administration Blood image on the second day ·· White blood cells: 3.8 χ i〇9 / l; Neutral rs -ri: ^ -7 · 3 · -10: 86%; ^^: 14%; ^ fe: 193x 1VL ; M: 3.49x10Vl; * 16 200522938 π white: 112g / L. . Symptoms after TPA administration: chills continued for 20 minutes, followed by fever, pC for 4 hours, and local irritation. Heart, liver, kidney, and lung functions are normal. Two men, 56. Diagnosed as bowel cancer. After the operation, cisplatin, VP16, 5-dun was used to determine chemotherapy. A) Le: 0.25 mg x 2 (1 day interval between doses). τρα blood before treatment: white blood cells: 109 / L; neutrophils: 63%; lymphocytes = 37%; platelets: 208 x 109 / L; cells: 4.0 x 1012 / L; hemoglobin: 104 g / L. TPA / r ^ i blood cells on the first day after the second administration of TPA: 4.0 X 109 / L; neutrophils · 60%; lymphocytes: 40%; blood small f ^ L98x 109 / L; erythrocytes: 4.1 x 1012; hemoglobin: ii2s / l. Post-f-shaped: chills, fever, local irritation. Heart, liver, kidney, and lung functions are normal. Male, 66. Diagnosis of adrenal metastases from lung cancer. Chemotherapy was performed with mitomycin and vinblastine after surgery. TAP administration: 0.25 mg x 2 (1 day interval between doses). TPA is used for months; · elephant · white blood cells 2 · 9 x 109 / L; neutrophils: 76%; lymphocytes: 24〇 / 0; TPA227 5 10 / L; red blood cells: 3.33 x 1〇 12 / L; hemoglobin: 100g / L. ^ Hematology on day 1 after administration · White blood cells · 5.1 · 109 · L; neutrophils · 82%;; Platelet: 93x109; blood on day 2: white blood cells: 5 〇χ109, neutrophils: 80%; lymphocytes: 20%; platelets: v / α; red blood cells: 3 25 X 1012 liver: #red = able 1if. Symptoms after TPA administration: cold face, fever, local irritation. Heart, (2 ^. Nn was diagnosed as liver cancer metastasis to the sacral cancer. Patients received chemotherapy such as Acetaxel, 7 and 7 Q workers, etc .. D was administered 2 mg. On the first and third days, 0.25 was administered separately. Do not give 0.5 on the 5th and 9th days. TPA blood before treatment: white blood cells: 0.7 χ 109 / L; medium, cells: 29%; lymphocytes: 71%; platelets: not measured; red blood cells : 2 82 丨 12 = · Albumin: 87 g / L. Blood image on day 2: White blood cells: · 9 χ 109) L, · Medium: Lymphocytes: 34%; Platelets: 82 X iOVl · , Red blood cells: 2.17 X io2; T66t protein · 72g / L. Blood on day 4: white blood cells · u x 10VL; medium j 109 / L; M: 2.09x 10Vl It, white 58g / L. Blood image on day 6: white blood cells: 19 χ 109 / L; neutral fine, '· lymphocytes · 5%, platelets: 43 xi〇9 / l; red blood cells: ι · g χ ^ 12 0' J white: 70g ^ L. Blood image on the 8th day: white blood cells: 2.3 x 10 vL; red blood cells: 1. 71 x '; / L ·; hemoglobin · 61 g / L. Blood image on day 13: white blood cells: l 9 χ 1〇92> 91 · x J, · 90% malignant cells: 10%; platelets: 32 χ 109 / L; red blood cells' Tian 2 / L; hemoglobin: 57 g / L. Symptoms after TPA administration: ^ x ^ time after the third administration is about 30 minutes. Heart, liver, kidney, and lung functions are normal. Females appear neck-bearing and last (21) D. Y, female, 32. Diagnosed as lymphoma bone metastases. The patient received cyclophosphine, mechanized. TPA administration ··························································································································· for 2 days for the first two days, and 0.5 mg for the first and second doses. Blood before TPA administration: white blood cells: i 1 /! Fj. 73% at 5, 6, and 8 days; lymphocytes: 27%; platelets: 144 x 1QVL; red / L 'medium' ^^: 17 200522938 3 eggs, 142g / L. Blood image on day 2: white blood cells: 0.6 x 10 volts ^ cells: not measured; platelets: 69 x 1 () 9 / L; red blood cells: 4.15 Γ 1012 · 91〇 red · air white: 117g / L. Blood on day 4: white blood cells ···· 6 X l. 9 / L, 22%, cells 72%; platelets: 68 X 109 / L; red blood cells: 3.95 X ο. $ .: Qi white: 109g / L. Blood image on day 7: White blood cells: 〇 · 8 χ 109 / L; x Ⅱ, ba cells: 12%; platelets: 60 χ 109; red blood cells, ... ^ Engineering protein: 110g / L. Blood image on day 9: White blood cells: h 5 χ 109 / L ·, X = two L ·, 80 / 〇; ^ muba cells · 20%; platelets · 69 χ 10 VL; red blood cells · 4 · 〇2: ^ helmet Red 5 white! Ji2g / L. Symptoms after TPA administration: no chills, no fever, local irritation. Heart: Yueshe lung function is the same as before TPA administration. Because the patient's lymphoma has metastasized to the bone, Γ22 口 ΛV Therefore, the longer course of TPA can only raise very low levels of Bai Er ^ (222 × · ίί, 34 ^ is known to be cervical lymph node metastasis of nasopharyngeal carcinoma. The patient has received 5-fluridorubicin, Methotrexate chemotherapy. TPA blood before treatment: white blood cells: 1 9 X 109/1 ·

Tpfi£. Γ；：： !18g/L ° TPA ： °- 25^ ； ft用，後弟1天血象·白血球：18 x 1〇9 /L ;中Tpfi £. Γ;:: 18g / L ° TPA: °-25 ^; for ft, blood sacrifice 1 day after the younger blood · white blood cells: 18 x 109 / L; Medium

2i〇/〇；： 116^/L ： 2 9 X ；〇9 /L ： 27〇/〇：： 123S/L ° ^ ^ ^ 二1X 1〇 A;中性細胞：82%;淋巴細胞：18%;血紅蛋白：118g/L。樂後症狀：寒顏’發熱(39· 2。C)持續4小時。心、肝、腎、肺功淋尸2 j ·用象·白血球· 2· 3 X 1〇9 /L ;中性細胞：52% ; f 胞· 48%、，血紅蛋白：144g/L。TPA 治療：〇· 25mg。TpA 用紅蛋L· 血/fjJ X 1〇VL ;中性細胞：53% ;淋巴細胞：^ 淋巴么田的·心if疋^血产：白血球：3· 9 X 1〇9/L ;中性細胞：44〇/° ; f ^細胞· 56%，血紅蛋白：i29g/L。第7天血象：白血球：3· 7 x 1〇VL ; 52% ；： 138g/L ° TPA ^ : 低^熱37·8 〇。心、肝、腎、肺功能正常。細胞血象蛋白 im6i°診&斷為多發性骨髓瘤。患者接受長春新域，阿霉素等 =用^則，象.白血球：L 1 x 1〇9 /L ;中性細胞：73% ;淋巴 ^/。，血、、工蛋白：112g/L。ΤΡΑ治療：〇· 25mg。ΤΡΑ用藥後第1天，血，：5· 3 X 1〇9 /L ;中性細胞：6〇% ;淋巴細胞：4〇% ;血紅 ^」i9g/L ^ΡΑ用藥後症狀··無寒顫，無發熱，無局部刺激。心、肝、月、肺功能正常。女，42。診斷為乳腺癌。患者接受環磷胺、絲裂霉素、5一氟噹。疋化療。TPA用藥前血象：白血球χ 1〇VL，•中性細胞：72〇/〇; Ϊ胞：28% ί血紅蛋白：126g/L。TPA治療：〇· 25呢。TPA用藥後第1 f疋H血球：6· 4 X 1〇9 /L ;中性細胞·· 90% ;淋巴細胞：10% ;血、、工蛋白.126g/L°TPA用藥後症狀：無寒顫，無發熱，因液體外漏而引起 18 200522938 局部紅腫疼痛，這些症狀第2天消失。心、肝、腎、肺功能正常。 (26) Q. W，男’ 56。診斷為食道癌手術後肝轉移。患者接受順翻，紫杉醇化療。TPA用藥前血象：白血球：3. 6 X 109 /L ;中性細胞：80% ;淋巴細胞：20% ;血紅蛋白：I24g/L。TPA治療·· 0· 25mg。TPA用藥後第1天血象·白血球：X 1〇9 /L ;中性細胞：83% ;淋巴細胞·· 17% ;血紅蛋白· 120g/L。第2天血象：白血球：5· 6 X 109 /L ;中性細胞：81% ; 淋巴細胞·· 19%;血紅蛋白：ii6g/L〇TPA用藥後症狀：發熱39。C持續 3小日$ ’月痛’腹;舄（症狀很快消失）。心、肝、腎、肺功能正常。以上編號11-26號案例之臨床療效總結如表二所示·· 表二 —___白血球數量（X 10s 編號 /L) 11.12. 13· 14· 15. 16.17. 18. 19. 20. 21. 22. 23. 24· 25. 26· TPA治療前TPA治唪後2i〇 / 〇 ;: 116 ^ / L: 2 9X; 〇9 / L: 27〇 / 〇 :: 123S / L ° ^ ^ ^ 2 1X 10A; neutrophil: 82%; lymphocyte: 18 %; Hemoglobin: 118g / L. Symptoms after music: Han Yan 'fever (39. 2 C) lasted 4 hours. Heart, Liver, Kidney, and Pulmonary Function Gonorrhea 2j · Elephant Elephant · White Blood Cells · 2.3 X 109 / L; Neutral Cells: 52%; F Cells · 48%, and Hemoglobin: 144g / L. TPA treatment: 0.25 mg. TpA with red egg L · blood / fjJ X 1〇VL; Neutrophil: 53%; Lymphocyte: ^ Lymphatic field · Heart if ^ Blood production: White blood cell: 3.9 X 109 / L; Neutral Cells: 44 ° / °; f cells 56%, hemoglobin: i29g / L. Blood image on day 7: white blood cells: 3.7 x 10 VL; 52%; 138 g / L ° TPA ^: low ^ heat 37.80. Heart, liver, kidney, and lung functions are normal. Cell hemoglobin protein im6i ° was diagnosed as multiple myeloma. The patient received Changchun Xinyu, doxorubicin, etc., using 则, like. White blood cells: L 1 x 109 / L; neutrophils: 73%; lymphatic ^ /. , Blood, engineering protein: 112g / L. TAP treatment: 0.25 mg. On the first day after TPA administration, blood: 5.3 × 10 9 / L; neutrophils: 60%; lymphocytes: 40%; blood red ^ ″ i9g / L ^ PHA symptoms after administration ·· no tremor No fever and no local irritation. Heart, liver, month, and lung function were normal. Female, 42. Diagnosis of breast cancer. The patient received cyclophosphamide, mitomycin, and 5-fluorobutane.疋 chemotherapy. Blood images before TPA administration: white blood cells χ 10VL, • neutrophils: 72〇 / 〇; cells: 28%; hemoglobin: 126g / L. TPA treatment: 0.25. 1st f 疋 H blood cells after TPA administration: 6.4 X 109 / L; neutrophils · 90%; lymphocytes: 10%; blood, engineering protein. 126g / L ° TPA symptoms after administration: None Shivering, no fever, local swelling and pain caused by fluid leakage 18 200522938 These symptoms disappeared on the second day. Heart, liver, kidney, and lung functions are normal. (26) Q. W, M’56. Diagnosis of liver metastases after esophageal cancer surgery. The patient received cisplatin and paclitaxel chemotherapy. Blood images before TPA administration: white blood cells: 3.6 X 109 / L; neutrophils: 80%; lymphocytes: 20%; hemoglobin: I24g / L. TPA treatment ... 25 mg. On the first day after TPA administration, hematology · white blood cells: X 109 / L; neutrophils: 83%; lymphocytes · 17%; hemoglobin · 120g / L. Blood image on day 2: white blood cells: 5.6 X 109 / L; neutrophils: 81%; lymphocytes · 19%; hemoglobin: ii6g / L. TPA symptoms after administration: fever 39. C lasts 3 small days. ‘Moon Pain’ belly; 舄 (symptoms soon disappear). Heart, liver, kidney, and lung functions are normal. The clinical efficacy summary of the cases No. 11-26 above is shown in Table II. Table II — ___ Number of white blood cells (X 10s number / L) 11.12. 13 · 14 · 15. 16.17. 18. 19. 20. 21. 22. 23. 24 · 25. 26 · After TPA treatment before TPA treatment

ί综寺，但由於患者對這些華物產★而0〜…博肥甘Ura-c) ^時間内就達到臨解，另外未出現骨髓抑制、感毕和屮^，士夕2 了療期間和治療後，患者均緩解已超過6 J月一 * 夕數患者自首次應用TPA治療起，臨床另外，TPA也可用於治療接受放、化療的腫瘤患者，以升高他們的白血 200522938 ，機體抗感染的白血球對化療藥物特別敏减，如果這此抗威毕高常發生顧ΤΡΑ治療後的-天相的’患者的白血球升肺癌腸癌、前列腺癌等等各類實體腫瘤因J發：低是，的，τρα *助於維持白血球或抗感染馳在適的作用疋包圍和破壞已進入機體内的細菌，TPA通過盆 ς 輕患者的感染，減少抗生素應有和縮短住院_用曰可減生物體可鎖獲得其免疫系統的重要瞻/Ί 白血球數錢，血球ί=ί有ίίί=|的作用’因此，本發明也適用於任何白 t ^ 冗:以改善白血球過低之情形，具有產業上化ig'j综 comprehensive temple, but due to the patient's treatment of these Chinese products ★ and 0 ～… 博肥甘 Ura-c) 解 within a short period of time, and no bone marrow suppression, sensation and depression ^, Shi Xi 2 during the treatment period and After treatment, all patients have been relieved for more than 6 months. * The number of patients has been treated with TPA for the first time. In addition, TPA can also be used to treat tumor patients receiving radiotherapy and chemotherapy to increase their white blood. 200522938 Leukocytes are particularly sensitive to chemotherapy drugs. If this is the case, anti-Wei Bi will often occur after the TPA treatment-patients with white blood cells, lung cancer, colon cancer, prostate cancer and other solid tumors due to J: , Τρα * helps to maintain the proper function of white blood cells or anti-infection. It surrounds and destroys bacteria that have entered the body. TPA can reduce the infection of patients and reduce hospitalization by reducing the infection of patients. The important thing that a body can acquire to obtain its immune system is: Counting money with white blood cells, blood cells ί = ί 有 ίίί = | 'Therefore, the present invention is also applicable to any white blood ^ Redundant: To improve the situation of white blood cells being too low, it has an industry on ig'j

Claims

200522938 Scope of patent application: within, including

(I) where Ri and R2 are selected from the group consisting of the following---C (0) -alkyl, lice root, alkyl groups containing 1 to 15 carbon atoms, he substituted dagger% U it?丄 tC (〇) · phenyl, -〇 groups: hydrogen and -C (O) ^ chain ^ group 2 ^ one is not hydrogen, R3 is selected from the group consisting of Related to the pharmaceutical composition, the carrier of which is a water-based 3 «Brain ™, Gang M composition 54, age-deprived, its napkin composition is specifically described in the white blood cell enhanced warship drug composition, and its napkin is the pharmaceutical composition Hydrogen. 1 and h, one of them is -0-C (0) -alkyl, the other is · 〇_c (〇)-short chain alkenyl, the chemical system is 7. As claimed, R2 is -0 —C (0) -CHr ^ There is a medicinal composition of leukocyte enhancer as described in above, wherein Ri and & at least 8 ^ = ^! Decanoate or myristate. 剂关The medicinal composition of the white blood cell enhancer according to item 1, wherein the medicinal composition is 90.1, 0.25 mg, and 0.5 mg. • The pharmaceutical composition of the white blood cell enhancer according to item 8 of IIA !! Substance, wherein the medicinal composition 1Q = is a t-pulse injection medicine enclosed in an ampoule .. The medicinal composition of the leukocyte enhancer according to item 9 of the scope of material and benefits, wherein the medicinal composition is ^) phorol-12-carboxylic acid] 3_ acetic acid (ph〇rb〇i-i2-myristate- 13-acetate, abbreviated as U. The white blood cell enhancer pharmaceutical composition as described in item 1 of the patent application scope, wherein the medicinal composition 21 200522938 can be used to treat leukemia. 12. The white blood cell enhancement described in item 1 of the patent application scope Medicinal composition, wherein the medicinal composition can be used for the treatment of tumor patients with low white blood cells after chemotherapy or radiation treatment ^. I3. The white blood cell enhancer medicinal composition according to item 1 of the patent application scope, wherein The effective dose is 1,000 mg to 1-5 mg per administration, 1 to 7 times per week, and continuous administration for 1 to 7 weeks. H. The pharmaceutical composition of the white blood cell enhancer as described in the 13th item of the patent application, wherein the effective dose is a Dosing 0.05mg ~ lmg, 1 ~ 7 times a week, continuous dosing for 1 ~ 7 weeks. ···, mother-human 15 · If the white blood cell enhancer medicine and product of the 14th patent application, Among them, 0.5 mg to 0.6 mg is effectively administered, and 1 weekly is administered. ~ 7 times, continuous administration for ~ 7 weeks. Moon hook mother long-term fine white blood cell enhancer pharmaceutical composition of item 15, wherein the effective dose includes each

22 200522938 (1) Designated representative map: (1) The designated representative map in this case is: (). (2) A brief description of the component representative symbols of this representative map:

捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention:

7