$13522 A7 B7 經濟部中央樣準局貝工消费合作社印装 五、發明説明（1) 本發明有關於一種用於預防内毒素休克所引起之死 亡的藥學組合物，其包括腐肉素以及藥學上可相容之載 體或稀釋劑。 病重病人對細菌抵抗力較弱，常會有細菌感染，其 中革蘭氏陰性細菌之細胞壁含内毒素（endotoxin)，主成 份為脂多聽體（lip〇p〇lysaccharide;LPS)，會使體内產生各 種組織介素（cytokines)，如腫瘤壞死因子（tumor necrosis factor)及IL-1等，會使血管擴張、血壓降低、產生休克 ，很多病重病人常死於此種内毒素休克。 這種休克至今尚無良方治療，過去慣用的超大量類 固醇靜脈注射[如甲基去氫氧化可體松 (methylprednisolone)，30毫克/公斤體重]的治療，已在 大型的雙盲臨床試驗中否定其療效。唯一可能有效的脂 多醣抗血清療法，則尚在進行臨床療效評估，這種休克 的醫治困難在於不明其發病機轉（mechanism)。 發明人前曾於中華民國第81 1 10533號專利申請案 (審查中）及美國第08/044,233號專利申請案（已核准）中發 現精胺酸l%(arginase)和精胺酸（arginine)皆能保護小白鼠 免於内毒素休克的死亡。由於精胺酸^•會分解精胺酸為 鳥胺酸（ornithine)及尿素（urea)，鳥胺酸還可轉變為腐肉 素（putrescine)，再繼續生成兩種多胺（polyamine)—精胺 素（spermidine)和精胺（spermine)，因此發明人亦曾試驗鳥 胺酸及精胺素對於内毒素休克的效果，結果發現鳥胺酸 和精胺素對於小老鼠的内毒素休克亦有保護作用，結果 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先聞讀背面之注意事項再填寫本頁) -裝. 訂$ 13522 A7 B7 Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (1) The present invention relates to a pharmaceutical composition for preventing death caused by endotoxin shock, which includes procarcin and pharmaceutically acceptable Compatible carrier or diluent. Seriously ill patients have weak resistance to bacteria and often have bacterial infections. Among them, the cell wall of Gram-negative bacteria contains endotoxin. The main component is lipopolysaccharide (LPS). It produces various cytokines, such as tumor necrosis factor and IL-1, which will cause blood vessels to dilate, lower blood pressure, and produce shock. Many seriously ill patients often die from this endotoxin shock. There is no cure for this shock. In the past, the treatment of very large amounts of intravenous steroids [such as methylprednisolone (30 mg / kg body weight)] has been used in large double-blind clinical trials. Denies its efficacy. The only possible effective lipopolysaccharide antiserum therapy is still undergoing clinical efficacy evaluation. The difficulty in treating this shock lies in its unknown mechanism. The inventor has previously found arginase and arginine in the patent application No. 81 1 10533 of the Republic of China (under examination) and the US patent application No. 08 / 044,233 (approved) All can protect the mice from the death of endotoxin shock. Since arginine ^ • will decompose arginine to ornithine (ureithine) and urea (urea), ornithine can also be converted to putrescine, and then continue to produce two kinds of polyamines-spermine Spermidine and spermine, so the inventors have also tested the effect of ornithine and spermine on endotoxin shock, and found that ornithine and spermine have protection against endotoxin shock in mice Function, the results of this paper scale are applicable to the Chinese National Standard (CNS) A4 specification (210X297mm) (please read the precautions on the back before filling this page)-Pack.
SlS〇22 經濟部中央標準局貝工消费合作杜印製 A7 --------- B7 五、發明説明^ " 亦記載於上述兩專利案中。 上述一系列物質中’另段腐肉素和精胺未予試驗其 對内毒素休克的效果。經發明人實驗發現精胺並無保護 作用，而腐肉素則有保護作用。 因此，本發明之目的，即為提供一種用於預防内毒 素休克所引起之死亡的藥學組合物’其有效成份為腐肉 素。 以下即舉一實施例，用以證明本發明藥學組合物之 藥理活性。 實施例 以Balb/C小白鼠六週大，重25 ± 1公克，腹腔注射 〇.9毫克的大腸和·菌（E.coli)脂多糖體（iip0p〇iySaccharjd.e， LPS)來引發内毒素休克。實驗以0 9毫克LPS來引發内 毒素休克，以一劑量預先選定’最容易顯見藥物之保護 效果。LPS及腐肉素均溶於麟酸緩衝液（pbs)中，含 0.01M磷酸鹽’ 0.15M氣化鈉，pH7.4。LPS及腐肉素 均講自Sigma公司。 (一）在注射LPS之前及之後不同時段，腹腔注射腐肉素（ putrescine)每隻10毫克，觀察存活率如下（以LPS 注射之時間為零時）： 本紙張尺度逋用中國國家標準（CNS ) A4規格（210X 297公釐） (請先閲讀背面之注意事項再填寫本頁) —裝. -訂- 線_ 3!3吻SlS〇22 The Ministry of Economic Affairs, Central Standards Bureau, Beigong Consumer Cooperation Du Printed A7 --------- B7 V. Description of invention ^ " is also recorded in the above two patent cases. Among the above-mentioned series of substances, 'carrionine and spermine were not tested for their effect on endotoxin shock. The inventor's experiment found that spermine has no protective effect, and carrion has a protective effect. Therefore, the object of the present invention is to provide a pharmaceutical composition for preventing death caused by endotoxin shock, the effective ingredient of which is saprocin. The following is an example to demonstrate the pharmacological activity of the pharmaceutical composition of the present invention. Example: Balb / C mice were six weeks old, weighed 25 ± 1 g, and were intraperitoneally injected with 0.9 mg of large intestine and E. coli lipopolysaccharide (iipopioi Saccharjd.e, LPS) to trigger endotoxin. shock. The experiment used 0 mg of LPS to trigger endotoxin shock, and the protective effect of the drug was most easily shown at a pre-selected dose. Both LPS and carrionine are dissolved in linolic acid buffer (pbs) and contain 0.01M phosphate ’0.15M vaporized sodium, pH 7.4. Both LPS and carrion are from Sigma. (1) Before and after the injection of LPS, putrescine was injected intraperitoneally at 10 mg each, and the survival rate was observed as follows (when the injection time of LPS was zero): This paper scale adopts the Chinese National Standard (CNS) A4 size (210X 297mm) (Please read the precautions on the back before filling in this page) — Pack. -Order- Line_ 3! 3 kiss
、發明説明（3. Description of the invention (
存活數/總數 存活率（〇/〇) P值 卜24 1/15 6.7 6/15 40 0.08 2/15 131.0 0/15 0 >1.0 (二）在注射〇.9毫克LPS之前24小時，腹腔注射不同 劑量的腐肉素，存活率如下： (請先閱讀背面之注意事項再填寫本頁) 丨裝. 存活數/總數 存活率（％) P值 *~ 腐肉素劑量（每隻之毫克數）Survival number / total survival rate (〇 / 〇) P value Bu 24 1/15 6.7 6/15 40 0.08 2/15 131.0 0/15 0 > 1.0 (2) 24 hours before injection of 0.9 mg LPS, abdominal cavity Injecting different doses of carrion, the survival rate is as follows: (please read the precautions on the back before filling in this page) 丨 Pack. Survival number / total survival rate (%) P value * ~ Carrionine dose (mg per each)
、1T 10/30 33 0.23 3_ 11/30 37 0.14 10 16/30 53 0.006 30 11/30 37 0.14 經濟部中央標準局員工消費合作杜印製 結果顯示’每隻25公克重的Balb/c小白鼠，以1 〇 毫克的腐肉素腹腔注射最能保護老鼠免於内毒素休克的 死亡’存活率達53% ，而腐肉素以LPS注射之前24小 時注射’最具保護作用，存活率達40〇/〇。 雖然本發明已以較佳實施例揭露如上，然其並非用 以限定本發明’任何熟習此項技藝者，在不脫離本發明 之精神和範圍内，當可作些許之更動與潤飾，因此本發 明之保護範圍當視後附之申請專利範圍所界定者為準。 本紙張用巾家標準（CNS ).以鄕_ ( 2丨G><297公董）, 1T 10/30 33 0.23 3_ 11/30 37 0.14 10 16/30 53 0.006 30 11/30 37 0.14 Du printing results of the employee consumption cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs showed that each Balg / c mouse weighing 25 grams Intraperitoneal injection of 10 mg of procarcinone can best protect mice from death from endotoxin shock, the survival rate is 53%, while procarcinone is injected 24 hours before LPS injection, and the most protective effect is 40%. 〇. Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any person who is familiar with this skill can make some changes and retouching without departing from the spirit and scope of the present invention. The scope of protection of an invention shall be deemed as defined by the scope of the attached patent application. The paper towel standard (CNS). To be _ (2 丨 G > < 297 public director)