藥 科 (二 )期 末 報 告
S c i F i n d e r
---隱形的生化武器 炭疽桿菌---
指導老師：吳建德老師
系級：藥學系三年級
學號：B303098121
姓名：徐安立
一、前言
On September 28, 2001, two employees, Stevens and anonymous, of American Media Inc. had fallen ill, with symptoms like unusually tired, feverish, and vomiting. After admitted to the hospital, laboratory analyses showed that they had been infected with B. anthracis. On October 7, looking for a common source of infection of these two employees working in the same building, investigators from the FBI found spores of B. anthracis on Stevens’ computer keyboard. An enquiry revealed that, on September 19, Stevens had received a strange letter containing some white powder. This letter must have contained the spores. From then on there started the anthrax letters crisis, with anxiety and then panic increasing by steps all over the country. Starting on October 12, seven individuals from the news media contracted cutaneous anthrax in New York. From the point of view of public health, this crisis was a minor event: only five persons died. However, it provoked a deep traumatism both in the USA and elsewhere. The crisis showed that anthrax spores could be used as a weapon by terrorists, and that even if it did not make many victims, it could easily disorganize a whole country. This sudden awareness induced the governments of many countries to devote major efforts to the prevention of what was soon called “bioterrorism”.
二、Anthrax 簡介
Anthrax is primarily a disease affecting herbivores. As such, it has been known for a very long time. Perhaps the first record of anthrax is in the Bible in Exodus, chapters 7–9. “The hand of the Lord will fall on your livestock in the fields, on horses, asses, camels, herds, and flocks, with a very severe murrain.” Anthrax epizootics were responsible for enormous domestic livestock losses in Europe from the seventeenth to the 19th century. Hence, in the middle of the 18th century, a major epidemic destroyed about half of the ovine population in Europe and took a similar heavy toll in some parts of France one century later.
Although anthrax is primarily a disease of herbivores, all mammals, including humans are susceptible.
A striking feature of the disease is its suddenness. After a short period of excitation, the animals look depressed, display signs of cardiac and respiratory failure, their mucosa become hemorrhagic, their throat and abdomen are swollen and blood leaks from the different body orifices. The blood is black and fails to coagulate.
In humans, the disease can take three forms, depending on the route of entry of B.
anthracis spores, cutaneous, gastrointestinal, or pulmonary. The gastrointestinal and
pulmonary forms are regarded as being most frequently fatal, owing to the fact that they can go unrecognized until it is too late to instigate effective treatment with the agents currently available. Cutaneous anthrax usually occurs among people who have contacts with diseased animals, primarily farmers and veterinarians, with skin lesions. The disease manifests itself with black scars, which, if untreated, may result in fatal septicemia. Pulmonary anthrax, which caused the death of the five victims of the anthrax letters, had long been known, especially as
the “wool-sorter disease”. If untreated, it rapidly leads to death. As for gastrointestinal anthrax, due to the absorption of meat from diseased animals, it caused considerable human fatalities simultaneous with anthrax epidemics in animals. Thus, for instance, in 1613, the disease made about 60,000 human victims in southern Europe. Anthrax is not only a disease of the past. It is still with us today, and not only as a potential weapon for bioterrorists.
三、 傳播途徑
The aetiological agent, Bacillus anthracis, was identified by French and German scientists in the 1860s and 1870s. This was the first time that a disease could be attributed to a specific microorganism. The scientist demonstrates unequivocally that a rod-like microorganism was consistently present in blood and tissue of diseased animals; that spores developed under starvation conditions; that these spores could transform into the rod-like bacilli under nutrient-rich conditions;
There are three major ways that Bacillus anthracis can be spread to livestock. Spores of bacteria
that the rod like organisms could be cultured in pure form; and finally that the cultured material, either in the form of rod-like microorganisms or spores, caused anthrax disease in experimentally infected animals.” Therefore, the bacterium was given the name Bacillus anthracis.
excreted by diseased animals or coming from their cadaver presumably remained in such fields for a very long time and later infected other animals. Pasteur, a scientist, actually showed the presence of the bacterium in the “cursed fields” and obtained evidence that earthworms could play a role by bringing back to the surface spores present in a buried animal cadaver. Another means whereby spores could contribute to the dissemination of the disease is because of the fertilizer. One fertilizer manufactured by a large company that processed animal corpses from miles around and that paid little attention when it turned them into fertilizer caused a quarter of a farmer’s stock to death. From this, Nocard, a veterinarian collaborator of Pasteur, drew conclusions about the probable role in the spread of anthrax of the use of artificial fertilizers that had been badly prepared from infected animal wastes. Another means whereby spores might be disseminated is by insect vectors. Even though there is evidence that the transmission of spores of B. anthracis by some insects, especially tabanids, might be responsible for the spreading of the disease over rather large areas, these remains to be demonstrated conclusively.
四、致病原因
Spores are extremely resistant to a variety of physical treatments and can survive for a very long time in natural or laboratory environments. Viable spores were even found in the bones of animals that died 200 years ago in Kruger National Park. Clearly, the fact that B.
anthracis easily yields spores with a high resistance to external conditions makes it a
For Pasteur, the pathophysiology of anthrax was very simple. The bacillus grew in the blood and, since it was aerobic, it depleted the oxygen, thus asphyxiating the red blood cells. However, Pasteur was only seeing the last step, that of septicemia, during which, indeed, asphyxia of the red cells is probably a major cause of death. Studies on the pathophysiology of anthrax led to the identification of two major virulence factors, the capsule, protecting the bacilli against phagocytosis, and a tripartite toxin.
The latter consists of two toxins with a
Unlike the capsule identified in other pathogenic bacteria such as Pneumococci and made of polysaccharides, the capsule of B. anthracis is a linear polymer of γ-D-glutamic acid. The capsule contributes to pathogenicity by enabling the bacteria to resist phagocytosis by macrophages.
common component (protecting antigen, PA) that allows the binding to and penetration into cells of two enzymes, the oedema factor EF, a calmodulin dependent adenylate cyclase, and the lethal factor LF, a specific zinc
metalloprotease. The primary targets of these toxins would seem to be cells of innate immunity that would otherwise impair multiplication of the bacilli. The precise role of the two toxins in anthrax pathology remains to be fully elucidated. Earlier studies suggested that the toxins were responsible for death, but recent acquisitions indicate that their primary targets are cells of innate immunity that would otherwise impair the multiplication of the bacilli. They do so by altering the c-AMP and MAPK signaling pathways which are essential for activation of immune cells. The two toxins would then act on many different cell types when they reach high
concentrations in the final stages of the disease following the widespread dissemination of B.
anthracis in the infected animal.
五、治療方法
Today, we know that antibiotics such as ciprofloxacin are very efficient in controlling B.
anthracis infections. Aside from antibiotics, additional methods are being investigated to control B. anthracis infections, for instance to prevent the action of toxins, in case bioterrorists would use an antibiotic-resistant strain, or to try and rescue an individual in whom bacteraemia would have already reached a high and potentially lethal level. Besides taking pills, Pasteur’s invention of a vaccine against anthrax, based on the use of an attenuated form of the bacillus, marked the history of medicine.
The vaccine consisted of bacteria grown for several days between 42 and 43 °C in the presence of oxygen, conditions were they did not form spores and became attenuated. However, this vaccine was far from perfect. Sometimes, it was insufficiently attenuated and
In a country as distant from France as Australia, it is estimated that the introduction of vaccination in 1890 led to the protection of about 8 million sheep against anthrax between 1894 and 1900. In the USA, the first distribution of vaccine occurred in 1897–1898. According to the “Bureau of Animal industry”, 127,369 animals were vaccinated. Whereas the average loss in livestock was 14% before the introduction of vaccination, it fell to 0.54% after vaccination.
killed the animals it was supposed to protect. In other instances, it was too attenuated, and failed to induce protection. A major improvement in the vaccine was introduced by Max Sterne in 1937–1942, who isolated a stable avirulent variant of the bacillus. Live spores of this strain, which gave reproducible results, thereafter became the base of the anthrax vaccine used worldwide for veterinary use. Overall, even though anthrax is a disease contracted without any notice, but if detected early enough, B. anthracis infections can be stopped by using antibiotics such as ciprofloxacin. Infection of animals can also be prevented by the administration of vaccines. 六、心得感想 在現今科技那麼發達的世代，搜尋資料對我們來說簡直是輕而易舉，但是令人擔心的是，我 們所查詢到的資料都是正確的嗎？有些網站會不會提供錯誤的資訊亦或是沒有經過專家認可的 訊息呢？之前在某一堂選修課某位老師介紹 google scholar 給我們認識，裡面查到的資料可以透 過引用的次數來辨別他是否具有可信度，現在又在這堂課學到另一個更具可信度的網站 scifinder，裡面的資訊不僅由博士群編輯，還收集發表於期刊、專利文件及其他來源的專業資訊 (如會議論文、圖書、學位論文、綜評、會議摘要、電子期刊、網路預出刊等)與其參考資料的文 獻資料庫。資料每日更新 3,000 筆以上，目前總收錄也已經超過 33,000,000 筆以上的資料，學 會了這個查資料的方法，讓以後查詢專業層面的資料又更方便了。 之所以會找尋與炭疽熱有關的資訊是因為有一次微免正課老師提到在人類歷史上炭疽熱經 常造成大量的人或牲畜死亡，但因為炭疽病毒是急性感染的疾病且生活中很難偵測到它的存在， 因此一但感染上，發病到死亡往往只需要兩周的時間，使得醫院對病患的治療要很精確且有效， 才能避免無謂的傷亡。老師也提到，恐怖分子也曾經利用寄信的方式，散播炭疽桿菌病毒到美國， 企圖造成另一個 911 事件，而引起全國大轟動。雖然炭疽桿菌在當時成為大家討論的焦點，但 是那時還懵懵懂懂的我沒有更進一步尋找相關資料，直到現在念了藥學系，在微免課聽到與生活 息息相關的訊息，才掀起我尋找炭疽病的動力。 這次查資料很幸運的找到一篇完整報導炭疽病的論文，他從過去戰爭使用過的武器到二十世 紀動物的大量死亡到 2001 年美國 911 恐怖攻擊事件之後，都有詳細的介紹，也因此這份資料對 我來說幫助很大，但是因為它是全英文的，所以費了我好大一番工夫才把所有文獻看完並挑出我 需要的資訊寫報告。裡面有很多專有名詞，也有很多新的資訊，例如：炭疽熱無色無味，傳感染 途徑以皮膚接觸（有傷口的皮膚）及呼吸道吸入為主。若是經由有傷口的皮膚接觸感染，傷口部 位上會出現 1～3 公分直徑、無痛的潰瘍，中央像黑色焦痂、周圍有水泡，初期像蟲咬，會產生 搔癢感， 1～2 週後結疤，而且感染會經由血液而散佈全身到導致發燒、頭痛、偎寒、噁心嘔吐 等全身性的不適。 炭疽病毒還會產生一種全身性毒素，使組織器官發生水腫，破壞凝血系統，造成臟器出血， 脾臟腫大並抑制中樞神經，可引發溫血動物急性、熱性敗血症而迅速死亡。炭疽熱菌種相當頑強， 抵抗環境能力極佳，在生存條件不利狀況下會轉化成芽孢形態，存在土壤、草叢、動物皮毛、空 氣及土壤中等資訊。看完資料之後才知道為什麼它那麼不容易被察覺，也因此很容易被恐怖分子 當作生化武器攻擊的工具，造成人類另一個恐慌。
查到治療方法時，我也看到熟悉的 ciprofloxacin，這個藥在藥化和藥理都出現過，因此更加 深了我的印象。除了抗生素外，現在也極力的開法穩定的炭疽桿菌疫苗或血清，目的就是在最緊 急的時刻做正確的判斷並給予正確用藥，以挽回病人的生命，因為據資料顯示，得到炭疽熱的人 有 20%會導致死亡，所以有效的製劑對預防和治療炭疽熱是很重要的一環。 Scifinder 這個網頁真的很厲害，用簡單的關鍵字他就能自動搜尋相關的資訊，不僅有完整 的論文文章，還可以練習畫結構式，如果想要更新的資訊還可以訂閱資訊，系統就會自動寄到信 箱，如此一來閱讀新論文就變成一項很簡單的事，而不需花費許多力氣去圖書館翻書或是上網查 期刊。而且這個網站不只是醫學相關的可以使用，所有以化學為基礎的自然科學領域，包括生物 化學、有機化學、製藥、農業科學、生物與生命科學、工程與應用化學、食品科學、普通化學、 地質科學、材料科學、醫藥科學、物理學、高分子科學、電化學、化妝品、光電科學等都可以查 的到資料。總括來說，這個系統對學術研究幫助太大了，相信有了以博士們編輯的資料庫，我們 在尋找資料上會更有效率，而且在這些領域更會蓬勃發展。 七、圖片 八、參考文獻
A short history of anthrax:
Molecular Aspects of Medicine Volume 30, Issue 6, December 2009, Pages 347-355 Bacillus anthracis, a bug with attitude
