ASCO 2009:5-FU過量的解毒劑顯示相當有效


  June 17, 2009 (佛州奧蘭多) — 根據發表於美國臨床腫瘤協會第45屆年會的一篇壁報,現在有可用於化療劑5-fluorouracil (5-FU)過量的解毒劑了。
  
  這個研發中的解毒劑vistonuridine(Wellstat Therapeutics公司),在一個小型研究中讓17名病患全都從5-FU過量恢復。
  
  主要作者、馬里蘭公司研發副總裁、發現與研發vistonuridine的Reid von Borstel博士表示,值得一提的是,17名病患中有14人是預期會致死的嚴重過量。
  
  未參與本研究的藥學博士Patrick L. McDonnell接受Medscape Oncology邀請發表評論時表示,化療過量的研究有其困難,因為這是個敏感的醫療領域。
  
  賓州Temple大學藥學院、臨床藥學副教授McDonnell博士表示,多數的藥物過量是因為醫療疏失與肇因於醫源性,即因為照護提供者引起的。他未參與ASCO會議。
  
  他指出,員工一般不願意公開討論過量,因為我們全都致力於「不要造成傷害」,而這類的討論對於從錯誤中學習仍有其重要性。
  
  儘管一般會試圖將化療過量的資料保密,但von Borstel博士等人在醫療文獻中發現11例5-FU過量案例;每個案例都是接受標準支持照護。
  
  這11個案例成為成功使用vistonuridine之17個案例的對照組。文獻中的這11個案例都是因為嚴重過量死亡。雖然這11個案例有支持照護,仍全部都死亡。
  
  von Borstel博士向Medscape Oncology解釋,5-FU中毒的嚴重度包括絕對劑量與給予劑量的輸注率。根據前述於文獻中發表的案例,不論是絕對劑量或輸注速率,加倍時均足以致死。
  
  至於研究中的每個案例,那些病患使用5-FU過量的醫師和聯繫Wellstat 公司。該公司獲得美國食品藥物管理局(FDA)緊急使用研發中新藥的免許證,可立即快遞vistonuridine給這些診間。
  
  Vistonuridine分別在5月1日、5月15日獲得FDA、歐盟醫療局指定為治療5-FU過量的孤兒藥。von Borstel博士表示,Wellstat公司將持續與相關當局討論有關上市許可。
  
  【隨處都可能發生過量】
  von Borstel博士等人在他們的壁報中寫道,在美國,每年約有275,000名病患接受5-FU,而且,根據國家健康研究中心(NIH),估計有3%經歷嚴重毒性反應,每年有超過1300名病患死亡。
  
  McDonnell博士表示,我對於NIH有關5-FU過量與死亡的資料感到驚訝。不過,他認為即使在運作最好的腫瘤科診間也會發生過量。
  
  McDonnell博士表示,隨處都可能發生過量,但是最常發生在新的或訓練中的員工。忙碌與分心也會造成。不過,最常見的原因是有關如何給予化療的知識不足。
  
  McDonnell博士舉一個知識不足的例子。在一些5-FU處方中,是連續靜脈注射給藥4到5天。員工— 特別是經驗不足的員工 — 可能會誤將全部劑量當作單日劑量,而造成過量,經驗不足是造成知識缺乏的關鍵。
  
  他強調,將整個療程的劑量當作單日劑量是醫療疏失的最佳案例之一,這也是最危險的情況之一。
  
  von Borstel博士表示,在vistonuridine的研究中,多數的過量是因為輸注幫浦設定錯誤。
  
  他回應McDonnell博士表示,輸注幫浦錯誤包括人為疏失與設備問題,而這之間的釐清往往不明確。在我們的經驗中,給予過量5-FU通常包括幫浦程式錯誤,導致給予的劑量高過所要的劑量,例如本應輸注4天卻只有輸注4小時。
  
  【克服給藥問題的設計】
  von Borstel博士表示,Vistonuridine專門用於5-FU與口服後產生5-FU的前驅藥,如capecitabine (Xeloda)和tefafure uracil (Uftoral)。
  
  他指出,Uridine這種天然的核甘,是已知的5-FU藥理解毒劑,但是uridine本身無法經口服適當吸收。
  
  他解釋,設計Vistonuridine來克服uridine的給藥問題;它可以有效地從腸道吸收進入血流,且迅速轉變成uridine。
  
  von Borstel博士指出,Vistonuridine是5-FU過量的第一個解毒劑。不過,少數其他化療的過量已經有其解毒劑,例如 leucovorin (folinic acid)用於methotrexate過量。
  
  【確認過量】
  von Borstel博士解釋,需要數天才能確認5-FU毒性,所以病患在過量當下可能不會發現任何異狀。
  
  他表示,有些胃腸道症狀可能在約4天內發生,嚴重毒性約在1週發生,包括白血球數量降低,比較容易讓病患發現的是,小腸內膜的損傷導致的黏膜炎或胃炎、噁心與腹瀉。
  
  病患在治療時通常會接受多個療程的5-FU和其他化療劑,相較於化療次數較少或未曾化療者,如果有人因為之前的治療發生過量時,過量的毒性可能會更嚴重、或者更容易發生。
  
  壁報作者全部都是Wellstat Therapeutics的員工。
  
  美國臨床腫瘤協會(ASCO)第45屆年會:摘要9616。發表於2009年6月1日。
  

ASCO 2009: Antidote for 5-FU Overdose Appears Highly Effective

By Nick Mulcahy
Medscape Medical News

June 17, 2009 (Orlando, Florida) — There is now an antidote for clinicians to use in the event of an overdose of the commonly used chemotherapy 5-fluorouracil (5-FU), according to a poster presentation here at the American Society of Clinical Oncology 45th Annual Meeting.

Use of the antidote, an investigational agent known as vistonuridine (Wellstat Therapeutics), resulted in recovery from 5-FU overdose in all 17 patients in a small study.

Notably, 14 of the 17 patients had severe enough overdoses that the expected outcome was death, said lead author, Reid von?Borstel, PhD, vice president of discovery research at Wellstat Therapeutics in Gaithersburg, Maryland, which discovered and developed vistonuridine.

It is difficult to study chemotherapy overdosage because it a sensitive area of medicine, said Patrick L. McDonnell, PharmD, who was not involved with the study but was approached by Medscape Oncology for comment.

"Most overdose is due to medication error and iatrogenic — caused by the caregiver," said Dr. McDonnell, who is associate professor of clinical pharmacy at Temple University School of Pharmacy in Philadelphia, Pennsylvania. He did not attend the ASCO meeting.

"Staff generally do not want to discuss overdose publicly because we all try to 'do no harm'," he added, saying that such discussion is nonetheless essential to learn from mistakes.

Despite the tendency to keep the details of chemotherapy overdose in private clinic files, Dr. von?Borstel and colleagues found 11 cases of 5-FU overdose in the medical literature; standard supportive care was provided in each case.

The 11 cases provided a comparator to the 17 cases in which vistonuridine was successfully used. In all 11 cases in the literature, the expected outcome was death because of the severity of the overdose. In all 11 cases, death resulted despite supportive care.

A doubling of either the dose or the infusion rate?.?.?. is likely to be fatal.

"The severity of 5-FU toxicity is a function of both absolute dose and infusion rate of a given dose. A doubling of either the dose or the infusion rate?.?.?. is likely to be fatal, according to the published cases available for analysis," Dr. von?Borstel explained to Medscape Oncology.

For each case in the study, Wellstat was contacted by physicians who had patients with 5-FU overdoses. The company obtained emergency-use investigational new-drug waivers from the US Food and Drug Administration (FDA) and immediately flew or couriered vistonuridine to the clinics.

Vistonuridine received orphan drug designation for the treatment of 5-FU overdose on May 1 from the FDA and on May 15 from the European Medicines Agency. Wellstat will continue its discussions with these agencies regarding marketing approval, said Dr. von?Borstel.

Overdose Can Happen Anywhere

In the United States, about 275,000 patients a year receive 5-FU and, according to the National Institutes of Health (NIH), an estimated 3% experience a serious toxic reaction and more than 1300 patients die annually, write Dr. von?Borstel and his Wellstat colleagues in their poster.

I was surprised by the NIH data on overdose and death with 5-FU.

"I was surprised by the NIH data on overdose and death with 5-FU," said Dr. McDonnell.

Nevertheless, he suggested that overdosage can happen even in the best-run oncology clinics.

"Overdose can happen anywhere but is more likely among new staff or those in training. Busyness and distractions are also contributing factors. However, knowledge deficit about how to administer a chemotherapy is one of the most common factors," said Dr. McDonnell.

Dr. McDonnell provided an example of knowledge deficit. "In certain regimens for 5-FU, the drug is given as a continuous IV for 4 to 5 days. Staff — especially inexperienced staff — may misconstrue the total dose as the daily dose and thus give an overdose," he explained, saying that lack of knowledge due to inexperience is key.

This is one of the best examples of medication error — when total cycle dose is given as a daily dose.

"This is one of the best examples of medication error — when total cycle dose is given as a daily dose," he emphasized, saying it was also one of the most dangerous.

In the vistonuridine study, most of the overdoses were due to infusion-pump errors, said Dr. von?Borstel.

"Infusion-pump errors can include both human error and equipment problems, and the boundary is not always distinct. Administration of 5-FU excess in our experience has often involved pump misprogramming, resulting in administration of an intended dose at a higher-than-intended rate, such as infusion over 4 hours instead of 4 days," he said, echoing Dr. McDonnell.

Designed to Overcome Delivery Problem

Vistonuridine is specific for 5-FU and for prodrugs that are converted to 5-FU after oral administration, such as capecitabine (Xeloda) and tefafure uracil (Uftoral), said Dr. von?Borstel.

"Uridine, a naturally occurring nucleoside, was known as the specific pharmacological antidote for 5-FU, but uridine itself is not adequately absorbed when given orally," he noted.

Vistonuridine was designed to overcome the uridine delivery problem; it is efficiently absorbed from the intestine into the bloodstream and rapidly converted to uridine, he explained.

Vistonuridine is the first antidote for 5-FU overdose, noted Dr. von Borstel. However, antidotes exist for a few other chemotherapy overdoses, such as leucovorin (folinic acid) for methotrexate overdose, he said.

Recognizing Overdose

5-FU toxicity takes several days to become established, so a patient may not notice anything unusual at the time of the overdose, explained Dr. von?Borstel.

"Some [gastrointestinal] symptoms may appear within about 4 days. Severe toxicities may be evident in about a week, and include declines in white blood cells and, much more noticeable to patients, damage to the intestinal lining, resulting in mucositis or stomatitis, nausea, and diarrhea," he said.

Patients often receive multiple courses of 5-FU and other chemotherapy agents during treatment, so if an overdose occurs in someone who has undergone previous treatments, the toxicity of an overdose may be more severe or more rapidly apparent than in someone who has received less or no previous chemotherapy, he further explained.

The authors of the poster are all employees of Wellstat Therapeutics.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract 9616. Presented June 1, 2009.

    



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