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靜脈氧化砷治療之心臟毒性研究:發生率、機轉及發生後之可逆性

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行政院國家科學委員會專題研究計畫 成果報告

靜脈氧化砷治療之心臟毒性研究:發生率、機轉及發生後之

可逆性

計畫類別: 個別型計畫 計畫編號: NSC91-2314-B-002-128- 執行期間: 91 年 08 月 01 日至 92 年 07 月 31 日 執行單位: 國立臺灣大學醫學院小兒科 計畫主持人: 吳美環 報告類型: 精簡報告 報告附件: 出席國際會議研究心得報告及發表論文 處理方式: 本計畫可公開查詢

中 華 民 國 92 年 10 月 28 日

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行政院國家科學委員會專題研究計畫成果報告

計劃名稱:靜脈氧化砷治療之心臟毒性研究:發生率、機轉及發生

後之可逆性

計畫編號:NSC 91--B-002-128

執行期限:91 年 8 月 1 日至 92 年 7 月 31 日

主持人:吳美環 教授 台大醫學院小兒科

共同主持人:蘇銘嘉 教授 台大醫學院藥理所

共同主持人:林君榮 助理教授 台大醫學院

共同主持人:鄭安理 教授 台大醫學院內科

一、中文摘要 靜脈三氧化砷治療對於急性骨髓前白 血病療效良好,但臨床經驗顯示有可能有 心臟毒性。本研究以分離兔心臟灌流之實 驗模式,探討是否三氧化砷有直接之心臟 毒性,包括其發生率、電生理特性之變化 與不整脈之誘發狀況。 我們發現,三氧化砷於臨床治療濃度 (1,3,10μM)或更高(30μM)之濃度, 並不會影響心電生理特性,但若以極高之 濃度(300μM)(此種濃度只有可能在中 毒下遇到)則 QT 間距會延長。此外,我 們另設立長期靜脈三氧化砷治療之動物模 式,實驗兔接受每天 0.2mg/kg 之靜脈三氧 化砷,30 天後再行測定。我們發現,接受 長期靜脈三氧化砷治療之實驗,其 QT 間 距延長顯著變長,且會誘發心室頻脈(1/7, 14%),組織濃度之檢定亦顯示砷堆積之 現象。但此種砷堆積之現象有可能於停藥 後,部分會再度排出。 關鍵詞:三氧化砷、心臟電生理學、不整 脈 Abstract

Although parenteral administration of As2O3 is highly effective in the treatment of

acute promyelocytic leukemia, cardiac toxicity has been reported. This study

employed Langendorff- perfusion to determine the direct effects of As2O3 in the

electrophysiological properties of rabbit hearts after acute or chronic As2O3 treatment

(0.2 mg/Kg/day intravenous for 30 days).

Tissue accumulations of arsenicals, pathological changes as well as the

reversibility of chronic As2O3 effects were

assessed. We found that cardiac conduction and repolarization were not altered

whatsoever after acute As2O3 treatment at

clinically relevant (1, 3, 10 μM) and higher (30 μM) doses. Nevertheless, an extremely high concentration of As2O3 (300μM)

prolonged the corrected QT interval.

Subsequent to chronic As2O3 administration

and with 30 μM As2O3 via Langendorff

perfusion, polymorphic ventricular tachycardia was observed (1/7, 14%). Corrected QT interval was prolonged, while basic cycle length was shortened.

Significant accumulation of arsenicals in the cardiac tissue was found, but without any pathological changes. After As2O3 was

discontinued for 30 days, the chronic As2O3

-induced electrophysiological changes improved, no ventricular arrhythmia was noted, and the tissue concentration of arsenicals decreased considerably. We therefore conclude that although no

immediate cardiac effects were discernable at clinically relevant doses, an extremely high concentration of As2O3 could prolong

ventricular repolarization. Chronic As2O3

treatment resulted in a prolonged ventricular repolarization, in association with arsenicals accumulation and with risk of ventricular tachycardia. These chronic cardiac toxicities and the tissue accumulation of arsenicals were, however, partially reversible after cessation of As2O3.

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Keywords: arsenic trioxide, heart, electrophysiology

二、緣由與目的

Arsenic trioxide (As2O3) may induce

complete remission in patients with relapsed or refractory acute promyelocytic leukemia (Shen et al., 1997; Soignet et al., 1998; 2001). However, clinical trials have demonstrated cardiac adverse events resulting from As2O3

therapy, including QT interval prolongation, complete atrioventricular block, premature ventricular contractions, ventricular

tachycardia, and a potentially fatal torsade de pointes ventricular arrhythmia (Huang, et al. 1998; Huang et al. 1998; Ohnish et al., 2000; Unnikrishnan et al., 2001). Because

reported cases of these events usually occurred in association with previous anthracycline therapy, electrolyte

disturbances or other systemic problems, the direct cause-effect relation between As2O3

treatment and these cardiac adverse events remains uncertain. In a recent study, As2O3

was shown to prolong the action potential duration in isolated guinea-pig papillary muscle with a slow pacing cycle length (Chiang et al. 2001). Nonetheless, the modification of cardiac electrophysiological profile and the proarrhythmic potential after As2O3 are still undefined.

The part I study was to define the direct effects of As2O3 after acute and chronic

parenteral administration of As2O3 by using

the intracardiac recording and stimulation in isolated hearts in Langendorff perfusion. 三、結果與討論

RESULTS

Acute As2O3 treatment

The acute effects of As2O3 at

concentrations including 1, 3, 10 and 30μM were assessed in 8 rabbits and at extremely high concentrations (30, 100 and 300μM) in another three rabbits. Previous study had indicated that the mean peak plasma arsenic level was 6.9μM (ranged 5.5 to 7.3μM ) in patients with acute promyelocytic leukemia receiving 10 mg daily As2O3 (Shen et al.,

1997). Therefore, concentrations used in this experiment may be representative of clinically relevant (1, 3 and 10μM), even 5 times higher (30μM), or only encountered accidentally concentrations (100 and 300μ M). Intracardiac recording was used to detect the atrial activities, His potential, ventricular activities and repolarization (T wave). Changes with regard to the electrophysiological parameters after acute treatment of As2O3 at concentrations of 1, 3,

10 and 30μM in the 8 rabbits are

summarized in Table 1. We found that the electrophysiological parameters were not significantly altered after As2O3 treatment.

The spontaneous cycle length, repolarization (QT interval and QT interval corrected according to the Bazett formula),

refractoriness and the conduction velocity over the cardiac tissues were not significantly changed. No arrhythmias were observed during the experiments.

After the treatment with an extremely high dose of As2O3 (30, 100 and 300μM ) that

may be encountered accidentally, most of the cardiac electrophysiological parameters were not significantly altered. Only the corrected QT interval was lengthened by extremely high concentration of As2O3 (300μM)

( from 362 ±19 to 414 ±23 ms, p = 0.02) Chronic As2O3 treatment

Chronic As2O3 effects were assessed in

7 rabbits that were killed after having received daily parenteral administration of As2O3 for 30 days.

Cardiac electrophysiological modification After chronic parenteral administration of As2O3, polymorphic ventricular

tachycardia occurred in one out of 7 rabbit hearts (14%). The corrected QT interval was significantly lengthened and the spontaneous cycle length was shortened. However, the conduction through the atrial, atrioventricular tissue and the His-Purkinje system was not slowed down. The

refractoriness of the cardiac tissues, including the atrial, atrioventricular, His-Purkinje system and ventricular tissues, was also not altered.

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chronic As2O3 treatment

The distribution of arsenicals in various organs of the 5 rabbits killed after chronic parenteral As2O3 treatment is summarized in

Table 3. Significant tissue accumulation was observed in liver, bladder, heart,lung and kidney. The concentration of arsenicals in cardiac tissue was comparable to that of bladder and higher than that of lung.

DISCUSSION

As2O3 therapy is highly effective for the

induction of remission in adults or children with promyelocytic leukemia (Shen et al., 1997, Soignet et al., 1998, 2001). However, adverse cardiac events, including QT

prolongation, atrioventricular block or torsade de pointes ventricular tachycardia have been reported in clinical trials of As2O3

(Soignet et al., 2001, Huang et al., 1998; Huang et al., 1999; Ohnish et al., 2000; Unnikrishnan et al., 2001). The

mechanisms responsible for these events are still unclear. This study observed the

following results: 1) Acute As2O3 treatment

at clinically relevant or 5 times higher doses did not modify the cardiac

electrophysiological properties, but acute As2O3 treatment at clinically 50 times higher

dose prolonged the cardiac repolarization; 2) After chronic As2O3 parenteral

administration, clinically 5 times higher dose of As2O3 could lengthen the repolarization of

cardiac tissue and was associated with increased risk of ventricular tachycardia; 3) After chronic As2O3 parenteral

administration, tissue accumulation of arsenicals occurred and may have accounted for the emergence of cardiac toxicities in the chronic phase of As2O3 therapy; and 4) The

electrophysiological effects and tissue accumulation of arsenicals after chronic As2O3 parenteral administration were

partially reversible after cessation of As2O3

administration.

In conclusion, this study found that cardiac toxicity could be induced by chronic parenteral administration As2O3 in rabbits.

Acute As2O3 treatment at clinically relevant

or 5 times higher concentrations did not significantly alter cardiac

electrophysiological properties in our animal model. At only extremely high

concentration, acute As2O3 administration

could prolong the corrected QT interval (ventricular repolarization). However, only after chronic parenteral administration, probably related to arsenicals accumulation in the cardiac tissue, were the corrected QT interval prolonged and the risk of ventricular arrhythmias increased by As2O3 at a dose that

was not associated with acute cardiac toxicity. The possible development of these direct cardiac toxicities should be closely

monitored during the chronic phase of As2O3

therapy. However, these chronic cardiac toxicities and tissue accumulation of arsenicals by As2O3 therapy were at least

partially reversible after cessation of As2O3

administration

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Goldsmith, S. and From, A.H. (1980). Arsenic-induced atypical ventricular tachycardia. N Engl J Med. 303, 1096-1098.

Huang, C.H., Chen, W.J., Wu, C.C., Chen, Y.C. and Lee, Y.T. (1999). Complete atrioventricular block after arsenic trioxide treatment in an acute

promyelocytic leukemic patient. PACE.

22, 965-967.

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Haematol. 103, 1092-1095.

Little, R.E., Kay, G.N., Cavender, J.B., Epstein, A.E. and Plumb, V.J. (1990). Torsade de pointes and T-U wave alternans associated with arsenic poisoning. PACE, 13,164-170. Lu, Z., Kamiya, K., Opthof, T., Yasui, K.,

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6

行政院國家科學委員會補助專題研究計畫

□ 成 果 報 告

□期中進度報告

靜脈氧化砷治療之心臟毒性研究:發生率、機轉及發生後之可逆性

計畫類別:□ 個別型計畫 □ 整合型計畫

計畫編號:NSC 91-2314 -B -002-128

執行期間: 91 年 8 月 1 日至 92 年 7 月 31 日

主持人:吳美環 教授 台大醫學院小兒科

共同主持人:蘇銘嘉 教授 台大醫學院藥理所

共同主持人:林君榮 助理教授 台大醫學院

共同主持人:鄭安理 教授 台大醫學院內科

成果報告類型(依經費核定清單規定繳交):□精簡報告 □完整報告

本成果報告包括以下應繳交之附件:

□赴國外出差或研習心得報告一份

□赴大陸地區出差或研習心得報告一份

□出席國際學術會議心得報告及發表之論文各一份

□國際合作研究計畫國外研究報告書一份

處理方式:除產學合作研究計畫、提升產業技術及人才培育研究計畫、列

管計畫及下列情形者外,得立即公開查詢

□涉及專利或其他智慧財產權,□一年□二年後可公開查詢

執行單位:

中 華 民 國 92 年 10 月 31 日

附件一

參考文獻

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