Clinical features of and effects of angiotensin system antagonists on amiodarone-induced pulmonary toxicity.
BACKGROUND
Amiodarone (AMD) is a strong antiarrhythmic drug but has severe side effects such as pulmonary toxicity. There are no indicators or drugs that can prevent the development of amiodarone-induced pulmonary toxicity (AIPT).


METHODS
We collected data for 96 consecutive patients treated with AMD and analyzed clinical factors related to AIPT. In addition, we examined the effect of AMD and angiotensin II (Ang II) on human lung alveolar epithelial cells (AEC) and verified the protective efficacy of an Ang II type 1 receptor blocker (ARB) in vitro.


RESULTS
During a follow-up period of 33.8+/-34.6 months, AIPT developed in 11 patients (11.5%). There were no differences in the dose of AMD, left ventricular ejection fraction, serum KL-6 and %DLCO level before starting AMD between patients with and those without AIPT. However, repeated episodes of congestive heart failure (CHF) were observed more frequently in patients with AIPT than in patients without AIPT (81.8% vs. 41.2%, P<0.011). In vitro examination, AMD progressively increased apoptosis of AEC and Ang II enhanced this effect of AMD (P<0.001). However, ARB inhibited the enhancement by Ang II of the AMD-induced apoptosis effect (P<0.001). Furthermore, patients with AIPT were administrated a lower dose of angiotensin system antagonists than were those without AIPT (P<0.05).


CONCLUSIONS
The results indicate that Ang II induced by CHF increases the risk of AMD-induced pulmonary toxicity. An angiotensin-converting enzyme inhibitor or ARB should be given at a sufficient dose during AMD treatment.
Nikaido
Akira
A
Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.
Tada
Takeshi
T
Nakamura
Kazufumi
K
Murakami
Masato
M
Banba
Kimikazu
K
Nishii
Nobuhiro
N
Fuke
Soichiro
S
Nagase
Satoshi
S
Sakuragi
Satoru
S
Morita
Hiroshi
H
Ohe
Tohru
T
Kusano
Kengo Fukushima
KF
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056809:Alveolar Epithelial Cells / Q000187:drug effects; D000638:Amiodarone / Q000009:adverse effects*; D000804:Angiotensin II / Q000097:blood / Q000187:drug effects* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure / Q000097:blood; D006801:Humans; D016015:Logistic Models; D008171:Lung Diseases / Q000139:chemically induced* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011650:Pulmonary Alveoli / Q000187:drug effects; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000889:Anti-Arrhythmia Agents; D000804:Angiotensin II; D000638:Amiodarone