Preclinical and clinical assessment of the safety and potential efficacy of thalidomide in heart failure.
BACKGROUND
Inflammatory mediators, especially tumor necrosis factor (TNF), have been implicated in heart failure (HF). Thalidomide has anti-inflammatory properties and selectively inhibits TNF. Thus far, thalidomide or thalidomide analogues have not been evaluated in patients with heart failure.


METHODS
Thalidomide was assessed in preclinical and clinical studies. First, isolated cardiac myocytes were pretreated with thalidomide or thalidomide analogues, and TNF production was assessed after lipopolysaccharide (LPS) provocation. Second, to determine the safety and potential efficacy of thalidomide, an open-label dose escalation safety study was conducted in seven patients with advanced heart failure.


RESULTS
Thalidomide and thalidomide analogues inhibited LPS-induced TNF biosynthesis in cardiac myocytes in a dose-dependent manner. Thalidomide analogues had a greater inhibitory effect on TNF production than did thalidomide. In patients with advanced HF, thalidomide was safe and potentially effective when used at lower doses. However, dose-limiting toxicity was observed in two patients. There was a significant increase in the 6-minute walk distance and a trend toward improvement in left ventricular ejection fraction and quality of life after 12 weeks of maintenance therapy with thalidomide.


CONCLUSIONS
Taken together these results suggest that thalidomide or its derivatives may be useful in selected patients with HF. This potential needs to be studied in larger clinical trials.
Agoston
Ildiko
I
Winters Center for Heart Failure Research, Cardiology Section, Department of Medicine, Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Dibbs
Ziad I
ZI
Wang
Feng
F
Muller
George
G
Zeldis
Jerome B
JB
Mann
Douglas L
DL
Bozkurt
Biykem
B
D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011788:Quality of Life; D013318:Stroke Volume / Q000187:drug effects; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D016207:Cytokines; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D013792:Thalidomide