Thalidomide causes sinus bradycardia in ALS

Meyer, Thomas; Maier, André; Borisow, Nadja; Dullinger, Jörn S.; Splettstößer, Gerald; Ohlraun, Stephanie; Münch, Christoph; Linke, P.

doi:10.1007/s00415-008-0756-3

Cited by 30 publications

(18 citation statements)

References 17 publications

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“…Bradycardia in our trial patients was largely asymptomatic and hence we did not feel that the rhythm change was worrisome. A German thalidomide/ALS trial similar to our own trial was terminated because of the high incidence of bradycardia (37). Efficacy in this trial was not reported.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

Stommel¹,

Cohen²,

Fadul³

et al. 2009

Amyotrophic Lateral Sclerosis

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Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-α) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-α pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-α inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects.

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Section: Discussionmentioning

confidence: 99%

Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

Stommel¹,

Cohen²,

Fadul³

et al. 2009

Amyotrophic Lateral Sclerosis

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“…A pilot study was carried out to determine the efficacy of thalidomide in amyotrophic lateral sclerosis 83 . Thalidomide was initiated at 100 mg per day for 6 weeks.…”

Section: Arrhythmiasmentioning

confidence: 99%

“…Furthermore, a patient died from sudden unexpected death. The study was terminated prematurely for safety concerns 83 . Therefore, thalidomide appears to induce bradycardia in some patients.…”

Section: Arrhythmiasmentioning

confidence: 99%

Mechanisms of Cardiotoxicity of Cancer Chemotherapeutic Agents: Cardiomyopathy and Beyond

Moudgil

Yeh

2016

Canadian Journal of Cardiology

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Tremendous strides have been made in the treatment of various oncological diseases such that patients are surviving longer and are having better quality of life. However, the success has been tainted by the iatrogenic cardiac toxicities. This is especially concerning in the younger population who are facing cardiac disease such as heart failure in their 30s and 40s as the consequence of the anthracycline’s side-effect (used for childhood leukemia and lymphoma). This resulted in the awareness of cardio-toxic effect of anticancer drugs and emergence of a new discipline: Onco-cardiology. Since then numerous anticancer drugs have been correlated to cardiomyopathy. Additionally, other cardiovascular effects have been identified which includes but no limited to the myocardial infarction, thrombosis, hypertension, arrhythmias and pulmonary hypertension. This review examines some of the anticancer agents mitigating cardiotoxicity and presents current knowledge of molecular mechanism(s). The aim of the review is to ignite awareness of emerging cardio-toxic effects as new generation of anticancer agents are being tested in clinical trials and introduced as part of therapeutic armamentarium to our oncological patients.

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“…For instance, thalidomide derivatives which suppresses TNF α message translation in addition to other actions are amongst the more effective drugs tested in SOD1 G93A mice [10, 37, 38]. Unfortunately, human clinical trials of thalidomide for ALS have been unsuccessful due to lack of patient tolerance and excessive occurrence of sinus bradycardia [39, 40]. Doses of thalidomide that were tolerated by the ALS patients were insufficient to noticeably shift patient cytokine profiles [39].…”

Section: Targeting Neuroinflammation By Suppressing Glial Activatimentioning

confidence: 99%

Progress in Therapy Development for Amyotrophic Lateral Sclerosis

Venkova-Hristova

Christov

Kamaluddin

et al. 2012

Neurology Research International

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that cannot be slowed substantially using any currently-available clinical tools. Through decades of studying sporadic and familial ALS (SALS and FALS), researchers are coming to understand ALS as a complex syndrome with diverse genetic and environmental etiologies. It is know appreciated that motor neuron degeneration in ALS requires active (gain of function) and passive (loss of function) events to occur in non-neuronal cells, especially astrocytes and microglia. These neuroinflammatory processes produce paracrine factors that detrimentally affect motor neurons, precipitating protein aggregation and compromising cytoskeletal integrity. The result is a loss of neuronal homeostasis and progressive die-back of motor axons culminating in death of the afflicted motor neurons. This review will discuss experimental therapeutics that have been tested in murine ALS models, with an emphasis on those that have progressed to human clinical trials. Reasons will be considered for the frequent failure of preclinical successes to translate into positive clinical outcomes. Finally, this review will explore current trends in experimental therapeutics for ALS with emphasis on the emerging interest in axon guidance signaling pathways as novel targets for pharmacological support of neural cytoskeletal structure and function in order to slow ALS.

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Thalidomide causes sinus bradycardia in ALS

Cited by 30 publications

References 17 publications

Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

Mechanisms of Cardiotoxicity of Cancer Chemotherapeutic Agents: Cardiomyopathy and Beyond

Progress in Therapy Development for Amyotrophic Lateral Sclerosis

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