Cardiac glycosides in prevention of ischemic stroke

(2006-07-11) Infarct Combat Project

Brazilian study confirm the findings of Duke University Medical Center researchers that cardiac glycosides provide neuroprotection in stroke occurrence. It was a study of 28 years that showed a low mortality for stroke in 1150 cardiac patients taking these drugs.

Using a novel screening technology, Duke University Medical Center researchers have shown that drugs called cardiac glycosides can protect brain cells from death after stroke in laboratory models, and that the drugs are effective even if delivered six hours or more after the onset of stroke conditions (1).

"This discovery is exciting because it may lead to interventions to prevent or lessen the amount of brain damage suffered after stroke," said Donald C. Lo, Ph.D., director of the Center for Drug Discovery and associate professor of neurobiology at Duke, and primary investigator on the study
Currently, only one drug has been approved by the Food and Drug Administration to treat stroke -- and it faces serious limitations, Lo said. Called recombinant tissue plasminogen activator, the drug must be given within a three-hour window after the onset of stroke. Also, because the drug is delivered intravenously and acts by breaking blood clots, it is ineffective against "hemorrhagic" strokes that happen when an artery bursts.

Lo speculates that cardiac glycosides may exert their beneficial effect during stroke in an analogous manner that in heart disease, by restoring calcium to healthy levels in brain cells and thereby preventing cell death. Calcium plays a key role in regulating normal cell function, and any changes in its cellular concentration -- such as those caused by stroke -- can be toxic (2).

Another recent study with statin drugs concluded that its use is associated with a reduced risk of stroke but not severity or mortality (3)

Related to the Duke University Medical Center research, a case study from Brazil confirm the very low mortality for stroke in 1150 patients with stable heart disease taking cardiac glycosides, during 28 years. The study was authored by Quintiliano H. de Mesquita and Claudio A. S. Baptista and published in Ars Cvrandi, a Brazilian medical journal in 2002 (4)

The stroke (ischemic + hemorrhagic) mortality in 28 years for the cardiac patients taking cardiac glycosides was:

- 994 patients w/out prior infarction - Stroke mortality: 13 cases (1.3%) = 0.04% per year.
- 156 patients with prior infarction - Stroke mortality: 7 cases (4.4%) = 0.15% per year.

For a better comparison in stroke mortality, with those taking cardiac glycosides, we can take the data from the HPS study, which had a follow-up of 5 years, involving 20.536 patients aged 40-80 years with coronary heart disease, other vascular diseases or diabetes. The HPS found a total stroke mortality of 0.9% (0.18% per year) in patients taking statins and 1.2% (0.24% per year) in patients taking placebo (5)

The permanent use of cardiac glycosides (Digitoxin, Digoxin, Acetildigoxin, Lanatoside-C, Betametildigoxin, or Proscillaridin-A) in low, daily therapeutic (non-toxic) doses from the Brazilian study was based on the Myogenic Theory of Myocardial Infarction and had as its objective the prevention of acute coronary syndromes (6, 7). The global mortality for the patients without previous myocardial infarction was 14.2% (0.5% per year), while the global mortality for the patients with previous myocardial infarction was 41.0% (1.4% per year). The numbers for mortality and morbidity are described in the Table 5 of the article. (1)

References

1. Cardiac glycosides provide neuroprotection agains ischemic stroke: Discovery by a brain slice-based compound screening platform, James K. T. Wang, Donald C. Lo et al, Proc Natl Acad Sci U S A. 2006 Jun 22; Full and free text at http://www.pubmedcentral.gov/picrender.fcgi?artid=1481664&blobtype=pdf
2. Study Spots Potential Stroke Drugs, http://www.dukemednews.org/news/article.php?id=9754
3. Statin use and sex-specific stroke outcomes in patients with vascular disease, Cheryl D. Bushnell et al, Stroke, 2006; 37:1427
4. Cardiotonico: Insuperavel na Preservacao da Estabilidade Miocardica como Preventivo das Sindromes Coronarias Agudas e Responsavel pela Prolongada Sobrevida--Casuistica de 28 anos (1972-2000), Mesquita, QHde e Baptista, CAS. Ars Cvrandi. May 2005, Volume 35, republished in 2005 at http://www.infarctcombat.org/28anos/digitalicos.html, with summary in English at http://www.infarctcombat.org/heartnews-16.html.
5. The effects of cholesterol lowering with simvastatin on cause-specific mortality and on cancer incidence in 20,536 high-risk people: a randomized placebo-controlled trial, Heart Protection Study Collaborative Group. BMC Medicine 2005, 3:6 -- http://www.biomedcentral.com/1741-7015/3/6
6. Myogenic Theory of Myocardial Infarction Book with summary in English at http://www.infarctcombat.org/LivroTM/parte8.htm.
7. Some articles in English about the Myogenic Theory are available at: http://www.infarctcombat.org/MyogenicTheory.html.