Lovastatin as a Treatment for Adrenoleukodystrophy

Lovastatin for X-Linked Adrenoleukodystrophy

 Lovastatin

In a study conducted by Singh et. al they have shown in animal studies that lovastatin can be used as a therapy for adrenoleukodystrophy. Lovastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and sodium phenylacetate, which inhibits mevalonate pyrophosphate decarboxylase. This then inhibits the induction of inducible nitric oxide synthase and proinflammatory cytokines involved in the pathogenesis of neurological damage in X-linked adrenoleukodystrophy. For those not in a science major here is some definitions that will help:

-       A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produce cholesterol

-         Sodium phenylacetate is an aromatic fatty acid, which displays cell growth inhibition, malignant phenotype reduction and cell differentiation

-       A cytokine is a are small cell signaling molecules that are usually produced during an immune reaction

Lovastatin has been shown to increase intracellular cyclic AMP and protein kinase A activity and normalize the levels of very-long chain fatty acids in skin fibroblasts from patients with childhood adrenoleukodystrophy.

The study was conducted by treating patients with 20 mg of lovastatin per day for two weeks, if not side effects occurred the dose was increased to 40 mg a day.  The fatty acids were measured throughout the study to observe the effects. According to their results the plasma levels of very-long chain fatty acids declines in each patient that completed the trial after 6 months.  These results suggested that lovastatin treatment may reduce the very-long chain fatty acids in adults with adrenoleukodystrophy, without any significant side-effects.  The effects of lovastatin are believed to be due to the drug blocking the induction of inflammatory mediators of neurological damage in adrenoleukodystrophy.

A comparative study conducted by Engelen et. al have stated that lovastatin should not be used for a treatment of adrenoleukodystrophy. The conducted their own study where they gave patient with adrenoleukodystrophy a 40 mg dose of lovastatin once daily compared to a placebo dose. The trial was designed to investigate whether lovastatin has a biochemical effect in vivo in patients with X-ALD. They concluded that lovastatin leads to a small decrease in levels of C24:0 and C26:0 in plasma. They also took into account that VLCFAs (very-long-chain fatty acids) are water soluble and therefore only a small amount binds to the albumin in the blood and most bind to the LDL cholesterol.  LDL did not decrease with the lovastatin dose and therefore they considered the results to be nonspecific due to the fact that LDL did not decrease.

With the opposing results of these two studies it is clear that more research is needed to study the effects of lovastatin in patients with adrenoleukodystrophy.  Whether this drug can be used as a therapy is still unclear and more time and resources must be placed on the study of this drug to determine if it holds any positive benefits.

References

Singh, I., Khan, M., Key, L. & Pai, S. 1998, Lovastatin for X-Linked Adrenoleukodystrophy. The New England Journal of Medicine, 339: 702-703

Engelen, M., Ofman, R., Dijkraaf, M., Hijzen, M. & Wardt, L. Lovastatin in X-linked Adrenoleukodystrophy. 2010. The New England Journal of Medicine, 362, 276-277.

Alisha M.