Once in a while you come across an interesting article which looks at re-purposing an existing medication for a new indication. For example, a while back I blogged about how the topical beta blocker timolol could be used to treat heel fissures. For those with longer memories there was a lot of interest in the a gastric ulcer drug cimetidine which showed promise in clearing cutaneous warts [1] but latterly failed to show effectiveness clinically due to the high dosage required and side effects. A while back I also mentioned the antifungal effects of statins in an earlier blog so I decided to do an update.
The development of a new treatment in dermatophyte skin infection is particularly welcome at this time as we are facing the real threat of antifungal resistance with only a few new antifungal drugs in the pipeline.
How do statins work?
There are a number of statins available in the UK - atorvastatin (Lipitor), fluvastatin (Lescol), pravastatin (Lipostat), rosuvastatin (Crestor), simvastatin (Zocor).
Statins are medications effective at lowering serum cholesterol. They are one of the most prescribed drugs in the world today. They competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Stains lower total serum cholesterol, triglycerides and in particular, serum low-density lipoprotein cholesterol (LDL-C), which is the main culprit in the development of atherosclerosis and cardiovascular disease [2]. Beyond this, statins are known to possess other potential benefits.
How do they act as antifungals?
Statins lower cholesterol levels through their action on 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, an essential enzyme for the biosynthesis of cholesterol. This molecule forms an essential part of the human cell wall. In contrast, fungi have a similar molecule ergosterol as the main component on their plasma membrane. The use of a statin reduces the amount of cholesterol and it is hypothesised that statins may effectively reduce ergosterol supply and growth effectively acting as a fungistatic or fungicidal agent. In addition, blocking of the enzymatic pathway has a negative effect downstream by disruption in the manufacture of cell surface G proteins required for normal fungal cell signalling [3].
How effective are they?
Since the discovery of their antifungal properties, their effectiveness against yeasts and filamentous fungi (molds) have been well studied [4] with evidence in the variation of effectiveness of statins against different fungi. In dermatological terms, most were found to have activity against dermatophytes. It’s important to mention that antifungal activity was only achieved when statins were used at concentrations much higher than normal physiological levels. This effectively means that they can probably only be used in combination of existing antifungal agents as an enhancement. Many combinations have been experimentally tested included statins in combination with common topical antifungals such as clotrimazole, terbinafine and miconazole. The interaction of systemic statins and systemic antifungals is well documented (such as atorvastatin and azoles) and so a topical route of application is preferable and safer.
Implications for practice
The track record of statins generally is considered safe in oral use so one could logically expect a very safe topical preparation too. Of course, this like all of these discoveries it requires research to establish clinical proof. At this stage research has been limited to mainly laboratory work with a few clinical studies but with the rising threat of fungal resistance we may witness an acceleration of product development. It is likely that the product will be a combination of an antifungal with a topical statin.
References
1. Glass AT, Solomon BA: Cimetidine therapy for recalcitrant warts in adults. Arch Dermatol 1996, 132:680-682.
2. Patel KK, Sehgal VS, Kashfi K: Molecular targets of statins and their potential side effects: Not all the glitter is gold. Eur J Pharmacol 2022, 922:174906.
3. Cordle A, Koenigsknecht-Talboo J, Wilkinson B, Limpert A, Landreth G: Mechanisms of statin-mediated inhibition of small G-protein function. J Biol Chem 2005, 280:34202-34209.
4. Galgóczy L, Nyilasi I, Papp T, Vágvölgy C: Statins as antifungal agents. World Journal of Clinical Infectious Diseases 2011, 30:4-10.