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Old stains leaving new marks in dermatology

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By Warren R. Heymann, MD
Oct. 15, 2018

gentian violet
A new blue-gray papule was noted on the left side of the neck and was excised as outlined by gentian violet surgical marker.
Credit: JAAD
Periodically I will pull an ancient tie from my rack. I’m delighted if I get a compliment on the “new” attire, especially since the CCI (Cravat Cost Index) has escalated exponentially over the decades. Dermatologists are often confronted by patients who simply cannot afford prescription medications. Repurposed, inexpensive drugs for new indications are satisfying both medically and economically. The “rediscovery” of gentian violet is such an agent.

Gentian violet (GV), a triphenylmethane dye (also known as crystal violet or methyl violet), was first synthesized in 1861 as the “Violet de Paris” by Charles Lauth, a French chemist. Hans Gram used GV to create the Gram stain for bacteria in 1884. (1)

In their comprehensive review of GV, Maley and Arbiser  note that medicinal uses of GV are broad. Significant antibacterial activity against gram-positive organisms (Streptococcus, Staphlylococcus, MRSA) and moderately effective bacteriostatic activity against gram-negative bacteria such as Pseudomonas is well-documented. Interestingly, GV’s efficacy may, in part, be due to its ability to disrupt biofilms. Antimycotic activity, especially against Candida, is well-known. Antiprotozoal (Chagas disease, Leishmania), antihelminthic (Strongyloides, Enterobium), and antiviral (oral hairy leukoplakia due to Epstein-Barr virus) effects have all been reported. Tantalizing area of research focus on the antiangiogenic and antineoplastic effects of GV. GV’s utility appears to be linked to two distinct mechanisms of action. In mammalian cells, GV inhibits the NADPH oxidase complex, including Nox 1,2, and 4, leading to downregulation of superoxide production. Decrease superoxide results in decreased oxidation of IkB, leading to NFkB inhibition and anti-inflammatory activity. In bacteria, fungi, and parasites, GV may form a covalent adduct with thioredoxin 2 (Trx2), leading to malfunction of TRX2 and subsequent cell death. The discovery that GV inhibits NADPH oxidase demonstrates that GV has an effect on the host as well as infectious organisms, and this can be used to augment antiangiogenesis and tumor immunity. (2)

What piqued my interest in GV was the article by Wu and Wood in which they used high-throughput screening to detect cleaved caspase 8 induced in cutaneous T-cell lymphoma (CTCL) cells by 1710 unique compounds. They determined that GV induced more total apoptosis than did nitrogen mustard (mechlorethamine). GV induced 4 to 6 times greater apoptosis in CTCL lines than in normal keratinocytes, suggesting a favorable topical toxicity profile. In addition to increasing caspase 8, GV also upregulated death receptors 4 and 5, tumor necrosis factor (TNF)-related apoptosis-inducing ligand, and Fas ligand but not the Fas receptor, TNF receptor, or TNF-α ligand. These results are consistent with induction of extrinsic apoptosis via the Fas and TNF-related apoptosis-inducing ligand pathways. They were also able to demonstrate that the increase in GV-induced apoptosis in CTCL was greater when combined with methotrexate. The authors rightly assert that patients with CTCL are often secondarily infected with staphylococcal infections – using GV could potentially serve as a valuable topical agent for CTCL, by treating the disease and associated secondary infections. (3)

Should clinical studies confirm that topical GV is at least comparable (if not superior) to topical nitrogen mustard (mechlorethamine) for CTCL, think of the savings — a 2-ounce bottle of over-the-counter GV is $5 compared to $3800 for a 60-gram tube of the proprietary brand of mechlorethamine (according to GoodRx).

GV has been utilized clinically in patients with lymphoma. Rao et al reported complete regression of a nodule of recurrent primary cutaneous diffuse B-cell lymphoma, leg type, with a single injection of intralesional GV, in an 84-year-old woman. She had previously been treated with radiation and rituximab. (4)

GV has also been successful in treating myriad dermatoses, including atopic dermatitis, prurigo nodularis, pachyonychia congenita (2), and erythema multiforme. (5)

Understandably, Pharma has little to gain by sponsoring comparative GV studies, although patients could benefit from prospective randomized trials for CTCL (and other dermatoses). I’m tempted to pull out Castellani’s paint and Vleminckx  solution from the old dermatological medicine chest to see what they can do!

Point to remember: Gentian violet may be valuable in cutaneous lymphomas by their pro-apoptotic activity.

1. Hsieh S, et al. The purple dye that heals. JAMA Dermatol 2016; 152: 495.
2. Maley AM, Arbiser JL. Gentian violet: A 19th century drug re-emerges in the 21st Exp Dermatol 2013; 22: 775-80.
3. Wu J, Wood GS. Analysis of the effect of gentian violet on apoptosis and proliferation in cutaneous T-cell lymphoma in an in vitro study. JAMA Dermatol 2018; Aug 29 [Epub ahead of print].
4. Rao S, et al. Regression of diffuse B-cell lymphoma of the leg with intralesional gentian violet. Exp Dermatol 2018; 27: 93-95.
5. Murthy RK, et al. Treatment of extensive erythema multiforme with topical gentian violet. Exp Dermatol 2017; 26: 431-2.

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