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Dr. Alpana Mohta Ranka, MD, DNB, IFAAD, is a dual-board-certified dermatologist with over 90 research publications in peer-reviewed scientific journals.

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A Fresh Perspective on Treating Melasma: The Case for Isoniazid

Updated: May 1

As dermatologists, we're no strangers to the serendipity of drug repurposing. We've seen it before—drugs initially designed for one purpose miraculously proving beneficial for another. Remember the transition of tranexamic acid from a hemophilia adjunct to a star player in melasma management? Now, we're seeing a similar story with an age-old drug against tuberculosis: isoniazid.


Representative image of a woman with left half showing melasma and the right half showing normal skin tone.

Why the Desperate Need for Better Melasma Treatments?


We've all been there – the frustration of treating melasma. Our go-to might be hydroquinone for its effectiveness, but it's so risky that countries like the UK, Japan, and Australia have banned it due to its potential carcinogenic and mutagenic properties. Then there's the dreaded mercury-causing skin poisoning; and topical steroids, notorious for their severe side effects like skin thinning and increased infection risk.


On the safer end, we have milder agents like kojic acid, mandelic acid, niacinamide, and vitamin C that gently coax the skin toward improvement, albeit at a painstakingly slow pace and with modest outcomes.


And let’s not forget tretinoin. Well, I absolutely love tretinoin! It works wonders not just for pigmentation but also for sun spots and wrinkles. However, patients have a love-hate relationship with it. Simply because tretinoin requires careful handling of sun exposure, and honestly, not everyone is as diligent with sun protection as we dermatologists would hope.

 



So, Why Bet on an Antitubercular Drug for Skin Lightening?


What sparked the interest in isoniazid for melasma? Researchers have known that inhibiting the peroxidase enzyme in melanocytes can effectively manage melasma. Turns out isoniazid can be metabolized by melanocyte peroxidase, potentially reducing the overactivity of these cells. Plus, isoniazid's structure is surprisingly similar to niacinamide (nicotinamide), a well-known skincare staple for treating hyperpigmentation.



Promising Results


Recently, a team of researchers from Iran and Switzerland set forth to discover whether topical isoniazid could be the new star in melasma treatment. They conducted a double-blind, randomized controlled trial with 20 women, comparing a 10% isoniazid formulation against a placebo, complemented by strict sun protection. Over 12 weeks, isoniazid significantly outshined the placebo, improving both the MASI (Melasma Area and Severity Index) and MelasQoL (Melasma Quality of Life scale).


Although participants experienced some mild side effects like erythema and scaling, these were not severe enough to halt treatment in any of the patients.



It Wasn't Just a Random Discovery!


Back in the day, while Ernest Huant was exploring whether niacinamide (also known popularly in the world of medicine as "nicotinamide"), a form of vitamin B3, could ease the side effects of radiation in cancer patients, he stumbled upon a surprising benefit—it was clearing up tuberculosis in some of his patients!


Meanwhile, across the pond, French physician Vital Chorine discovered that high doses of nicotinamide halted TB progression in guinea pigs, but not because of its vitamin properties. This piqued the interest of Herbert Fox at Hoffmann-La Roche, who started hunting for compounds similar to niacin. This led to the discovery of isoniazid, marking it as the first drug with specific and potent action against TB.


Fast-forward to today, when niacinamide has become a staple in skincare,

its younger cousin, isoniazid, isn't far behind.


Topical Isoniazid has Been Around for Sometime Now


The transdermal delivery of topical isoniazid was first discovered to be a successful route of drug delivery in 2015 on porcine skin.


Later, in 2017, a group of Chinese researchers used topical isoniazid to manage a case of erythema induratum as an alternative to oral anti-tubercular drugs due to their side effects, such as gastrointestinal distress and thrombocytopenia. They formulated a 3.75% isoniazid ointment by combining crushed tablets (1500 mg) with a 40 g zinc oxide ointment, with a treatment duration planned for nine months.


The treatment was a success and free from any side effects, making the researchers recommend its use as a supplementary therapy for cutaneous tuberculosis.


Subsequent innovation included a collaboration between Brazilian and U.S. researchers who developed a topical cocrystal of Isoniazid and Resveratrol for cutaneous tuberculosis in 2019.


From my understanding, these formulation should only be considered an adjunct to oral anti-tubercular therapy rather than a standalone treatment for cutaneous tuberculosis, especially in multibacillary tuberculosis.



What About Concerns Regarding Isoniazid Resistance?


However, there's an obvious concern about the potential of topical isoniazid to contribute to the development of oral isoniazid resistance.


To take the bull by its horns, I would like to draw insights from a recent publication from Lancet which questions the usage of isoniazid as a first line anti tubercular drug altogether. The report makes mention of multiple studies that has found an anti tubercular regimen without isoniazid to be just as effect.


Originating from trials in the 1950s among the Navajo in Arizona, the drug's side effects, such as severe hepatitis and peripheral neuropathy, were deemed acceptable due to the urgent need for effective tuberculosis treatment. These issues raise questions about its approval under current standards.


That said, isoniazid's role is still unparalleled while managing complicated cases of tuberculosis. It has excellent penetration in the central nervous system in cases like tuberculosis meningitis or managing sepsis with a high mycobacterial load.



Just Thinking Out Loud Here


Coming back to melasma and the current research, these are promising results from just one study. There's a long road ahead to see how topical isoniazid stands up over time and against other contenders.


Moreover, isoniazid is a first line anti-tubercular drug and must be use cautiously for an aesthetic concern like melasma.


Nevertheless, as a dermatologist who sees the daily struggle and frustration of patients with recurring melasma, I'm cautiously optimistic about this old wine in a new bottle until it proves its mettle!


Whether it turns out to be a genius move or just another step in the ongoing search for even better treatments, only time will tell.

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