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Nitric oxide treatment works for genital warts

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Study expands frontier despite limitations

Nitric oxide is an unassuming simple diatomic lipophilic gaseous molecule which in fact is anything but, involved in almost every biological process and serving as possibly the most important signaling molecule in the human system. From antimicrobial action to vasodilation to the dichotomous role as a pro and anti-inflammatory agent, it is no surprise that there is a frantic race to develop means to translate our massive fund of knowledge on this biomolecule to the bedside. As an NO enthusiast, scientist, and participant in this rat race, it is no question exciting to see an NO related technology evaluated in a clinical trial. True, there are some inherent flaws with this delivery system and study protocol. Firstly, we are not presented with any pharmacokinetics with respect to concentration of NO generation, duration, permeation, etc. This is extremely important as how much NO is produced, where it is produced, for how long it is produced are key to its activity in vivo. Depending on the answers to these questions, the biologiocal impact can range for cytoregualtory to cytotoxicity. Second, the reduction of nitrite by an acid results in a rapid burst of NO formation with limited potential for sustained delivery. The concentrations used are exceedingly high (6 gm/100 ml nitrite; 9 gm/100 ml citric acid), likely generating a massive bolus of NO that could possibly be toxic to eukaryotic cells (not discussed). Third, the lack of citric acid alone as a control is extremely concerning, as we often use acidic agents as keratolytics to destroy verruca, not to mention instigate an immune response through injury to aid in lesion resolution. Could citric acid along be responsible for these successful results? It’s possible.

However, even with these flaws, I commend the authors/investigators for pushing the frontiers of NO biomedical applications. I believe all NO researchers will agree, we are all on the same team, hoping to translate the awesome power of NO to the bedside. Pointing the spotlight on NO, especially in a high level journal such as JAMA Dermatology, only furthers the cause and fuels further investigation. Kudos.

Dr. Adam Friedman is currently Director of Dermatologic Research at Montefiore – Albert Einstein College of Medicine in Bronx, N.Y. He had no relevant financial conflicts to disclose, but he serves as a member of the Dermatology News Editorial Advisory Board.


 

References

The coapplication of two topical creams, one containing 6% sodium nitrite and another containing 9% citric acid, together producing nitric oxide, was effective in treating genital warts in close to one-third of patients, in a study published online April 29 in JAMA Dermatology.

In a randomized, placebo-controlled trial, 31% of patients treated with the nitric oxide topical treatment had complete clinical clearance within 12 weeks, compared to 14% of those assigned to placebo (P = .01), Dr. Anthony D. Ormerod of the University of Aberdeen, Scotland, and associates reported (JAMA Derm. 2015 April 29 [doi:10.1001/jamadermatol.2015.0381]).

Researchers randomized 299 patients (64% men) from 40 treatment centers across Europe to one of three dose regimens of sodium nitrite and citric acid, or placebo. Sodium nitrite reacts with citric acid to produce nitric oxide, which acts as an antiviral and antimicrobial; for the study, patients applied two separately prepared creams, allowing the agents to combine at the treatment site. Only the highest-dose combination studied, sodium nitrite 6% and citric acid 9% applied twice daily, was shown to be significantly more effective than placebo.

Patients receiving the highest dose also saw the highest rate of adverse effects in the study: Of the 73 patients in that arm, 92% reported treatment site adverse events, including itching, pain, edema and skin staining. “This study proves the concept that acidified nitrite is effective in treating anogenital warts and has identified the dose required for efficacy,” Dr. Ormerod and associates wrote. “For the sensitive anogenital application site, this dose probably represents the optimal one for further evaluation. For future research, extending the duration of treatment might improve the efficacy,” they said.

The researchers noted that studies of another agent used to treat genital warts, imiquimod, demonstrated clearance rates of between 37% and 52%.

The study was funded by the pharmaceutical manufacturer ProStrakan, with additional support from Origin Pharmaceuticals. Dr. Ormerod reported honoraria and royalties from ProStrakan and disclosed patents filed on acidified nitrite for treatment of skin infections. Four other co-authors reported support from ProStrakan.

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