10.5826/dpc.1301a11
Introduction: Favipiravir creates fluorescence on nails, which can be seen with Wood's light.
Objectives: The objectives of this study are to examine the properties of fluorescence in the nail due to favipiravir and to observe whether other drugs also produce fluorescence in the nail.
Methods: The research is descriptive, prospective, and quantitative. This study recruited 30 healthcare workers who received favipiravir treatment and 30 volunteers who took or did not take any medication except favipiravir from March 2021 to December 2021. Fingernails of the patients and control groups were examined under Wood's light in the darkroom. If fluorescence was observed in the fingernails, we followed up once a month until the fluorescence disappeared. We calculated the nail growth rate by dividing the distance of nail fluorescence from the proximal nail fold by the number of days since favipiravir was started.
Results: We found nail fluorescence in all patients receiving a loading dose of favipiravir. The fluorescence in the nail decreased and disappeared in the 3rd month. The average nail growth rate at the first visit was 0.14 mm/day. The nail growth rate at the second visit was 0.10 mm/day. A statistically significant difference was found between the first and second visit nail growth rates (z: -2.576; p=0.010&lt;0.05). We found that other drugs did not produce any fluorescence in the nail.
Conclusions: Nail fluorescence induced by favipiravir is dose-dependent and decreases in intensity over time. Nail fluorescence due to favipiravir is likely due to the active ingredient of the drug.
text/xml
2160-9381
2370
en
Zeynep Güneş Özünal
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Drug
Follow-up of Favipiravir-Induced Nail Fluorescence: Implications for Nail and Drugs
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-01-31
2022-02-06
2023-01-31
2023-02-27
e2023011
Dermatol Pract Concept
Introduction: Favipiravir creates fluorescence on nails, which can be seen with Wood's light.
Objectives: The objectives of this study are to examine the properties of fluorescence in the nail due to favipiravir and to observe whether other drugs also produce fluorescence in the nail.
Methods: The research is descriptive, prospective, and quantitative. This study recruited 30 healthcare workers who received favipiravir treatment and 30 volunteers who took or did not take any medication except favipiravir from March 2021 to December 2021. Fingernails of the patients and control groups were examined under Wood's light in the darkroom. If fluorescence was observed in the fingernails, we followed up once a month until the fluorescence disappeared. We calculated the nail growth rate by dividing the distance of nail fluorescence from the proximal nail fold by the number of days since favipiravir was started.
Results: We found nail fluorescence in all patients receiving a loading dose of favipiravir. The fluorescence in the nail decreased and disappeared in the 3rd month. The average nail growth rate at the first visit was 0.14 mm/day. The nail growth rate at the second visit was 0.10 mm/day. A statistically significant difference was found between the first and second visit nail growth rates (z: -2.576; p=0.010&lt;0.05). We found that other drugs did not produce any fluorescence in the nail.
Conclusions: Nail fluorescence induced by favipiravir is dose-dependent and decreases in intensity over time. Nail fluorescence due to favipiravir is likely due to the active ingredient of the drug.
Zeynep Güneş Özünal
2023/01/31
10.5826/dpc.1301a11
e2023011
Department of Pharmacology, Medical Faculty, Maltepe University, Istanbul, Turkey 
2160-9381
Drug
en
e2023011
Palmeri A, Pichini S, Pacifici R, Zuccaro P, Lopez AJCp. Drugs in nails. 2000;38(2):95-110.
Follow-up of Favipiravir-Induced Nail Fluorescence: Implications for Nail and Drugs
https://dpcj.org/index.php/dpc/article/download/2370/1951
 Follow-up of Favipiravir-Induced Nail Fluorescence:
          Implications for Nail and Drugs
                                          Hüsna Güder1, Zeynep Güneş Özünal2


1 Department of Dermatology, Medical Faculty, Maltepe University, Istanbul, Turkey
2 Department of Pharmacology, Medical Faculty, Maltepe University, Istanbul, Turkey



Key words: favipiravir, nail, fluorescence, drug
Citation: Güder H, Güneş Özünal Z. Follow-up of Favipiravir-Induced Nail Fluorescence: Implications for Nail and Drugs. Dermatol Pract
Concept. 2023;13(1):e2023011. DOI: https://doi.org/10.5826/dpc.1301a11
Accepted: July 31, 2022; Published: January 2023
Copyright: ©2023 Güder et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication
Corresponding Author: Hüsna Güder, Department of Dermatology, Medical Faculty, Maltepe University, Feyzullah Caddesi no:39,
Maltepe/Istanbul, Turkey. Tel: +905056916918 Email: husnaguder@gmail.com




  ABSTRACT              Introduction: Favipiravir creates fluorescence on nails, which can be seen with Wood’s light.
                        Objectives: The objectives of this study are to examine the properties of fluorescence in the nail due
                        to favipiravir and to observe whether other drugs also produce fluorescence in the nail.
                        Methods: The research is descriptive, prospective, and quantitative. This study recruited 30 health-
                        care workers who received favipiravir treatment and 30 volunteers who took or did not take any
                        ­medication except favipiravir from March 2021 to December 2021. Fingernails of the patients and
                         control groups were examined under Wood’s light in the darkroom. If fluorescence was observed in
                         the fingernails, we followed up once a month until the fluorescence disappeared. We calculated the nail
                         growth rate by dividing the distance of nail fluorescence from the proximal nail fold by the number of
                         days since favipiravir was started.
                        Results: We found nail fluorescence in all patients receiving a loading dose of favipiravir. The
                        ­fluorescence in the nail decreased and disappeared in the 3rd month. The average nail growth rate at
                         the first visit was 0.14 mm/day. The nail growth rate at the second visit was 0.10 mm/day. A statisti-
                         cally significant difference was found between the first and second visit nail growth rates (z: -2.576;
                         p=0.010<0.05). We found that other drugs did not produce any fluorescence in the nail.
                        Conclusions: Nail fluorescence induced by favipiravir is dose-dependent and decreases in intensity
                        over time. Nail fluorescence due to favipiravir is likely due to the active ingredient of the drug.




Original Article | Dermatol Pract Concept. 2023;13(1):e2023011                                                                      1
Introduction                                                          all participants. Those who were pregnant or breastfeeding
                                                                      were not included in the study. We recorded the age, gender,
The human eye can only process visible light (400−720 nm),            drug use, vitamin and supplement use of the study and con-
which is a narrow segment of the electromagnetic spectrum             trol groups. The drugs taken as a criterion for systemic drug
(EMS). Our retina is not capable of sensing light in the UV           use were taken at least 15 days before and drugs taken for
spectrum (10-400 nm) but can detect longer wavelength flu-            more than 5 days were recorded.
orescence caused by the interaction of UV light with skin                Approval from the Ministry of Health of the Republic
chromophores. Wood’s light is frequently used in dermatol-            of Turkey with the number 2021-01-13T13_41_11 and per-
ogy to detect fluorescence produced by exogenous or endog-            mission from the ethics committee of Maltepe University
enous chromophores [1].                                               with the number 2021/900/19 were obtained.
    Favipiravir, a pyrazine carboxamide derivative (6-­fluoro-           We conducted this study among 30 healthcare workers
3-hydroxy-2-pyrazine carboxamide), is a broad-spectrum                who received favipiravir treatment and 30 volunteers who
antiviral drug with inhibitory effects on a variety of RNA            took or did not take any medication between 04/03/2021
­viruses [2]. Favipiravir is widely used in Turkey to treat corona-   and 25/12/2021. The fingernails of the patients and con-
virus disease 2019 (Covid-19) based on the Covid-19 treatment         trol groups were examined under Wood’s light (Lumio®UV,
guide of the Ministry of Health, Republic of Turkey. A load-          3Gen DermLite™, 40 UV LEDs, 75 mm 2x lens, U.S.A.) in
ing dose of 2x1600 mg (first day) of favipiravir followed by          the darkroom. If fluorescence was observed in the finger-
2x600 mg/day (4 days) for a total of 4 days is recommended.           nails, we followed up once a month until the fluorescence
    Wood’s lamp is a high-pressure mercury arc lamp filtered          disappeared. The length of the third fingernails of the left
with barium silicate and nickel oxide, emitting ultraviolet           hand of all patients was measured. The left hand was chosen
in the 320-400 nm spectrum with a peak at 365 nm. When                as it is usually the non-dominant hand and the middle finger
examining a Wood’s lamp in a dark room, fluorescence is               because it is easy to position. The cuticle (eponychium) was
seen if there are fluorophores[3]. So far, the following fluo-        not included when measuring nail length or fluorescence. We
rescence has been reported in the nail due to drug use: yel-          measured the size of the fluorescence in the nail. In addi-
low for tetracycline, yellow/green for quinacrine, and yellow/        tion, the distance of the fluorescence from the distal tip of
green/blue fluorescence for favipiravir [4-9].                        the nail and the proximal nail fold was also measured. Mea-
    We wanted to follow up on whether nail fluorescence in            surements were made from the midpoint of the nail using a
all patients using favipiravir persisted or not and how long          digital caliper (Figure 1). It was not possible to see all of the
nail fluorescence persists. Data on the fluorescence of drugs         patients in the 1st month and the 2nd month. 1st month was
in nails are limited to a few drugs. We wanted to collect in-         accepted as 31±3 days, 2nd month was 61±3 days.
formation about whether other drugs create fluorescence                  The first visit nail growth rate was calculated as mm/
in the nails by including people who use drugs as a control           day by dividing the distance between the proximal nail fold
group in our study. We thought that the data we obtained              and the first distal fluorescence by the measurement day.
could provide information about drug transfer to the nail             The 2nd visit nail growth rate was obtained by subtracting
and the relation between drugs and nails.                             the distance of the distal fluorescent from the proximal nail
                                                                      fold measured at the 2nd visit from the first measured at
                                                                      the 1st visit and dividing by the number of days in between
Material and Methods
                                                                      (Figure 2).
Patients who received favipiravir treatment due to severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase            Statistics
chain reaction (PCR) positivity diagnosis among healthcare            Power analysis in the research was carried out with the G
workers at our hospital were included in the study as the study       Power 3.1.9.7 program. Assuming that the difference be-
group. Only an observational study was planned, without any           tween 2 observations will be examined, the t-test family was
interference with patients’ drug doses or treatment duration.         taken as reference, and the effect size was accepted as 0.8 us-
The reason for choosing healthcare professionals is to facilitate     ing the wide Cohen reference since there was no similar prior
follow-up and eliminate the risks that may occur due to pa-           study. In addition, it was concluded that it would be suffi-
tients coming to the hospital. In the control group, individuals      cient to have 15 people in the analysis of the main hypothesis
who did not receive favipiravir treatment and were or were not        at 80% power and 5% significance levels. Since there were
using another systemic drug were included in the study. The           20 people who could be followed up in the study, the sample
research is descriptive, prospective, and quantitative.               size obtained was considered sufficient.
    Volunteer adults between the ages of 18-65 were included             The SPSS 22.0 (IBM Corporation, Armonk, New York,
in the study. An informed consent form was obtained from              United States) program analyzed the variables. We used the



2                                                                         Original Article | Dermatol Pract Concept. 2023;13(1):e2023011
     Figure 1. Measurement methods (A: Measurement method for the midpoint of the nail fluorescence B: The measurement of the
     third fingernails of the left hand).




Figure 2. The first (A) and second (B) visit measurement of the nail fluorescence size (Black lines indicate the size of the fluorescence. The
red line shows the distance between the distal end of the fluorescence and the proximal nail fold).



Pearson chi-square test to examine whether there was a                       Quantitative variables were expressed as mean (± stan-
gender difference between the control group and the study                dard deviation), and median (minimum-maximum), while
group. We examined the distribution of age by skewness and               categorical variables were shown as n (%). The variables
kurtosis (-1 - +1). Accordingly, we examined the ages of the             were analyzed at a 95% confidence level, and a p-value less
study/control groups with the t-test.                                    than 0.05 was considered significant.
    When comparing the elongation rates of the nail fluores-
cence, the Gaussian distribution was examined and it was
                                                                         Results
found that it was not normal. Accordingly, the Wilcoxon
Signed-Rank test was used. Hypothesis tests were performed               24 (80.0%) of the participants included in the study group
with the help of the SPSS 22.0 program at a 95% confi-                   were women; 6 of them (20.0%) were male. Their mean age
dence level.                                                             is 36.10±9.03 years. The average length of the left-hand third



Original Article | Dermatol Pract Concept. 2023;13(1):e2023011                                                                              3
                             Table 1. Demographic Data of Study and Control Groups.
 Study group
                                                          n                                      %
 Female                                                  24                                      80
 Male                                                     6                                      20
 Total                                                   30                                     100
                                                         Min              Max                  Mean                    SD
 Age                                                     21                51                 36.1000               9.03003
 Left-hand 3rd nail length                               7.80            15.30                11.2833               1.88334
 Control group
                                                          n                                      %
 Female                                                  20                                     66.7
 Male                                                    10                                     33.3
 Total                                                   30                                     100
                                                         Min              Max                  Mean                    SD
 Age                                                     19                64                  37.37                  13.12
 Left-hand 3rd nail length                               8.60            15.70                11.8633               1.85370



     Table 2. Comparison of Study and Control                      the proximal nail in the other (Figure 4). Furthermore, in
    groups according to left-hand 3rd nail length.                 a patient who received favipiravir twice, examined on the
                                                                   62nd day of the 1st dose and the 48th day of the 2nd dose,
                 n       Mean           SD         t          p
                                                                   fluorescence was observed in the entire nail (Figure 5).
 Study         30     11,2833         1,88334
                                                -1,202    0,234       In the measurements made from the 3rd nail of the left
 Control       30     11,8633         1,85370
                                                                   hand, the nail fluorescence of 10 patients could be measured
t: Independent samples t-test value                                in the 1st month. The mean nail fluorescence length was
                                                                   3.95±0.67 mm (min-max 3-5) in the first month. The nail
                                                                   fluorescence of 20 patients could be measured in the second
fingernails is 11.28±0.188. In the control group, 20 (66.7%)       month and the mean nail fluorescence length was 4.3±0.77
of the 30 participants were female, and 10 (33.3%) were            mm (min-max 2.9-5.9).
male. Their mean age is 37.37±13.12. The average length of            The last visits of the patients were between 62-122
the left-hand third fingernails is 11.86±1.85. In total, 44 of     days (92.07±11.28). Nail fluorescence intensity gradually
60 participants were women; 16 of them were male. Their            ­decreased in all patients with fluorescence and disappeared
mean age is 36.73±11.19 years. The average length of the           completely in the third month.
left-hand third fingernails is 11.57±1.88 (Table 1).                  The first visit nail growth rate could be calculated in 25
     When the study and control groups were compared ac-           patients, and the mean was 0.14 mm/day min-max 0.06-0.22.
cording to the length of the left-hand third fingernail, no sta-   The second visit nail growth rate could be calculated in 20
tistically significant difference was found (p>0.05) (Table 2).    patients whose fluorescence measurement could be made in
     In the study group, fluorescence was observed in 27 of 30     the 2nd-month follow-up, and it was 0.10 mm/day min-max
patients (90%) using favipiravir. The three patients without       0.07-0.19. In the analysis comparing the differences between
fluorescence did not use the total dose of favipiravir. One of     the first and second nail growth rates, a statistical difference
these patients vomited after taking eight tablets on the first     was found (z: -2.576; p=0.010<0.05) (Table 3).
day, one took only five tablets of favipiravir, and one did not       Some patients in the study group took additional medi-
take the loading dose on the first day (Figure 3). Blue fluores-   cations such as valproic acid, lithium carbonate, levothyrox-
cence was observed in the fingernails of all patients who used     ine, olanzapine, mirtazapine, methylphenidate, paroxetine,
2x1600 mg (day 1) of favipiravir, followed by 2x600 mg/day         vitamin D3, zinc, vitamin B1/B2/B6/B12, vitamin C, nico-
for a total of 4 days.                                             tinamide, biotin, folic acid, paracetamol, enoxaparin, nebiv-
     The earliest evaluation after starting favipiravir was on     olol, N-acetyl cysteine, magnesium, colchicine, prednisolone,
the 5th day of treatment, and we did not see fluorescence          metformin, pantoprazole, pheniramine maleate, amoxicillin/
in her nail. 2 patients were evaluated on day eight, and we        clavulanic    acid, ketoprofen, levocetirizine/montelukast,
found fluorescence of 1 mm in one patient and 3.3 mm in            acetylsalicylic acid, omega 3 and blackberry extract. The



4                                                                      Original Article | Dermatol Pract Concept. 2023;13(1):e2023011
Figure 3. Patients without nail fluorescence. (A: The patient vomited after taking eight tablets, B: The patient took only five tablets, C: The
patient did not take the loading dose of favipiravir.




Figure 4. The earliest evaluation of the nail fluorescence for three patients after starting favipiravir. A: 5th day of treatment, and no fluo-
rescence is visible. B: 8th day of treatment, and 1 mm fluorescence is seen. C: 8th day of treatment and 3.3 mm of fluorescence is observed).



Original Article | Dermatol Pract Concept. 2023;13(1):e2023011                                                                               5
                 Figure 5. The patient received favipiravir twice. (A: Upon examination on the 62nd day of the 1st dose
                 and the 48th day of the 2nd dose, nail fluorescence was observed in the entire nail. B: Upon examination
                 on the 103rd day of the 1st dose and the 89th day of the 2nd dose, nail fluorescence disappeared.


                     Table 3. Comparison of 1st visit and 2nd visit nail growth rate (N=20).
                                                           Mean±SD                        Median (Q1-Q3)               z             p
 1st visit nail growth rate                                0.14±0.044                     0.14 (0.10-0.19)          -2.576        0.010*
 2nd visit nail growth rate                                0.10±0.034                     0.09 (0.08-0.11)

z: Wilcoxon signed-rank test statistics value; Q1: 25. percentile; Q3: 75. percentile; *: p<0.05



fluorescence seen in the nail was consistent with the intake              nail bed. The elongation of fingernails is about 0.1 mm/day
of favipiravir, we did not observe that the above-mentioned               and differs between individuals [10]. While aging, acute in-
drugs affected this fluorescence.                                         fections, systemic illness, and malnutrition slow down nail
    In the control group, the drugs taken by the patients include         growth, nail growth is faster in those with pregnancy, warmer
metformin, nebivolol, sertraline, levothyroxine, d
                                                 ­ rospirenone/           temperatures, and minor trauma [11]. In the study group, the
ethinylestradiol, desloratadine/montelukast, fluoxetine,                  1st visit nail growth rate, which represents approximately
budesonide/formoterol, isotretinoin, ibuprofen, ramipril/                 the 1st month, was found to be significantly higher than the
­hydrochlorothiazide, iron/folic acid, terbinafine, perindopril/          2nd visit nail growth rate, which approximately represents
indapamide, alfuzosin, diltiazem, pregabalin, duloxetine,                 the 2nd month. The increase in nail growth rate may be re-
carvedilol, escitalopram, telmisartan, amlodipine, candesartan,           lated to Covid-19 infection, use of favipiravir, taking vita-
enalapril, ofloxacin, zinc, biotin, and melatonin. Nail fluores-          mins due to illness, or trying to eat better. Since we could not
cence was not observed in any of the control group patients.              evaluate the nail growth rate in the control group, we cannot
                                                                          comment. Since we could only make the nail growth rate

Discussion                                                                comparison in 20 patients, it is impossible to say this with
                                                                          certainty. In addition, since what we are measuring is fluores-
The nail plate is composed of layers of keratinized cells                 cent, the intensity of the light decreases over time, which may
produced by the nail matrix and extends distally over the                 have caused inaccuracies in the measurements.



6                                                                               Original Article | Dermatol Pract Concept. 2023;13(1):e2023011
    The incidence of fluorescence in nails due to the use of       the patient and control groups, and fluorescence was not ob-
favipiravir was previously reported as 81.9% and 84% [9,           served in the nails due to these drugs in these patients. Based
12]. Similar to the findings in these studies, we observed flu-    on this information, we think that favipiravir-induced nail
orescence in the nail in 90% of our patients using favipiravir,    fluorescence is mainly caused by the drug rather than the
and we observed that there was fluorescence in the nail in         favipiravir tablet additives. However, since these drugs were
100% of the patients who received the full loading dose.           one-per-day tablets, it would not be correct to compare the
    Nail manifestations associated with COVID-19 included          dose with 16 tablets a day, as in favipiravir.
a red half-moon sign, transverse orange nail lesions, Mees’            Since the nail is in a structure that can indicate long-term
lines, and Beau’s lines [13]. No nail disorder was observed in     exposure to a substance, it is used to evaluate environmental
any of our patients who had Covid-19.                              exposure, in the detection of abused drugs and poisoning
    Nail fluorescence due to favipiravir was seen in all           [20]. It should be taken into account that the substance accu-
patients who received the total dose of favipiravir. It was        mulated in the nail may decrease over time when drug mea-
observed that the density decreased in the 2nd month and           surement is made in the samples obtained by nail clipping.
disappeared in all patients in the 3rd month. Nail fluores-        And although the time the nail is cut varies from person to
cence was not observed in patients who did not receive the         person, it gives information about 3-4 months prior in the
loading dose. The fluorescence produced by favipiravir in the      average fingernail.
nails is dose-dependent and decreases over time. These find-
ings showed that the drug dose is important in drug transfer
                                                                   Conclusion
to the nail.
    Drug delivery to the nail is most important in the treat-      Favipiravir-induced nail fluorescence is dose-dependent, and
ment of onychomycosis. Continuous therapy and intermit-            its intensity decreases over time. We think that the concen-
tent pulse regimens for terbinafine and itraconazole can be        tration of the drugs in the nails decreases over time. Nail
used to treat onychomycosis. Similar efficacy and side-effect      fluorescence due to favipiravir is probably due to the active
rates have been reported in a meta-analysis [14]. We evalu-        ingredient in the drug. We think that the information we
ated the fluorescence in the nails due to the use of high-dose     have obtained may be useful in the treatment of conditions
favipiravir for 5 days in our patients as an opportunity to        such as onychomycosis where drug transfer to the nail is im-
monitor the transfer of the drug to the nails and how long         portant and in determining the concentration of nail expo-
it took to disappear. And the decrease of this fluorescence        sure substances.
over time showed that the drug concentration in the nail did
not remain the same, and we did not see any fluorescence
in the distal 1/3 of the nail, except in one patient who took      References
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