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ПИСМО ДО РЕДАКТОРА
LETTER TO THE EDITOR
МЕДИЦИНСКИ ПРЕГЛЕД, 2023, 59 (5) 5
1,213
1Onkoderma – Clinic for Dermatology, Venereology and Dermatologic Surgery
2Department of Dermatology and Venereology, Medical Institute of Ministry of Interior
3Department of Pathology, University of Virginia, Charlottesville, USA
Prof. Georgi Tchernev, MD
Onkoderma – Policlinic for Dermatology,
Venereology and Dermatologic Surgery
26 General Skobelev blvd.
Bg – 1606 Sofia
e-mail: georgi_tchernev@yahoo.de
Phone: 00359885588424
: nitrosamines, skin cancer, metformin, sartan, ranitidine
There is no conflict of interest. No financial disclosure.
Nitrosamine exposure in the form of dust, as well as its
influence on workers in the rubber industry, has been well
studied over the years and according to data in the litera-
ture, it suggests a serious or significant risk in terms of de-
veloping almost all types of cancer, including those of the
esophagus, oral cavity, pharynx, bladder, lungs, stomach,
prostate, pancreas and liver, as well as leukemia, multiple
myeloma, and others [1-3].
Based upon the results of significant epidemiological
studies, there is a direct connection between the intake/in-
halation of nitrosamines and the development of various
forms of cancer, as well as an increased mortality rate in a
significant number of them [1].
Despite the establishment, in 2021, of permissible
levels of nitrosamines in medications on the market (in-
cluding, but not limited to, antihypertensive medications)
[4], the problem with their availability has expanded sig-
nificantly in the last year, as other classes of medications
are also affected, including: oral antidiabetic medications,
such as metformin [5], ACE inhibitors/quinapril [6]/ACE
inhibitors in combination with hydrochlorothiazide [7], an-
giotensin receptor blockers/sartans [8], and smoking cessa-
tion drugs [9].
Even more concerning are the statistically significant
links (published as a meta-analysis in March 2022) between
angiotensin receptor blockers/sartans and the development
of heterogeneous cancers [10]. Unfortunately, the authors
do not weigh in on the possible role of nitrosamines as key
factors in carcinogenesis [10].
According to similar published data, but based upon
the observation of single patients, the dose-dependent time
intervals for the generation of melanomas, after taking sar-
tans that are potentially contaminated with nitrosamines
(as monotherapy), seem to be approximately the same [8,
11] as those for sartans in combination with hydrochloro-
thiazide; i.e., approximately 3 years [12-15].
6 G. Tchernev, S. Kordeva, J. W. Patterson. Nitrosamines and Skin Cancer: Rather Reality than a Myth?
Relatively shorter intervals to the development of
melanomas – e.g., under 3 years – could be associat-
ed with the parallel intake of potentially contaminated
medications with thiazide diuretics [12, 13, 15].
The combined intake of sartans with potentially ni-
trosamine-contaminated metformin could also be of key
importance in terms of exceeding the acceptable daily
intake (ADI) dose, but in this case, related to the intake
of more than one medication. There are also cases in
the scientific literature in which the simultaneous intake
of sartans and metformin has been associated with the
subsequent occurrence of melanoma or atypical fibrox-
anthoma in combination with prostate carcinoma [12,
16]. These reports further suggest that nitrosamines are
capable of causing heterogeneous forms of skin cancer
– not a surprise, since mutagens are practically accepted
as carcinogens [12, 16].
Similar issues arise when there is simultaneous in-
take of ranitidine or ACE inhibitors (with sartans and/
or hydrochlorothiazide), bearing in mind their suspected
(and, actually, repeatedly established) official contami-
nation [6, 17].
The risk of developing neoplasms with the simul-
taneous ingestion of ranitidine and metformin in com-
bination with sartans, sartans/hydrochlorothiazide, or
ACE inhibitors, is apparent. It is a situation that occurs
all too often in clinical practice. And yet, even now, the
problem remains unresolved. Variations in oral intake
of these potentially contaminated drug combinations
from different classes are quite possible and difficult
to control.
In the case of the simultaneous intake of two or
more potentially contaminated, though perhaps other-
wise unrelated, medications, the cumulative daily dose
of a sartan (i.e., to generate cancer) could be lower than
that described by Sipahi I [10] or lower than the recom-
mended ADI dose for nitrosamines from the EMA [4,
10], but the total daily dose of nitrosamine from several
contaminated medications could well be higher, signifi-
cantly exceeding the ADI dose.
The reason that this is such an important issue is
precisely due to the use of multiple medications by poly-
morbid patients that could contain nitrosamines: sartan,
thiazide diuretic, ACE inhibitor, ranitidine, metformin,
and probably many other contaminated, but currently
unidentified and undisclosed medications. This is the
reason that the calculation of the ADI turns out to be
somewhat irrelevant, especially when it concerns the
contamination of only one medication, and not all po-
tentially contaminated preparations taken by a given pa-
tient during the day.
Unfortunately, the association between the use of
sartans and hydrochlorothiazide and the development
of skin cancer – melanoma and keratinocyte cancer –
appears to be non-sporadic, statistically significant,
and established repeatedly based on serious retrospec-
tive studies in the USA and Europe [18-20], but at a
time when there was no data/information in the medi-
cal community about the potential contamination with
nitrosamines.
One of the most important international retrospec-
tive studies, presented formally as an American Acad-
emy of Dermatology (AAD) poster in Washington, DC,
in 2016, was designed to search for an association be-
tween the development of skin cancer and the use of
various antihypertensive drugs [18]. The results of this
study clearly showed a doubling of the risk of develop-
ing melanoma after administration of angiotensin recep-
tor blockers [18]. A similar constellation was observed
for thiazides (TZ) [18].
Sable at al. also found small risk (about 36%) of
developing BCCs after the use of angiotensin receptor
blockers/sartans [18].
For ACE inhibitors, the risk for developing BCC
was about 30% [18].
Even more indicative is the relationship between the
development of SCC and the intake of angiotensin re-
ceptor blockers (ARB), angiotensin-converting enzyme
inhibitors (ACEIs) and TZ [18].
A few years later Nardone B et al. had similar obser-
vations [19]: in practice, there is a two- to four-fold risk
of developing keratinocyte cancer after administration
of the most common antihypertensive drugs [19].
The risk of developing melanomas after the appli-
cation of the already mentioned medications is the fol-
lowing one: 1) ACEIs (adjusted OR; 1.71; 95% confi-
dence interval (CI): 0.97-3.00), 2) ARBs (adjusted OR;
1.24; 95% confidence interval (CI): 0.54-2.85) and 3)
TZ (adjusted OR; 1.82; 95% confidence interval (CI):
1.01-3.82) [19].
Schmidt SA et al. were the first to demonstrate the
relationship between the risk of skin cancer and the in-
take of various antihypertensive preparations [20].
The question remains open, but without the need for
an answer: “What is the connecting point between the
intake of high blood pressure medications with radically
different mechanisms of action, such as ACEIs, ARBs,
TZs, etc., and the development of all types of skin can-
cer: 1) the availability of up to 3 nitrosamines/carcino-
gens in them, reflected in the currently established of-
ficial position of regulatory bodies and pharmaceutical
companies, or 2) the active substances themselves?”
Even more troubling could be the answer to the
question arising from the results reported by Schmidt
SA et al. [20]: Are nitrosamines also contained in other
medications, such as potassium-sparing agents, non-
МЕДИЦИНСКИ ПРЕГЛЕД, 2023, 59 (5) 7
aldosterone antagonist potassium-sparing agents, low-
ceiling diuretics, and sulfonamides, for which statisti-
cally significant risks for cancer development have been
established as far back as 2015 [20]?
1. Hidajat M, McElvenny DM, Ritchie P, et al. Lifetime exposure to rub-
ber dusts, fumes and N-nitrosamines and cancer mortality in a cohort
of British rubber workers with 49 years follow-up. Occup Environ
Med. 2019 Apr;76(4):250-258. doi: 10.1136/oemed-2018-105181.
2. Straif K, Weiland SK, Bungers M, et al. Exposure to high concentra-
tions of nitrosamines and cancer mortality among a cohort of rubber
workers. Occup Environ Med. 2000 Mar;57(3):180-7. doi: 10.1136/
oem.57.3.180.
3. Nutt A. Rubber work and cancer--past, present and perspectives.
Scand J Work Environ Health. 1983;9 Suppl 2:49-57.
4. https://www.gmp-compliance.org/gmp-news/sartan-medicinal-prod-
ucts-emas-assesment-report-defines-nitrosamine-limits-and-report-
ing-deadlines
5. Nasr NEH, Metwaly MG, Ahmed EO, et al. Investigating the root
cause of N-nitrosodimethylamine formation in metformin pharma-
ceutical products. Expert Opin Drug Saf. 2022 Feb;21(2):285-287.
doi: 10.1080/14740338.2021.1983312.
6. https://www.pfizer.com/news/press-release/press-release-detail/pfiz-
er-voluntary-nationwide-recall-lots-accuprilr-quinapril
7. https://www.pfizer.com/news/press-release/press-release-detail/pfiz-
er-voluntary-nationwide-recall-lots-accuretictm
8. Tchernev G, Temelkova I. Valsartan Induced Melanoma?! First De-
scription in Medical Literature! Open Access Maced J Med Sci. 2018
Dec 18;6(12):2378-2380. doi: 10.3889/oamjms.2018.517.
9. https://www.reuters.com/business/healthcare-pharmaceuticals/
pfizer-halts-distribution-anti-smoking-drug-after-finding-carcino-
gen-2021-06-24/
10. Sipahi I. Risk of cancer with angiotensin-receptor blockers increas-
es with increasing cumulative exposure: Meta-regression analysis
of randomized trials. PLoS One. 2022 Mar 2;17(3):e0263461. doi:
10.1371/journal.pone.0263461.
11. Tchernev G, Temelkova I. Irbesartan Induced Cutaneous Melanoma!
Second Case in the Medical Literature! Open Access Maced J Med
Sci. 2019 Jan 9;7(1):121-123. doi: 10.3889/oamjms.2019.043.
12. Tchernev G, Patterson JW. Telmisartan/hydrochlorothiazide-induced
nevus-associated cutaneous melanoma: first report in the medical lit-
erature. Expert Rev Clin Pharmacol. 2021 Mar;14(3):289-293. doi:
10.1080/17512433.2021.1890581.
13. Tchernev G, Temelkova I. Valsartan/hydrochlorothiazidе induced
prostatе carcinoma in a patient who subsequently developed melano-
ma. J Biol Regul Homeost Agents. 2019 Jul-Aug;33(4):1125-1127.
14. Tchernev G, Temelkova I. Drug-Induced Melanoma: Irbesartan In-
duced Cutaneous Melanoma! First Description in the World Litera-
ture! Open Access Maced J Med Sci. 2019 Jan 9;7(1):114-116. doi:
10.3889/oamjms.2019.042.
15. Tchernev G, Poterov G. Drug induced cancers: Simultaneously de-
velopment of cutaneous melanoma, colon carcinoma and Kaposi
sarcoma under Valsartan/Hydrochlorothiazide. Clin Res Dermatol
Open Access 2020; 7 (5): 1-8.
16. Tchernev G, Oliveira N, Kandathil LJ, et al. Telmisartan (and/or Ni-
trosamine) induced prostate carcinoma and atypical fibroxanthoma:
first report in World literature. Medical Review (Bulgarian) 2022;
58(1):65-67.
17. https://www.drugwatch.com/zantac/lawsuits/
18. Sable L, Majewski S, Nardone B, et al. Association of melanoma
and nonmelanoma skin cancer with antihypertensive drugs: A report
form the Research on Adverse Drug Events and Reports Project. J
Am Acad Dermatol 2016; 74(5): AB221.
19. Nardone B, Majewski S, Kim AS, et al. Melanoma and Non-Mela-
noma Skin Cancer Associated with Angiotensin-Converting-Enzyme
Inhibitors, Angiotensin-Receptor Blockers and Thiazides: A Matched
Cohort Study. Drug Saf. 2017 Mar;40(3):249-255. doi: 10.1007/
s40264-016-0487-9.
20. Schmidt SA, Schmidt M, Mehnert F, et al. Use of antihypertensive
drugs and risk of skin cancer. J Eur Acad Dermatol Venereol. 2015
Aug;29(8):1545-54. doi: 10.1111/jdv.12921.
