THE NITROSAMINE CONTAMINATION IN BETA BLOCKERS (BISOPROLOL/ METOPROLOL), ACE INHIBITORS (LISINOPRIL/ PERINDOPRIL), THIAZIDES DIURETICS (HCT), CALCIUM CHANNEL BLOCKERS (AMLODIPINE/ FELODIPINE), SARTANS (CANDESARTAN) AND ТHE SUBSEQUENT SKIN CANCER DEVELOPMENT AND PROGRESSION: APOCALYPSE NOW

Abstract

The problem of contamination of the most commonly
used medicines with nitrosamines is worsening worldwide.
According to recent literature data, this ʺcontaminationʺ is the
cause not only of skin cancer (keratinocytic/melanoma) but also
of gastrointestinal neoplasms, brain tumours, neuroblastoma,
rectal carcinoma, acute lymphoblastic leukaemia, and many
others. It is these clinical manifestations that are associated with/
or already directly linked to the nitrosamine content of drugs
and food products used by patients in previous periods. And
it is this permissive availability/contamination that could prove
to be the most likely, powerful inducer of acquired mutations
underlying the worldwide cancer pandemic.
Of further concern is the evidence of contamination of newer
classes of medications by nitrosamines- namely: beta blockers,
calcium antagonists and selective serotonin reuptake inhibitors
(SSRIs). In practice, mankind faces the problem of certainly
over 1 billion patients taking nitrosamine-contaminated drugs:
280 million patients with depression (antidepressants), over 1
billion patients with arterial hypertension (antihypertensive
drugs), over half a billion patients with type 2 diabetes
mellitus (oral antidiabetic drugs/metformin/ sitagliptin), over 4
billion patients with gastritis (ranitidine), over 5 million with
tuberculosis (rifampicin), and probably a number of others.
The calculations are apocalyptic, since even if only 20-30% of
the groups were affected, the number of patients taking these
drugs would, by a rough calculation, currently amount to over 1
billion. And there are certainly other classes of drugs yet to be
announced.
It is for this reason that we should not be surprised that the
data on the development of keratinocyte cancer after intake
of nitrosamine-contaminated preparations is growing at a
breakneck pace. This data indirectly but strongly confirms
the importance of a newly introduced concept in the medical
science : Nitrosogenesis of skin cancer.
A concept, until recently unknown, incomprehensible, but at
the same time frightening and gradually accepted, imposing
itself and which with each passing day is gaining more and more
scientific significance and ʺvisibilityʺ, ʺscientific tangibility,
receptivity, and acceptability.ʺ
This article presents, for the first time in the world literature,
patients who developed single/multiple forms of keratinocytic
cancer (partly in combination with melanoma precursorsdysplastic moles) after administration of two new classes of
potentially nitrosamine-contaminated antihypertensive drugs:
beta blockers (bisoprolol, metoprolol) and calcium antagonists
(amlodipine, felodipine).
For the first time in the scientific literature, the contributory
pro-carcinogenic role of another potentially nitrosaminecontaminated ACE inhibitor- lisinopril , as well as that of
candesartan: in the development of keratinocytic cancer is also
discussed.
For the first time in the world literature, the conclusion
regarding the pathogenetic relationship between the intake of
potentially contaminated drugs (from different drug groups)
and cancer development is based on the model of the equivalent
clinical manifestation of skin tumors (rather than on controlled
long-term prospective analyses). Nitrosamine contamination in
these drug groups appears to be the sole and major unifying
factor or causative agent for these manifestations.

Full text

EORGIAN
EDICAL
EWS
ЕЖЕМЕСЯЧНЫЙ НАУЧНЫЙ ЖУРНАЛ
Медицинские новости Грузии
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No 1 (322) Январь 2022
ISSN 1512-0112
ТБИЛИСИ - NEW YORK
NO 4 (337) Aпрель 2023

GMN: Georgian Medical News is peer-reviewed, published monthly journal committed to promoting
the science and art of medicine and the betterment of public health, published by the GMN Editorial
Board and The International Academy of Sciences, Education, Industry and Arts (U.S.A.) since
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full text content is available through EBSCO databases.
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SCOPUS-is, PubMed-is da ВИНИТИ РАН-is monacemTa bazebSi. statiebis sruli teqsti
xelmisawvdomia EBSCO-s monacemTa bazebidan.
GMN: Georgian Medical News is peer-reviewed, published monthly journal committed to promoting
the science and art of medicine and the betterment of public health, published by the GMN Editorial
Board since 1994. GMN carries original scientic articles on medicine, biology and pharmacy, which
are of experimental, theoretical and practical character; publishes original research, reviews, commen-
taries, editorials, essays, medical news, and correspondence in English and Russian.
GMN is indexed in MEDLINE, SCOPUS, PubMed and VINITI Russian Academy of Sciences. The full
text content is available through EBSCO databases.
GEORGIAN MEDICAL NEWS
GMN: Медицинские новости Грузии - ежемесячный рецензируемый научный журнал, издаётся
Редакционной коллегией с 1994 года на русском и английском языках в целях поддержки
медицинской науки и улучшения здравоохранения. В журнале публикуются оригинальные
научные статьи в области медицины, биологии и фармации, статьи обзорного характера, научные
сообщения, новости медицины и здравоохранения. Журнал индексируется в MEDLINE, отражён
в базе данных SCOPUS, PubMed и ВИНИТИ РАН. Полнотекстовые статьи журнала доступны
через БД EBSCO.
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formats of the Agency of Medical Information of the Georgian Association of Business Press.
Published since 1994. Distributed in NIS, EU and USA.
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avtorTa sayuradRebod!
redaqciaSi statiis warmodgenisas saWiroa davicvaT Semdegi wesebi:
1. statia unda warmoadginoT 2 calad, rusul an inglisur enebze, dabeWdili
standartuli furclis 1 gverdze, 3 sm siganis marcxena velisa da striqonebs
Soris 1,5 intervalis dacviT. gamoyenebuli kompiuteruli Srifti rusul da ing-
lisurenovan teqstebSi - Times New Roman ( Кириллица), xolo qarTulenovan teqstSi
saWiroa gamoviyenoT AcadNusx. Sriftis zoma – 12. statias Tan unda axldes CD
statiiT.
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literaturis siis da reziumeebis (inglisur, rusul da qarTul enebze) CaTvliT.
3. statiaSi saWiroa gaSuqdes: sakiTxis aqtualoba; kvlevis mizani; sakvlevi
masala da gamoyenebuli meTodebi; miRebuli Sedegebi da maTi gansja. eqsperimen-
tuli xasiaTis statiebis warmodgenisas avtorebma unda miuTiTon saeqsperimento
cxovelebis saxeoba da raodenoba; gautkivarebisa da daZinebis meTodebi (mwvave
cdebis pirobebSi).
4. statias Tan unda axldes reziume inglisur, rusul da qarTul enebze
aranakleb naxevari gverdis moculobisa (saTauris, avtorebis, dawesebulebis
miTiTebiT da unda Seicavdes Semdeg ganyofilebebs: mizani, masala da meTodebi,
Sedegebi da daskvnebi; teqstualuri nawili ar unda iyos 15 striqonze naklebi)
da sakvanZo sityvebis CamonaTvali (key words).
5. cxrilebi saWiroa warmoadginoT nabeWdi saxiT. yvela cifruli, Sema-
jamebeli da procentuli monacemebi unda Seesabamebodes teqstSi moyvanils.
6. fotosuraTebi unda iyos kontrastuli; suraTebi, naxazebi, diagramebi
- dasaTaurebuli, danomrili da saTanado adgilas Casmuli. rentgenogramebis
fotoaslebi warmoadgineT pozitiuri gamosaxulebiT ti formatSi. mikrofoto-
suraTebis warwerebSi saWiroa miuTiToT okularis an obieqtivis saSualebiT
gadidebis xarisxi, anaTalebis SeRebvis an impregnaciis meTodi da aRniSnoT su-
raTis zeda da qveda nawilebi.
7. samamulo avtorebis gvarebi statiaSi aRiniSneba inicialebis TandarTviT,
ucxourisa – ucxouri transkripciiT.
8. statias Tan unda axldes avtoris mier gamoyenebuli samamulo da ucxo-
uri Sromebis bibliografiuli sia (bolo 5-8 wlis siRrmiT). anbanuri wyobiT
warmodgenil bibliografiul siaSi miuTiTeT jer samamulo, Semdeg ucxoeli
avtorebi (gvari, inicialebi, statiis saTauri, Jurnalis dasaxeleba, gamocemis
adgili, weli, Jurnalis #, pirveli da bolo gverdebi). monografiis SemTxvevaSi
miuTiTeT gamocemis weli, adgili da gverdebis saerTo raodenoba. teqstSi
kvadratul fCxilebSi unda miuTiToT avtoris Sesabamisi N literaturis siis
mixedviT. mizanSewonilia, rom citirebuli wyaroebis umetesi nawili iyos 5-6
wlis siRrmis.
9. statias Tan unda axldes: a) dawesebulebis an samecniero xelmZRvane-
lis wardgineba, damowmebuli xelmoweriTa da beWdiT; b) dargis specialistis
damowmebuli recenzia, romelSic miTiTebuli iqneba sakiTxis aqtualoba, masalis
sakmaoba, meTodis sandooba, Sedegebis samecniero-praqtikuli mniSvneloba.
10. statiis bolos saWiroa yvela avtoris xelmowera, romelTa raodenoba
ar unda aRematebodes 5-s.
11. redaqcia itovebs uflebas Seasworos statia. teqstze muSaoba da Se-
jereba xdeba saavtoro originalis mixedviT.
12. dauSvebelia redaqciaSi iseTi statiis wardgena, romelic dasabeWdad
wardgenili iyo sxva redaqciaSi an gamoqveynebuli iyo sxva gamocemebSi.
aRniSnuli wesebis darRvevis SemTxvevaSi statiebi ar ganixileba.

GEORGIAN MEDICAL NEWS
No 4 (337) 2023
Alireza Hamidian Jahromi, Sydney H. Arnold, Petros Konofaos.
APPLICATIONS OF VISCOELASTIC TESTING IN MICROSURGERY: A SYSTEMIC REVIEW AND META-ANALYSIS……..……..6-12
Ayat J. Kadam, Abdulsamie H. Alta’ee, Adel H. Al-Handawy, Zakariya M. Al-Ghazali, Mufeed J Ewadh.
LONG-TERM USE OF GLUCOCORTICOID MODULATED PARATHYROID HORMONE LEVELS IN OSTEOPOROSIS
PATIENTS………………………………………………………………………………………………………............................................…13-15
Azzam A. Ahmed.
ISTENT INJECT W AND KAHOOK DUAL BLADE FOR TREATING MILD-TO-MODERATE GLAUCOMA…………….........………16-20
Kachanov D.A., Elistratov L.M., Guseinov H.M., Balaeva K.V., Popova N.A.
A COMPARATIVE REVIEW OF THE USE OF DANIO RERIO (ZEBRAFISH) AS A MODEL OBJECT IN PRECLINICAL
STUDIES………………………………………………………………………………………....................................………………………..21-24
Mahde S. Hamad, Athraa Essa Ahmed, Shaimaa Essa Ahmed, Entedhar R. Sarhat, Moayad M. Al Anzy.
SERUM LIPOCALIN-2, AND FETUIN-A LEVELS IN PATIENTS WITH ALZHEIMER’S DISEASE…….....................................……....25-29
Larisa M. Chernukha, Yaroslav V. Khrebtiy, Denis V. Tsygalko, Mikola O. Melnichuk.
RESULTS OF TREATMENT OF DEEP VEINS THROMBOSIS IN PATIENTS WITH CONGENITAL ANOMALIES OF THE INFERIOR
VENA CAVA…………………………………………………………………………………………………..............................................….30-33
Osinskaya T.V, Zapolsky M.E, Shcherbakova Yu.V, Dzhoraieva S.K.
PREVALENCE OF CHLAMYDIA AMONG WOMEN IN PLACES OF DEPRIVATION OF LIBERTY….....................................……….34-37
Mohammed N. Almulayounis, Ahmed A. Al-Ali.
EFFECT OF HEAT TREATMENT DURATION AND COOLING CONDITIONS ON TENSILE PROPERTIES AND HARDNESS OF
SELECTIVE-LASER-MELTED COBALT-CHROMIUM ALLOY………………………………………........................................................38-42
Leonid Markin, Tetiana Fartushok, Nadiia Fartushok, Larysa Soyka, Yuri Fedevych.
DIABETES MELLITUS AND COVID-19: TODAY’S CHALLENGES………………………………........................……………………….43-50
Shaymaa Mohammed Allow, Entedhar R. Sarhat.
METFORMIN EFFECTS ON BLOOD LEVELS OF GREMLIN-1 IN POLYCYSTIC OVARIAN WOMEN….............................................51-55
Maryam Taher Tawfeq, Entedhar Rifaat Sarhat.
METFORMIN EFFECTS ON NEUREGULIN-1 IN POLYCYSTIC OVARIAN WOMEN……………….................................…………….56-62
Tchernev G, Kordeva S.
NITROSOGENESIS OF SKIN (HUMAN) CANCER- THE HIDDEN TRUTH OF A NEVERENDING STORY: NITROSAMINE
CONTAMINATION IN OLMESARTAN, VALSARTAN AND HCT AS MAIN RISK FACTOR FOR THE DEVELOPMENT OF
KERATINOCYTE CANCER…………………………………………………………………….…...................................................................63-67
Pantus AV, Rozhko MM, Makhlynets NP, Kovalchuk NY, Yarmoshuk IR.
CLINICOROENTGENOLOGICAL PECULIARITIES OF THE CONGENITAL AND ACQUIRED CRANIOFACIAL
ANOMALIES……………………………………………………………………………………………………………….....………………..68-76
Tamta Motsonelidze, Sophio Kakhadze, Dudana Gachechiladze, Tea Changelia, Mamuka Gurgenidze, Teona Buachidze.
SIGNIFICANCE OF TWO-DIMENSIONAL SHEAR WAVE ELASTOGRAPHY IN PREDICTING ESOPHAGEAL VARICOSE VEINS
DURING CHRONIC LIVER DISEASE…………………………………………………………………….77-84
Sergey Didenko, Vitaly Subbotin, Yuri Hupalo, Oleksandr Ivanko, Oleksandr Orlych.
STUDY OF THE HEMOMICROCIRCULATORY CHANNEL IN PATIENTS WITH DIABETES AND THREATENING ISCHEMIA OF
THE LOWER LIMB…………………………………………………………………...........................................................................………..85-88
Kordeva S, Cardoso JC, Tchernev G.
CONGRESS REPORT OF THE 5TH NATIONAL CONGRESS OF THE BULGARIAN SOCIETY FOR DERMATOLOGIC SURGERY,
SOFIA, 11TH MARCH 2023 WITH MAIN TOPICS: NITROSAMINES AS MOST POWERFUL TRIGGER FOR SKIN CANCER
DEVELOPMENT AND PROGRESSION / PERSONALISED ONE STEP MELANOMA SURGERY AS POSSIBLE SKIN CANCER
TREATMENT OPTION………………………...........................................................................................................................................……89-95
Ia Murvanidze, Otar Tsetskhladze, Eteri Saralidze, Teona Gogitidze, Rajneesh Khurana, Nino Kedelidze, Tamar Peshkova, Ilia Nakashidze,
Irina Nakashidze.
THE STUDY OF LIVER AND KIDNEY FUNCTION WITHIN COVID-19 PATIENTS…….................................…………………………96-98
Salome Glonti, Nino Kedelidze, Nana Chelidze, Irine Kalandadze, Megi Inaishvili, Rajneesh Khurana, Aleena Shaik, David Dzneladze, Davit
Baratashvili, Givi Tsetskhladze, Irina Nakashidze.
THE STUDY OF VDR FOKL RS2228570 SNP IN AUTOIMMUNE THYROIDITIS………………...................................……………….99-103
Liudmyla Hordiienko.
JUSTIFICATION OF THE COMPREHENSIVE PROGRAM OF PREVENTION OF HYPERTENSION DISEASE IN MEDICAL
WORKERS……………………………………………………………………………………………….............................………………..104-109

Rurua Magda, Ratiani L, Sanikidze T, Machvariani K, Pachkoria E, Ormocadze G, Mikadze I, Didbaridze T.
IMPACT OF THE ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS ON THE COURSE OF THE SEPTIC
SHOCK DEVELOPED DURING COVID-19 AND OTHER SEVERE RESPIRATORY INFECTIONS IN PRESENCE OF
HYPERFERRITINEMIA……………………………………………………………………………...........................................…………..110-117
Dubivska SS, Omelchenko-Seliukova AV, Lazyrskyi VO, Viedienieva RY.
STUDY OF THE PROCESSES OF LIPID PEROXIDATION, THE STATE OF THE ANTIOXIDANT SYSTEM IN PATIENTS WITH
POLYTRAUMA AND ALCOHOL ANAMNESIS……………………………………………..........................................................………118-124
Danielyan M.H, Karapetyan K.V, Sarkisyan S.H, Nebogova K.A, Isoyan A.S, Chavushyan V.A.
INFLUENCE OF LONG-TERM VIBRATION ON THE ACTIVITY OF THE SUPERIOR VESTIBULAR NUCLEUS NEURONS UNDER
THE CONDITIONS OF STIMULATION OF THE HYPOTHALAMUS NUCLEI………...........................................................................125-131
Ahmad Mohammed SMADI, Salam Bani Hani, Abedalmajeed SHAJRAWI, Marwa Alhalabi.
COMPLIANCE AND CHALLENGES OF TRANSMISSION BASED PRECAUTION PRACTICES AMONG NURSES IN JORDANIAN
HOSPITALS DURING THE NOVEL COVID-19: A DESCRIPTIVE STUDY….....................................................................................…132-137
Georgi Tchernev.
THE NITROSAMINE CONTAMINATION IN BETA BLOCKERS (BISOPROLOL/ METOPROLOL), ACE INHIBITORS (LISINOPRIL/
PERINDOPRIL), THIAZIDES DIURETICS (HCT), CALCIUM CHANNEL BLOCKERS (AMLODIPINE/ FELODIPINE), SARTANS
(CANDESARTAN) AND ТHE SUBSEQUENT SKIN CANCER DEVELOPMENT AND PROGRESSION: APOCALYPSE NOW..…138-145
Boldyreva Yu.V, Zaharchuk E.V, Lebedev I.A, Tersenov G.O, Duboshinskii R. I.
MOLECULAR EFFECTS OF RESVERATROL IN THE TREATMENT OF AUTOIMMUNE DISEASES…...........................................146-147

GEORGIAN MEDICAL NEWS
No 4 (337) 2023
© GMN 138
THE NITROSAMINE CONTAMINATION IN BETA BLOCKERS (BISOPROLOL/
METOPROLOL), ACE INHIBITORS (LISINOPRIL/ PERINDOPRIL), THIAZIDE
DIURETICS (HCT), CALCIUM CHANNEL BLOCKERS (AMLODIPINE/ FELODIPINE),
SARTANS (CANDESARTAN) AND ТHE SUBSEQUENT SKIN CANCER DEVELOPMENT
AND PROGRESSION: APOCALYPSE NOW!
Georgi Tchernev1,2 .
1Department of Dermatology, Venereology and Dermatologic Surgery, Medical Institute of Ministry of Interior, General Skobelev 79, 1606
Sofia, Bulgaria.
2Onkoderma- Clinic for Dermatology, Venereology and Dermatologic Surgery, General Skobelev 26, 1606 Sofia, Bulgaria.
Abstract.
The problem of contamination of the most commonly
used medicines with nitrosamines is worsening worldwide.
According to recent literature data, this ʺcontaminationʺ is the
cause not only of skin cancer (keratinocytic/melanoma) but also
of gastrointestinal neoplasms, brain tumours, neuroblastoma,
rectal carcinoma, acute lymphoblastic leukaemia, and many
others. It is these clinical manifestations that are associated with/
or already directly linked to the nitrosamine content of drugs
and food products used by patients in previous periods. And
it is this permissive availability/contamination that could prove
to be the most likely, powerful inducer of acquired mutations
underlying the worldwide cancer pandemic.
Of further concern is the evidence of contamination of newer
classes of medications by nitrosamines- namely: beta blockers,
calcium antagonists and selective serotonin reuptake inhibitors
(SSRIs). In practice, mankind faces the problem of certainly
over 1 billion patients taking nitrosamine-contaminated drugs:
280 million patients with depression (antidepressants), over 1
billion patients with arterial hypertension (antihypertensive
drugs), over half a billion patients with type 2 diabetes
mellitus (oral antidiabetic drugs/metformin/ sitagliptin), over 4
billion patients with gastritis (ranitidine), over 5 million with
tuberculosis (rifampicin), and probably a number of others.
The calculations are apocalyptic, since even if only 20-30% of
the groups were aected, the number of patients taking these
drugs would, by a rough calculation, currently amount to over 1
billion. And there are certainly other classes of drugs yet to be
announced.
It is for this reason that we should not be surprised that the
data on the development of keratinocyte cancer after intake
of nitrosamine-contaminated preparations is growing at a
breakneck pace. This data indirectly but strongly conrms
the importance of a newly introduced concept in the medical
science : Nitrosogenesis of skin cancer.
A concept, until recently unknown, incomprehensible, but at
the same time frightening and gradually accepted, imposing
itself and which with each passing day is gaining more and more
scientic signicance and ʺvisibilityʺ, ʺscientic tangibility,
receptivity, and acceptability.ʺ
This article presents, for the rst time in the world literature,
patients who developed single/multiple forms of keratinocytic
cancer (partly in combination with melanoma precursors-
dysplastic moles) after administration of two new classes of
potentially nitrosamine-contaminated antihypertensive drugs:
beta blockers (bisoprolol, metoprolol) and calcium antagonists
(amlodipine, felodipine).
For the rst time in the scientic literature, the contributory
pro-carcinogenic role of another potentially nitrosamine-
contaminated ACE inhibitor- lisinopril , as well as that of
candesartan: in the development of keratinocytic cancer is also
discussed.
For the rst time in the world literature, the conclusion
regarding the pathogenetic relationship between the intake of
potentially contaminated drugs (from dierent drug groups)
and cancer development is based on the model of the equivalent
clinical manifestation of skin tumors (rather than on controlled
long-term prospective analyses). Nitrosamine contamination in
these drug groups appears to be the sole and major unifying
factor or causative agent for these manifestations.
Key words. Nitrosamines, contamination, Candesartan,
bisoprolol, metoprolol, amlodipine, felodipine, lisinopril,
perindopril, Skin cancer, BCC, melanoma, apocalypse.
Introduction.
The issue of nitrosamines and their availability in a number
of medicinal products is still far from a denitive solution or a
solution for the benet of the end users - the patients.
An avalanche of new data and scientic papers on the
subject have been published, linking the intake of nitrosamine-
contaminated medicinal products to the development of various
cancers.
Recently, a worrying signicant risk of developing brain
tumours, neuroblastoma, and acute lymphoblastic leukaemia
after intake of nitrosamine-contaminated drugs during
pregnancy has also been identied [1].
Importantly, another newly published prospective
observational study associated intake of nitrosamine-rich food
with a signicant risk of developing a particular form of cancer,
namely rectal cancer [2].
The so-called ʺdietary componentʺ currently remains an
unclear factor in the development of skin cancer, and certainly
plays an additional role in the bodyʺs nitrosamine load.
A new, ʺfresh meta-analysisʺ links/associates increased
intake of nitrate, nitrite and nitroso compounds contaminated
foods, drinking water, cigarette smoke, work environment and
the indoor air again with the occurrence of gastrointestinal
neoplasms [3].
The development of melanomas after intake of nitrosamine-
contaminated sartans or sartans in combination with
hydrochlorothiazide are not exceptions in this respect, but on
the contrary conrm the thesis of the role of nitrosogenesis in
the development of melanomas [4-6].

139
The association between intake of nitrosamine-contaminated
antihypertensive drugs from the ACE inhibitor group and
the development of keratinocytic cancer and/or keratinocytic
cancers in combination with melanoma precursor lesions
appears to be similar to completely analogous [7,8].
We present 4 cases of patients with keratinocytic tumors
occurring concomitantly or in parallel with melanoma precursors
(dysplastic nevus) within the context of the intake of various
antihypertensive drugs actually/potentially contaminated with
nitrosamines.
For the rst time, keratinocytic cancers occurring after, during,
or within the intake of beta blockers (bisoprolol/ metoprolol)
and calcium channel blockers (amlodipine/ felodipine) are
presented in the world literature: two new classes of drugs
for which nitroso contamination is known but has never been
thematized towards drug side eects and skin cancer [9-11].
The nitrosogenesis of skin cancer appears to be, in eect, a key
new, so far unexplored element of its pathogenesis, however
unpleasant this may sound to regulators in the face of the EMA
and FDA.
Case 1.
We report an 85-year-old patient who visited the dermatologic
surgery outpatient clinic for a complaint of a bleeding skin
neoplasm localized 2 cm below the medial orbital angle (Figure
1a). The lesion was no more than 2 years old. On dermatologic
examination, a tumor-like, rounded lesion, approximately 1.4
cm in diameter, partially pigmented, with central necrosis,
clinically and dermatoscopically suggestive of basal cell
carcinoma was observed (Figure 1a).
Figure 1. 1a: Drug-induced basal cell carcinoma (Bisoprolol/
Lisinopril) in the area under the left eyelid and immediately above the
nasolabial fold.
1b: Oval excision of the tumor.
1c & 1d: Conduction of an island ap to cover the resulting defect.
The patient's known comorbidities included: arterial
hypertension and heart failure since 2010; diabetes mellitus
since 2010; gout; and benign prostatic hyperplasia.
Patient's concomitant medications include: Colchicine 0.5 mg
-one tablet every 12 hours; Bisoprolol fumarate 5 mg half tablet
in the morning (from 2015 to present); Torasemide 10 mg- 1
tablet in the morning from 2014 ; Lisinopril 10 mg- 1 tablet in
the morning/ from 2020 to 2023; clopidogrel 75 mg- 1 tablet in
the morning from 2019; solifenacin succinate/ tamsulosin 6/ 0,
4 mg - once daily from 20213/3; atorvastatin 10 mg once daily
from 2013; isosorbide mononitrate 20 mg once in the evening
from 2011, human insulin 100 IU/ml - 8E in the morning and
4E in the evening.
A cardiology consultation was conducted to change
medication, and bisoprolol 5 mg and lisinopril were stopped,
with amlodipine 5 mg prescribed if needed.
Clopidogrel was stopped preoperatively and switched
to nadroparin calcium for 4 days, and nadroparin was not
administered on the day of surgery. Surgical removal of the
tumor under local anesthesia was performed as follows: the
primarium was initially excised as an oval excision (Figure 1b),
and the defect was closed by island plasty (Figures 1c-d). The
postoperative course was without complications. Histological
ndings were suggestive of nodular type basal cell carcinoma
with tumor size less than 2cm and central ulceration of 1 to
2mm. Screening showed no evidence of metastasis. The patient
was referred to the regional cancer hospital for follow-up.
Medication with bisoprolol and lisinopril was stopped during
the inpatient stay. The case could also be considered as the
rst case of basal cell carcinoma after taking a potentially
nitrosamine-contaminated beta blocker, bisoprolol (Both drugs
are in the group of drugs declared by regulatory authorities or
potentially nitrosamine-contaminated ones).
Case 2.
We report a 74-year-old female patient with a history of
complaints of approximately two years in the form of a rapidly
growing tumor localized in the medial orbit. Dermatological
examination revealed a nodular lesion elevated above the
skin level, measuring 1.7 cm by 1.6 cm, circular in shape and
indistinct from the surrounding tissue, suggestive of nodular
basal cell carcinoma (Figure 2a).
The patient's known comorbidities were arterial hypertension
in 2013, status post partial cervical resection in 2016 , status post
laparoscopic cholecystectomy in 2021, Hashimoto's thyroiditis.
Patient's concomitant medications include: euthyrox 75
micrograms once daily; hydrochlorothiazide 25 mg - ½ tablet
daily in the morning / since 2015; felodipine 5 mg once daily, in
the morning / since 2018.
Surgical excision of the tumor was performed (2b), and the defect
was closed using an island ap (2c-d). Smooth postoperative
period, no complications occurred. Histopathological ndings
were suggestive of nodular basal cell carcinoma with tumor
size of less than 2 cm, clean resection lines/ histology: A well-
demarcated dermally located epithelial lesion represented
by orthohyperkeratosis, epidermal atrophy, proliferation of
atypical basaloid keratinocytes forming heterogeneous nests
and pseudofollicular structures with a palisaded periphery,

GEORGIAN MEDICAL NEWS
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© GMN 140
demarcated by a retraction phenomenon, and brinous, well-
vascularized stroma. Perineural and lymphovascular inltration
is absent. Clean resection lines.
Figure 2. 2a: Drug-induced (Hydrochlorothiazide/ Felodipine) basal
cell carcinoma in the medial orbital angle. Toxic antihypertensive drug
combinations containing nitrosamines.
2b: Removal of the defect by oval excision.
2c: Conduction of an island ap to cover the defect.
2d: Postoperative photograph immediately after covering the defect
by island ap.
No evidence of process dissemination within the staging. The
patient was referred to the regional cancer hospital for follow-
up.
In view of the dicult control of blood pressure values during
the inpatient stay, a change of systemic treatment for the arterial
hypertension to hydrochlorothiazide and felodipine (announced
potential availability of nitrosamines as early as 2022) was
recommended by the attending cardiologist in the outpatient
setting.
Case 3.
We report an 89-year-old female patient with complaints
(according to history) of several months' duration in the form
of tenderness and bleeding in the nasal area and left eyebrow
(Figure 3a). Clinical and dermatoscopic attention during
the dermatological examination focused on an endophytic
growing verruciform lesion localized in the apex of the nose
(subsequently identied histologically as squamous cell
carcinoma of the skin with intracellular keratinization, 3/2 mm
in size and free resection margins of 5 and 2 mm) (Figure 3a).
Lesion diameter of 1.3 cm, relatively clear demarcation from
healthy tissue, hyperkeratotic surface, clinically suggestive of
spinocellular carcinoma (Figure 3a).
A second lesion, exophytically growing, with a diameter of
no more than 0.4 cm, bleeding and painful, suggestive of basal
cell carcinoma (veried histopathologically postoperatively as
nodular type basal cell carcinoma measuring 2 by 2 mm and
free resection margins of 1.2 and 5 mm) was found in the nasal
area again and adjacent to the medial orbital angle on the right
(Figure 3a).
A third lesion was found above the left eyebrow- hyperkeratotic,
dense in consistency, painful and bleeding , with a diameter of
1.5 to 0.7 cm (relative horizontal to vertical direction),( Figure
3a), suggestive of hyperkeratotic actinic keratosis/seborrheic
keratosis (histopathologically veried postoperatively as
seborrheic keratosis). A pigmented lesion, clinically and
dermatoscopically suggestive of dysplastic melanocytic nevus,
was found in the dorsal region (Figures 3f, 3f).
As comorbidities, the patient had arterial hypertension,
gastritis, colitis, and ischemic heart disease.
The patient's current medications at the time of hospitalization
included: amlodipine 5 mg/half a tablet per day, intake since
4 years; bisoprolol fumarate 2.5 mg-one per day, intake since
3 months; molsidomine 2 mg-intake since 6 years, one tablet
per day; piracetam 1200 mg-one per day since 3 months;
vinpocetine 10 mg-one per day since 6 years.
The lesions above the left eyebrow and near the medial orbital
angle on the right were removed by elliptical excisions, and
the defects were covered by using single skin sutures (Figure
3b). The lesion at the apex nasi was excised in depth to the
cartilage by means of oval excision. The defect was covered
using a full thickness mesh graft with skin taken from the neck
area (Figures 3b-d). A compression dressing was made with
sterile compression, xed with diametrically placed sutures (left
intraoperatively deliberately longer for the purpose) to better x
the graft and avoid possible hematoma (Figures 3b ). The patient
refused excision of the dysplastic nevus in the dorsal area.
Due to the potential availability of nitrosamines ocially
announced by the regulatory authorities for the two drugs
(bisoprolol, amlodipine), it was recommended that in the
outpatient setting the medication should be substituted after
assessment by a cardiologist.
Case 4.
We report a 62-year-old patient with complaints of
approximately one year's duration, localized in the right temporal
area as a raised neoplasm above the skin level with a diameter of
0.6 cm, central necrosis, and a pearly rim, suggestive clinically
and dermatoscopically of basal cell carcinoma (Figure 4a).
The patient's known comorbidities included dyslipidemia,
hypertensive heart with congestive heart failure, tricuspidal
insuciency, hypercholesterolemia, aorto-coronary bypass
graft, hypertensive heart disease/grade III, left ventricular

141
Figure 4. 4a: Drug-induced (Мetoprolol/ Perindopril/ Candesartan) basal cell carcinoma localized in the right temporal region. Nitrosamine
contamination in beta blockers seems to have the same procarcionogenic eect as Perindopril and Candesartan preparations.
4b: Preoperative marking of the resection lines.
4c: Postoperative ndings after successful surgical excision.
Figure 3. 3a: Drug-induced (Amlodipine/ Bisoprolol) basal cell carcinoma of the nose and spinocellular carcinoma of the nose after amlodipine
and bisoprolol administration. Nitrosamine contamination in Amlodipine and Bisoprolol as substantial skin cancer trigger.
3b: Postoperative ndings after skin grafting in the form of full thickness mesh graft from the neck to the tip of the nose. There were 2 elliptical
excisions of the tumors above the eyebrow and to the right of the dorsum of the nose.
3c/d: Free skin graft from the neck and its subsequent adaptation in the nasal area. Closure of the neck defect using single skin sutures.
3e/ 3f: Drug-induced dysplastic nevus in the dorsal area after Amlodipine and Bisoprolol administration. Nitrosamine contain in commonly
prescribed antihypertensive medication seems to have a key role in the pathogenesis or Skin cancer and skin cancer precursor lesions.

GEORGIAN MEDICAL NEWS
No 4 (337) 2023
© GMN 142
diastolic dysfunction, and status post mitral valve annuloplasty
(performed for prolapse and high-grade mitral insuciency in
2019).
Concomitant medication within the hospitalization included:
metoprolol 25 mg once daily in the morning from 2009 to
present; perindopril arginine 5 mg once daily for the period
between 2009-2019, subsequently replaced by candesartan
cilexetil 16 mg once daily to present; acetylsalicylic acid 100
mg once daily in the evening from 2009; rosuvastatin 10 mg
once daily in the evening (from 2019).
Surgical elliptical excision of the tumor under local anesthesia
was performed. The defect was closed using single skin sutures
(Figures 4b-c). The histological nding was suggestive of
basal cell carcinoma , stage 1. The postoperative period was
uneventful.
Outpatient drug switch with candesartan and metoprolol was
recommended by the supervising cardiologist after benet/risk
assessment.
The case could be considered as indicative of a rst case
related to the development of basal cell carcinoma occurring
after the combined administration of a potentially nitrosamine-
contaminated beta blocker (metoprolol) , an ACE inhibitor
(perindopril) and subsequent replacement of the ACE inhibitor
with SARTAN (Candesartan).
Discussion.
The presentation of this scientic work aims to focus the
attention of clinicians on the role of nitrosogenesis in the
development of keratinocytic/melanocytic skin cancer.
A case of basal cell carcinoma of the face occurring after
combined administration of bisoprolol and lisinopril (patient
1) is also presented for the rst time in the world literature,
commenting on the inuence of the nitroso component in both
drugs on the potential generation of a malignant cell clone.
The mechanism of development of cutaneous tumours after
amlodipine and felodipine should be similar.
The problems with the mutagenic/clastogenic action of nitroso
derivatives formed within the in vitro reaction of beta blockers
with sodium nitrite have been known not since today or yesterday,
but since as far back as 1994 [12]. The clastogenic/mutagenic
activity of N - nitroso derivatives of 5 beta adrenergic blocking
drugs was then demonstrated in partially hepatectomized rats,
nding that: all 5 N-nitroso derivatives of beta blockers induced
a statistically signicant increase in the frequency of hepatocyte
micronuclei, the mutagenic action of NO-propranolol, NO-
metoprolol and NO-nadolol being slightly stronger than that of
NO-atenolol and NO-sotalol [12].
Within the two models tracking the mutagenic eect (after
administration/application) of dierent doses of nitrosode
derivatives in beta blockers (in vivo/in vitro), it was found that
the clastogenic/mutagenic eect was also present in the in vitro
experiments: it was denitely stronger than that in the in vivo
ones conducted [12].
Consideration must also be given to the fact that there are
signicant dierences in the calculation/estimation of in vivo
mutagenic eects in experimental animals and human subjects
who are not /or have been subjected to randomization within
some studies relative to the prospective/retrospective follow-
up model (our submitted 4 patients), namely: In retrospective/
prospective follow-up and subsequent analysis of patients (such
as the 4 cases or part of them we presented), contamination of
concomitant medication with nitrosamines or their derivatives
is taken into account. On the other hand, we also follow the
cumulative total potential/actual mutagenic eect of the
concomitant medication over the years, which is essential for
the generation of a malignant cell clone or a given cancer form.
These factors have not been calculated in comparative analyses
of the clastogenic eects (in vivo/in vitro) of nitrosopyride in
beta blockers described in the past [12]. Nevertheless, both
phases of the experiment do not reject but conrm the thesis
that a clastogenic/mutagenic eect is present: both in vivo and
in vitro [12].
Would it be reasonable to assume that the eect of bisoprolol
taken by our patient would be similar to analogous, to that
described in the shared data (patient 1) [12]? Especially when
combined and with the intake of another class of drugs, the so-
called ACE inhibitors, lisinorpil, also catalogued as actually/
potentially contaminated [13].
Monomedication with ACE inhibitors has in turn been
described as risky in terms of generating keratinocytic cancers
due to its potential/actual contamination with nitrosamines [7,8].
This medication has also been shown to be risky with respect
to the development of keratinocytic cancers such as basal
cell carcinoma of the skin in combination with melanoma
precursors- dysplastic nevi [14].
Regarding the presented patient number 2 and the intake
of hydrochlorothiazide and felodipine, the following could
be mentioned: hydrochlorothiazide has a photosensitizing
eect, which according to the latest literature data suggests
or predisposes patients taking it to keratinocytic but also
melanocytic skin cancer [15].
However, should not precisely ʺthis one-sided interpretation
[15]ʺ of its action shift the focus away from the role of
nitrosamines in thiazide diuretics as an additional , if not even
more potent, inducer of the development of keratinocytic but
also melanocytic skin tumors? Because precisely:
1) hydrochlorothiazide or certain batches of it have been
withdrawn from the market due to elevated doses of nitrosamines
[16].
2) the data on nitrosation of hydrochlorothiazide have been
known since as far back as 1977 [17] but have been studiously
ignored until now.
3) there are dozens of publications that ʺsuggestʺ that
the clastogenic/mutagenic action of the nitrosamines in
hydrochlorothiazide is present and quite real with respect to the
development of diverse cancers (not just skin cancer) [5,18-21].
Even this interpretation of the data/facts alone points clinical
thought in the direction of a strong general pro-carcinogenic
eect (based on the presence of carcinogenic impurities in the
drug) and against the thesis/hypothesis of a ʺone of a kindʺ
photosensitizing eect and subsequent development of skin
cancer [18-21]. Recent follow-up studies in the literature have
associated specically hydrochlorothiazide monomedication
(high cumulative daily dose/daily intake) with a signicant

143
association in terms of generating the most common forms
of skin cancer seen by clinicians: basal cell carcinoma and
squamous cell carcinoma [22]. Future analyses should in
all likelihood also focus on the aforementioned nitrosamine
issue, rather than ʺdisregardingʺ and ignoring it as a topic for
discussion and subsequent detailed analysis. Otherwise, we risk
facing the wave of side eects again, this time also caused by
monomedication with hydrochlorothiazide.
The synergistic additive mutagenic eect (due to reported
nitrosocontamination and of combination preparations
containing calcium antagonists as well) of the addition of
felodipine medication over time probably does not require
detailed analysis. The role of calcium antagonists in relation to
skin cancer nitrosogenesis will be discussed in more detail in
patient number 3.
The third case we presented was of an elderly patient who
developed 2 epithelial tumors in the facial area (Figure 3), as
well as a dysplastic nevus in the back (Figure 3). The lesions
occurred after 4 years of taking amlodipine, and a beta blocker
was taken additionally- bisoprolol fumarate for the last months
before the hospitalization (case 3). Starting from 1) ocial
bulletins/data on possible potential contamination also of
calcium antagonists with nitrosamines (nitroso-amlodipine)
[22], and 2) the recall of batches of nitrosamine-contaminated
combination antihypertensive drugs, containing amlodipine and
sartans [23], the hypothesis/thesis of possible contamination
of monomedication with amlodipine or analogues of the same
drug group could also be expressed. This should be prioritized
as a future follow-up and goal.
Preliminary, as yet unpublished (our) data on side eects are
indicative of just such a relationship. The clinical manifestation
of these 4 tumor lesions does not exclude the potential/actual
mutagenic inuence of a beta-blocker or N -Nitroso- Bisoprolol
taken in parallel, albeit for a short period [24].
Supporting these claims are a number of other clinical
observations reported over the years as publications in the
world literature such as : 1) the development of basal cell
carcinoma and dysplastic nevus after systemic administration
of valsartan in combination with hydrochlorothiazide [25]. 2)
the development of basal cell carcinoma and dysplastic nevus
after starting treatment again with valsartan and bisoprolol
[26]. 3) the occurrence of melanoma of the heel in combination
with 3 verrucous carcinomas within the intake of valsartan and
olmesartan, as well as a short-term intake of the amlodipine/
valsartan combination, subsequently eliminated from the
drug market because of nitrosamine contamination above
the permissible daily limits [27], development of basal cell
carcinoma and dysplastic nevi after a potentially nitrosamine-
contaminated ACE inhibitor-ramipiril [28].
What all of the above and previously published data have
in common is : 1) the development of similar to completely
identical clinical combinations of keratinocytic cancers in
combination with melanomas or melanoma precursor lesions,
and 2 ) the development of these combinations following
administration of radically dierent classes of drugs that have
been declared as potentially/actually nitrosamine contaminated.
And for those who have diculty understanding ʺpathogenetic
relationshipsʺ, the following anecdote could be shared: ʺIf a
young and beautiful lady walks in 4 dierent city/suburban
parks and is ʺattacked each timeʺ, then in all likelihood the
attacks are not determined by the parks, the alleys, the owers,
the weather, or the atmospheric pressure (as well as random
association/sporadicity)-they would be determined by a
common, unifying factor, and that could be one party: 1) either
the lady's challenging attire/behavior, or 2) someone following
her to all four parks. ʺ Similar is the case with the presence of
nitrosamines (in the park) and the pattern of manifestation of
skin tumours (in the lady).
Interesting how and why, but these data of ours overlap
completely with the statistics of Beatrice Nardone's data from
2017, which remain enigmatic and up to date at the moment-
namely that: the risk of developing basal cell carcinomas,
spinocellular carcinomas and cutaneous melanomas is present
after taking all three classes of drugs: ACE inhibitors, ARB
blockers-Sartans and HCT- Hydrochlorothiazide [29]. It
should not be overlooked that batches of all three classes of the
mentioned groups of drugs have been declared as potentially/
actually contaminated and withdrawn from the market due to
elevated concentrations of nitrosamines above the permissible
levels. However, the same pattern of manifestation of skin
tumours after taking amlodipine can be added to these groups of
drugs. Which in turn would be a logical rationale for amlodipine
monomedication (but also felodipine case 2) to be checked for
nitrosamine contamination and new batches of medication
withdrawn from the market! The dierence in these cases
is that the starting point is back to front- namely: the clinical
picture, from which conclusions are drawn about the potential
contamination of the currently or formerly administered
medications. Аnd this in turn is a good reason for checking
previously unpublicised and in all likelihood nitrosamine-
contaminated medications.
Absolutely analogous and completely overlapping
considerations are the development of skin tumors and their
precursor forms after the administration of beta blockers
contaminated with nitrosamines described in patient number
1, for example, as well as after the administration of ACE
inhibitors [7,8].
In the fourth patient we described who developed basal cell
carcinoma, his medication included metoprolol for a total of 14
years in combination with perindopril for 10 years. Perindopril
was subsequently replaced by candesartan for a period of 4 years
- until the time of hospitalization (see exact data for patient 4).
The availability of nitrosamines has been reported and described
in the literature for each of the drug classes described.
Large-scale studies from the recent past have found
(analogous to the case presented) a signicantly signicant
association between monomedication with ACE inhibitors and
Sartans with the development of basal cell carcinomas (more
than twofold increased risk for both classes of drugs) [29].
These signicant associations have been conrmed in recently
published analyses regarding the role of ACE inhibitors in the
development of keratinocytic cancer [30]. However, it is a great
pity that both publications do not nd what the likely cause of
these relationships might be [29,30], in contrast to the very well
presented new and detailed data published recently [31], it is
these that etablate the role of nitrosamines in ACE inhibitors

GEORGIAN MEDICAL NEWS
No 4 (337) 2023
© GMN 144
in relation to keratinocyte cancer development [8,31], but not
only [8].
Sartans in general, and eprosartan (contaminated with
nitrosamines) in particular, are similarly associated with the
development of keratinocytic cancer [29,32].
The indierent, somewhat ʺgentlemanly roleʺ of regulatory
entities with respect to the regulation and elimination of carcinogenic
substances in pharmaceuticals certainly does not contribute to the
elucidation of ubiquitous nitrosamine contamination nor to the
containment of the cancer pandemic [33].
Conducting certain mutation tests in the form of the so-called
AMES Test (but not only) in order to prove their mutagenic/
carcinogenic eect (OF NITROSAMINS), the subsequent
accurate identication/elimination from the ʺdrug menuʺ of
patients, should be a priority [34].
Because ʺpermissive availabilityʺ allows cancer to occur in
practice, it does not restricts it. It only distances it in terms of
time relative to the intake of the relevant amount of carcinogen.
And this amount is not constant and can be increased from 20
to 200 times-a fact that turns out, however, to be unregulatable.
Similar to the manifestation of skin cancer.
Conclusions.
The contributions of the presented scientic work consist
mainly in the formalization of two completely new classes
of drugs: beta blockers (bisoprolol, metoprolol) and calcium
antagonists (amlodipine, felodipine), actually/potentially
contaminated with nitrosamines and after whose administration
the development of keratinocytic skin tumors or keratinocytic
tumors in combination with precursor lesions of melanoma
(dysplastic nevi) is observed.
For the rst time, the role of a new potentially nitrosamine-
contaminated ACE inhibitor, lisinopril, in skin cancer/
keratinocytic cancer nitrosogenesis is described and commented
upon, as is that of candesartan.
Considering that candesartan has been described in the
literature as a generator of multiple melanomas and dysplastic
nevi [6], its actual role in practice represents: an overlap of its
pro-carcinogenic eect in the direction of keratinocytic cancer
as well. This combination has been described by us repeatedly
with respect to other classes of contaminated drugs.
Clinical patterns of manifestation in the form of the same
combinations of cutaneous tumors could be considered as
indicative or at least suggestive of their possible common
pathogenesis.
The commonality in all the described classes of drugs could be
only one: the presence of the same unifying component known
as NITROSAMINE.
The nitrosogenesis of skin cancer opens doors that lead to
unraveling the puzzle of carcinogenesis worldwide.
A carcinogenesis that is opening a business for billions and a
carcinogenesis that is costing human lives or put another way:
Apocalypse now!.
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