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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

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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.
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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
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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
No 4 (337) 2023
© 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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... Nitrosogenesis concerning keratinocytic cancers is not new as a concept for the academic community [1,2]. Polymedication and polymorbidity in the era of polycontamination with nitrosamines in all likelihood have a role regarding skin cancer carcinogenesis [1,2]. ...
... Nitrosogenesis concerning keratinocytic cancers is not new as a concept for the academic community [1,2]. Polymedication and polymorbidity in the era of polycontamination with nitrosamines in all likelihood have a role regarding skin cancer carcinogenesis [1,2]. It is within this framework of polycontamination that the so-called daily allowable doses of certain carcinogens/nitrosamines/NDSRIs in a drug become difficult to conform to or comply with. ...
... The third patient presented developed basal cell carcinoma in the medial orbital angle area and was on systemic treatment with a combination agent containing amlodipine and perindopril, both of which are described in the FDA listings as having potential contamination with nitrosamines or NDSRIs [3]. Both preparations have been described as dangerous or risky to patients' health in terms of the development of keratinocytic skin cancer within the context of possible polycontamination [1,2]. Similar considerations have been made regarding concomitant administration of the beta blocker metoprolol [2,3] as well as the centrally acting sympatholytic moxonidine [15,16] (in the patient described). ...
Article
Full-text available
The Nitrosogenesis of skin cancer is a modern newly introduced concept in medicine, mainly concerning melanoma, but also keratinocytic cancers such as basal cell carcinoma. The nitroso-contamination of more than 300 drugs worldwide and the permanent (relatively short-term) intake of mutagencontaminated drugs could create serious prerequisites for the development of skin cancer. Retrospective but also prospective analyses following potentially contaminated polymedication with a heterogeneous type of nitrosamines in real patients are indicative of a causal connection rather than a sporadic association between 1) intake of a possibly nitrosamine-contaminated drug and 2) generation of keratinocytic skin cancer. The pathogenesis of high-risk periocular localized basal cell carcinomas was until recently shrouded in mystery as it was mainly and until now associated with 1) intake of phototoxic drugs and 2) intense exposure to UV radiation (without intake of drugs), 3) congenital or acquired immunodeficiencies, and 4) Goltz Gorlin syndrome or 5) Xeroderma pigmentosum. Nitrosamines/ NDSRIs within the framework of polycotaminated drug intake appear to be one reasonable additional explanation for the association between carcinogen intake and subsequent skin cancer development and progression, and a relatively short-term one at that. Recently published scientific data provide information on a new ability of some of the nitrosamines - namely that some of them are photocarcinogenic or genotoxic after activation with UVA radiation. We present 4 patients who developed high-risk periocular localized basal cell carcinomas of the skin after/within the intake of potentially nitrosamine-contaminated drugs. The presented data are confirmatory with respect to previously published scientific observations on the carcinogenic effects of valsartan, candesartan, bisoprolol, metoprolol, perindopril, lisinopril and amlodipine. The contribution of newly validated data concerning potential/actual carcinogenic/genotoxic activity in the article is also due to the following newly announced nitroso preparations: torasemide, moxonidine and mirabegron. The expansion of the ˝bases of the pyramid˝ determining the stability of drug related (Photo) Nitrosogenesis/ Carcinogenesis (in terms of skin cancer generation) is growing daily. Exogenously/drug-induced Nitrosogenesis and the subsequently triggered carcinogenesis are a completely new explanatory concepts concerning the pathogenesis of skin tumors that remained unanalyzed and hidden for decades. Until now. The official lack of 1) availability, and of 2) precise concentrationsregarding nitrosamines in medicinal preparations, are some of the most unexplained acts of irresponsibility to end-users and remain for the moment without a definitive answer from either regulators and manufacturers respectively. Polycontamination of polymedication in polymorbid patients remains highly problematic, at least as a cofactor in the development and progression of keratinocytic cancers, and this in the short term. Recently published data but also data from the past are suggestive that nitrosamines in tobacco are pivotal in the development of acquired mutations in p53 and RAS oncogenes in humans and rodents. The same genes are also affected by mutations in keratinocytic cancer patients. The overlapping mutation patterns of UV radiation-induced mutations in target genes such as p53 and RAS with those caused by some nitrosamines is indicative of a synergism available in terms of gene toxicity or possibly photocarcinogenicity of the latter. What leads the scientific community to believe that the nitrosamines in drugs, similar in composition and carcinogenic potency, act differently, is unclear. The link between drug intake, nitrosamine contamination, generation of some acquired mutations and subsequent cancer development becomes more than obvious and logically conditioned. The thesis of the controlled spread of cancer sounds more than logical today because: whoever controls and regulates the spread of carcinogens/mutagens/nitrosamines is also able to control the occurrence and spread of skin cancer. The Pharmacooncogenesis of skin cancer is determined by exogenously mediated Nitrosogenesis or the permissive availability for certain nitrosamines in drugs worldwide.
... First report about the possible connection between single/multiple forms of keratinocytic cancer after administration of potentially nitrosamine-contaminated antihypertensive medications, including beta blockers (bisoprolol, metoprolol) and calcium antagonists (amlodipine, felodipine), was conducted by Tchernev [29]. A true "apocalypse" as it is said and described by the author, mainly because there is an issue with over 1 billion patients consuming potentially nitrosamine-contaminated drugs, is anticipated [29]. ...
... First report about the possible connection between single/multiple forms of keratinocytic cancer after administration of potentially nitrosamine-contaminated antihypertensive medications, including beta blockers (bisoprolol, metoprolol) and calcium antagonists (amlodipine, felodipine), was conducted by Tchernev [29]. A true "apocalypse" as it is said and described by the author, mainly because there is an issue with over 1 billion patients consuming potentially nitrosamine-contaminated drugs, is anticipated [29]. This includes 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 many more [29]. ...
... A true "apocalypse" as it is said and described by the author, mainly because there is an issue with over 1 billion patients consuming potentially nitrosamine-contaminated drugs, is anticipated [29]. This includes 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 many more [29]. Even if only 20-30% of the patients within these groups were affected, the potential number of patients taking these drugs is alarming and could possibly exceed 1 billion [29]. ...
Article
Full-text available
Keratinocytic cancers, particularly basal cell carcinoma, remain as the most prevalent type of skin cancer in the white population, experiencing a global increase in incidence rates each year. The interaction between UV-radiation, the phenotype and genotype contributes to the etiopathogenesis of the condition. However, newly emerged data in recent years has raised serious questions about the current understanding of the patho-genesis of skin cancer. Recently, in the forefront, oncopharmacogenesis has emerged as the primary event behind the cancer development, particularly skin cancer. Most of the nitrosamines are potent carcinogens. A large amount of data, ranging from single case reports to large-scale retrospective studies, has shown the significant connection between the nitrosamines and the onset of skin cancer. Considering 1) the carcinogenic potency, 2) relatively short manifestation of tumors post-initial drug intake, and 3) the development of rather uniform types of cancer, it can be concluded that nitrosamine contamination in the medications has a key role in the pathogenesis of skin cancer. Dealing with Nitrosamine Drug Substance-Related Impurities (NDSRIs) introduces challenges due to the uncertainty about the specific effects of each ingredient within the medical product, making it difficult to discern whether they have mutagenic, carcinogenic, or both effects. We report a case series consisting of 3 non-related case reports, in which middle aged (in their 50-60s) patients developed basal cell carcinomas shortly after oral intake of potentially contaminated mono-or combined therapies for arterial hyperten-sion: irbesartan/hydrochlorothiazide, irbesartan; nebivolol; bisoprolol and propafenone. Except for the propafenone, the medications were administrated for 4-7 years (in the different case reports), a duration sufficient enough for the development of nitrosamine-induced skin cancer. Dermatosurgical management of the problematic lesions was successfully performed, resulting in a favorable esthetic outcome. The concepts of "Nitroso-genesis" and ʺOncopharmacogenesisʺ in skin cancer will be discussed, while reviewing the existing literature and offering additional perspectives on the current "skin cancer pandemic". Our main focus is to raise awareness about the potential risk or “side effect” of developing keratinocyte cancer, due to the intake of potentially nitrosamine/NDSRIscontaminated medications, particularly different types of antihypertensives (irbesartan, hydrochlorothiazide, nebivolol, bisoprolol) and antiarrhythmics (propafenone). Link for PDF: https://link.springer.com/epdf/10.1007/s10354-024-01039-7?sharing_token=kzzWa2FpJ3z5WR2o0DBq2ve4RwlQNchNByi7wbcMAY78LfIJINeRvMILJNW_KrkKwj5kabMgnr7bhx9DBV-IvGJBxyawtjwDFJ3o2DBsw7Jj4bWXLq507a1MpjxKBgeVT046IM4ID8gSRSTCGc28ZjtqB4dC7-IXipwY1BlYjmg%3D
... The ability to unravel and explore these two concepts closely is provided mainly and entirely as background information by the FDA [1, 2]. The relationship of these concepts to skin cancer is due to the hundreds of currently clinicopathologic correlations observed after or within the initiation of potentially contaminated drugs and the subsequent onset of keratinocytic cancers [3][4][5][6]. ...
... Interestingly, the study calculated separately the risks associated with NDMA and NDEA, considering the assumption of exposure to only one nitrosamine in a given drug product [23]. Only a few publications have addressed the impact of nitrosamines in polymedication on skin cancer [3][4][5][6]. ...
... Case report 1, as presented by us, confirms the association of three drugs used for the treatment of arterial hypertension -bisoprolol, lisinopril, and amlodipine -with several clinicopathological correlations contributing to the development of keratinocyte cancer [4,6]. A probable/possible/potential link between various forms of keratinocytic cancer and the intake of potentially/really nitrosamine-contaminated antihypertensive medications, including bisoprolol and amlodipine, was reported by Tchernev [6]. ...
Article
Full-text available
The exact pathogenetic mechanism associated with Nitrosogenesis and Pharma-co-oncogenesis/Onco-Pharmacogenesis in keratinocytic cancer and melanoma remained unclear until recently. The lack of formal recognition or definitive formaliza-tion of the presence of certain carcinogens/mutagens, also known as nitrosamines/ nitroso compounds, in the packaging of drugs of heterogeneous types has severely hampered analyses, evaluation and conclusions regarding their pathogenetic role in skin cancer development and progression. It remains a widely accepted and well-known fact that mutations in the genome regulator p53 and RAS oncogenes contribute significantly to the development of basal cell carcinomas and cutaneous melanomas. Nitrosamines are also involved in the induction of mutations in the RAS oncogenes and in p53. Following these well-known findings, it would not surprise anyone that nitrosamines/NSDRIs, which are "potentially or actually" present in the most widely distributed drugs worldwide, could also exert a certain carcinogenic/mu-tagenic effect on human DNA. The article serves to 1) confirm findings documented recently and to date in the world literature regarding certain drugs such as: biso-prolol, metoprolol, nebivolol, lisinopril, perindopril, losartan, telmisartan/amlodipine, felodipine and the subsequent activation of cutaneous carcinogenesis. Furthermore, the scientific work 2) introduces new data regarding other potentially/actually contaminated drugs such as clopidogrel, nicergoline, apixaban, triamterene/hydrochlo-rothiazide, dipyridamole, tamsulosin, tofacitinib, allopurinol, alprazolam, duloxetine and rosuvastatin/zetimibe, and the occurrence of skin cancer is discussed in the context of polycontamination and polymedication.
... According to a number of clinical observations, nitrosogenesis is a novel concept underlying the generation of cutaneous tumors, at least as a nonnegligible co-factor [1,2]. This concept or new model of interpretation concerns keratinocytic tumors as well as dysplastic nevi and melanoma in particular [3]. ...
... The role of amlodipine as an ˝additional contribution˝ to the cumulative daily intake of mutagens in the context of polymedication has already been discussed in relation to nitrosogenesis and skin cancer in other scientific works [1,2]. ...
... The de novo occurrence of pedunculated advanced giant cell melanoma after Hydrochlorothiazide administration was presented in patient 2 and is entirely and strongly confirmatory, analogous to American data concerning heterogeneous collectives linking Hydrochlorothiazide monomedication to the occurrence of cutaneous melanomas [11,12]. Unfortunately, these data again do not comment on potential or actual nitrosamine contamination, which does not, however, exclude it as a cofactor in the induction of cutaneous melanomas [2,3]. ...
Article
Full-text available
The idea of drug-induced/exogenic Nitrosogenesis is driven by the possibility of prolonged exposure of the human body to the influence of nitrosamines within the drug intake – substances or contaminants that have been proven to be carcinogenic or mutagenic one. Until recently, there was a complete lack of data in the scientific literature on the relationship between cancer, polymedication and polycontamination with nitrosamines. In the last decade, melanoma has been described repeatedly in the medical literature as a possible side-effect within the intake of possibly with nitrosamines contaminated medications such as: Valsartan, Hydrochlorothiazide, Amlodipine, Nebivolol, Bisoprolol and Perindopril. However, the contribution of the currently presented new data (5 new patients) is also due to the establishment of the possible pathogenetic role (with respect to melanoma) of several completely new drugs, previously unknown to the scientific community (potentially/actually contaminated with carcinogens/nitrosamines), such as: Ranitidine, Rosuvastatin, Lercanidipine, Rilmenidine, Trandolapril, Moxonidine and Verapamil. The leading and connecting link in shared new and old drug combinations of heterogeneous drug classes (polymedication) and melanoma development and progression remains again one and the same : the possible availability of nitroso component in the frame of exogenous nitrosogenesis according to the official FDA lists of 2023. The number of drugs shared as contaminated with nitrosamines after whose intake melanomas occur is increasing. Nitrosogenesis remains a new beginning, a new understanding and new interpretation of the carcinogenesis concerning melanoma, but probably also of cancer in general. Its further elucidation looks more than promising and is yet to come. More than worrying at the moment remains the fact that the scientific community has to clarify if : 1) peak concentrations of nitrosamines or NDSRIs within the framework of monomedication or 2) normal concentrations within the polymedication (catalogued in the list of FDA/ 2023 as potentially contaminated with hypothetical carcinogens), could hide relatively short-term risk of the development of real tumors: cutaneous melanomas and/or their precursor lesions. The validation of the concept of Nitrosogenesis and its relationship to Сarcinogenesis, is achieved in practice on the basis of the following facts: that it is the occurrence of the same monomorphic clinical pattern (melanoma/dysplastic nevi) , developing after the intake of drugs with different mechanism of action, contaminated with nitrosamines / NDSRIs. The unifying link between the intake of certain drugs and the development of certain tumours remains the presence of nitrosamines. Ingredients that are present in drug preparations, identified as availability and as carcinogenic potency, but not yet reflected in packaging or prescriptions. The question remains: why?
... В подписях к микрофотографиям следует указывать степень увеличения через окуляр или объектив и метод окраски или импрегнации срезов. 7. Фамилии отечественных авторов приводятся в оригинальной транскрипции. ...
... Modern, although still speculative according to some colleagues, notions concerning the pathogenesis of skin tumors link contact or intake of nitrosamines contaminating mono-or polymedication in polymorbid patients to the development of several types of skin neoplasms, including keratinocytic cancers [6,7]. Their role as a cofactor is in all likelihood due to the permanent, long-term intake of drugs potentially contaminated with nitrosamines or NDSRIs, and the occurrence of multiple keratinocytic tumors during intake has been previously described [6,7]. ...
... Modern, although still speculative according to some colleagues, notions concerning the pathogenesis of skin tumors link contact or intake of nitrosamines contaminating mono-or polymedication in polymorbid patients to the development of several types of skin neoplasms, including keratinocytic cancers [6,7]. Their role as a cofactor is in all likelihood due to the permanent, long-term intake of drugs potentially contaminated with nitrosamines or NDSRIs, and the occurrence of multiple keratinocytic tumors during intake has been previously described [6,7]. Once it has emerged that this intake has been regulated by regulatory authorities, it remains a difficult task for the academic community to become convinced itself that the risk of developing cancers after long-term intake of carcinogenesis is real, and this includes the risk of skin cancer. ...
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According to scientific databases, nitrosogenesis and carcinogenesis have been inextricably linked for decades and are undoubtedly one of the most serious causes of cancer induction (not only skin cancer) known to humankind. Some of the most potent modifiers of human DNA turn out to be numerous, known since the last century, difficult to classify as carcinogenic potency, yet available for decades as additional, unregulated, often undisclosed ingredients in about (currently) 300 drugs used by at least 5 billion patients worldwide. While this may sound ridiculous, this information turns out to be reality. A reality accompanied by a drastic jump in the incidence of skin cancers (keratinocytic and melanoma) , but also of predicted general cancers, in relation to the year 2040 and disclosed by Globocan. Starting from the thesis of nitrosogenesis and possible contamination with mutagens, we present a case of a 95-yearold female who developed 13 keratinocytic tumors within the potentially/actually contaminated intake of drugs from the group of ACE inhibitors/Enalapril and Sartans/Losartan. A correlation was made between the carcinogenic potency of the possible contaminants (according to the 2023 FDA classification) and the number of cancers occurring within that intake follow-up. The patient was successfully treated surgically with a melolabial flap for the high-risk tumor under the right eyelid and multiple elliptical excisions for the remaining tumors, followed by extension flaps to cover the defects. The role of nitrosogenesis and its relationship to keratinocytic cancers is discussed and analyzed.
... The polycontamination of polymedication with nitrosamines in polymorbid patients appears to be a currently unsolvable dilemma [1-3]. This dilemma is mainly driven by the lack or difficulty in finding an alternative medication that is unaffected by universal contamination [1][2][3][4]. ...
... Beta blockers , calcium antagonists, antiarrhythmic drugs, and sartans are among the drugs most affected by potential nitrosamine contamination [1, [2][3][4]. It is this fact that determines the difficulty in finding substitutes in cases of 1) contamination with nitrosamines detected after screening or 2) the occurrence of side effects such as skin tumors [2][3][4]. ...
... Beta blockers , calcium antagonists, antiarrhythmic drugs, and sartans are among the drugs most affected by potential nitrosamine contamination [1, [2][3][4]. It is this fact that determines the difficulty in finding substitutes in cases of 1) contamination with nitrosamines detected after screening or 2) the occurrence of side effects such as skin tumors [2][3][4]. We present a patient who was taking 2 potentially nitrosaminecontaminated antihypertensive drugs, which are substituted during the cardiologist's check-up with 2 other potentially nitrosamine-contaminated antihypertensive drugs/ (according to the current list of possible nitrosamine contamination/NDSRIs as of April 2023). ...
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The data on the polycontamination of multimedication in polymorbid patients with a heterogeneous class of carcinogens/ nitrosamines, NDSRIs (classified according to the FDA regulation to the companies of 2023 to those with a carcinogenic potency between 1 and 5), are one of the most important steps to clarify the concept of skin cancer nitrosogenesis/ pathogenesis. The FDA is the first regulatory institution in the world to courageously declare that a problem exists and should be addressed. The main and currently unexplained and somewhat controversial issue lies in 1) the sporadic nature of polycontamination in different geographical regions, and 2) the lack of official data from the established international, but also regional pharmaceutical market regulators on the results of the checks conducted for nitrosamine contamination of the respective batches. It is this that leads scientists to the idea of (albeit seemingly) speculative but entirely possible controlled contamination of the production in certain geographical regions. This (hypo)thesis is supported, albeit indirectly, by the fact that: a recent regional check for possible contamination of sartans in a particular geographical region was not indicative of the presence of any nitrosamines/NDSRIs. But this fact is indicative of several extremely important things: 1) contamination is not ubiquitous, its genesis is heterogeneous; 2) contamination could be completely avoided at production level in certain geographical regions; 3) ˝controlled contamination˝ or carelessness of a heterogeneous nature should be excluded by the relevant regulators. Regular inspection and certification of medicinal products in relevant geographical regions to exclude contamination with nitrosamines/NDSRIs would be the surest method to protect public health globally. The initial parameters of the restrictive processes for the availability of nitrosamines in medicines have been established by the most powerful regulator globally in the face of the FDA, with the hope being that manufacturers will find a short-term solution to the problem. We report another patient who simultaneously developed 2 cutaneous tumors under potentially/actually nitrosamine contaminated drugs such as: beta blockers- atenolol, calcium antagonists- nifedipine/amlodipine, sartans- valsartan andantiarrhythmics- propafenone. One of the tumors was localized in the upper lip area (keratoacanthoma) and the other in the right shoulder area (basal cell carcinoma). Successful surgical treatment of the tumors was performed in the form of upper lip advancement rotation flap and elliptical excision of the second lesion. The evolution/growth rate of the tumors in relation to the potential mutagens/carcinogens heterogeneous in their potency contained in the drugs is commented.
... 4. К статье должны быть приложены краткое (на полстраницы) резюме на английском, русском и грузинском языках (включающее следующие разделы: цель исследования, материал и методы, результаты и заключение) и список ключевых слов (key words). 5. Таблицы необходимо представлять в печатной форме. ...
... We report a polymorbid patient who developed 2 epithelial tumors and one superficial spreading melanoma during his relatively short-term multimedication intake. The potential relationship of possible contamination in the context of skin cancer nitrosogenesis is discussed [5]. ...
... Although even under experimental conditions beta blockers show antiproliferative or antitumor effects [10], its clinical significance/relevance at present , remains more than controversial [1,5]. ...
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The era of nitrosogenesis is the era that is conditioned by the permanent and prolonged intake of carcinogens/mutagens, also known as nitrosamines/NDSRIs in the context of polymedication/polycontamination in polymorbid patients. Until recently, the favoured and universally accepted thesis by the scientific community that polymorbidity determines the risk of developing cancer has been shown to be weakly substantiated and superseded by the more modern notion that: it is the polycontamination with carcinogens in the context of concomitant medication/ polymorbidity that determines to a large extent the risk of developing heterogeneous cancers, including skin cancer: keratinocytic and melanocytic. The FDA is the organization that first pulled back the curtain on the backstage back in 2018 on this topic. It was not until 2023 that the FDA again catalogued over 250 drugs that are affected by contamination with carcinogens/mutagens/NDSRIs having varying carcinogenic potencies graded between 1 to 5. The expectations of clinicians and patients globally at the moment remain hopeful that the diplomatic recommendations of regulators will soon be replaced by more restrictive regimes and sanctions. The reason for the need to clarify this issue quickly is due to the following circumstances: 1) The reassuring calls and analyses of the regulators that the minimum intake of carcinogens ( nitrosamines or intake within reference values) , could not become a threat to the health of patients even after 70 years of intake, appear to be rather inconsistent; 2) Lack of any official data on any drug batch that has at least been declared by the FDA/EMA (if declared at all) as potentially contaminated; 3) Another not insignificant reason is that a number of scientific publications are indicative of exactly the opposite: short-term concomitant intake of polycontaminated drugs leads to shortterm cancer development while shortening cumulative survival and quality of life for those affected. Only the transparency of the results of checks carried out on the presence of carcinogens in drug batches can guarantee peace of mind, and this in turn can be guaranteed by the regulatory authorities. 4) In parallel, the number of clinical data indicating an association between the intake of potentially nitrosaminecontaminated drugs (mainly for high blood pressure, but not only) and - in particular - keratinocytic and/or melanocytic skin cancer is growing avalanche-like. The dramatic increase in skin cancer in general/ worldwide is in absolute contradiction to the continuous explanations that the most important factor in the generation of skin cancer is ultraviolet light and sunburn: the incidence of skin cancer is increasing despite the widespread intensive use of sunscreen protection creams, the lack of any sun exposure in certaingroups of patients, and its occurrence in areas not exposed to solar radiation. It follows only that solar radiation is not the only and perhaps not the most important factor determining the occurrence and progression of skin cancer. We report another concomitant intake of potentially nitrosamine contaminated blood pressure medications: bisoprolol and furosemide, taken over a period of 7 years that resulted in the concurrent occurrence of a medium-thickness cutaneous melanoma and 2 basal cell carcinomas. Successful surgical treatment of the tumors was performed, and the role of concurrent administration of ˝hypothetical˝ class 4 carcinogens within the framework of polymedication, polycontamination, and polymorbidity is discussed.
... The year 2023 should definitely go down as a memorable one in terms of the FDA update/regulation on 1) the 250 drugs originally announced as potentially/actually contaminated with nitrosamines/NDSRIs/potent carcinogens , and 2) the identification of the five classes of carcinogens (according to their potency) that could be identified as contamination in the drugs themselves [1]. This is in effect a kind of self-recognition , but also a telling example that polycontamination worldwide is/ could be of ʺmonstrous proportionsʺ and that the intake/problem of contaminated drugs in polymorbid patients could hardly be limited or overcome [2,3]. ...
... Another official message from the regulatory authorities concerning mutagen/carcinogen contamination is that nitrosamines do not cause cancer if taken for prolonged periods and in certain doses. However, regulatory bodies do not thematize the issue of carcinogen intake within the framework of polymedication and polycontamination [2][3][4]? ...
... It is interesting how nitrosamines in cigarettes have been identified as carcinogenic to the human race in terms of lung cancer, for example [16], nitrosamines in food have been identified as carcinogenic in terms of the development of gastrointestinal or urogenital forms of cancer [17,18], but nitrosamines in medicines were not dangerous and should not be feared within their intake ? Although this intake is indicative of the development of melanomas and keratinocytic forms of cancer [2,3,4], but not only. It remains an open question: are these compounds in practice analogous to completely overlapping in structure and mechanism of action ? ...
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The purposeful oblivion of the objective truth, the disregard of scientific reality, the denial of the contributions and successes of surrounding researchers, the substitution of priorities in clinical routine and the unwillingness to reason in the right direction often lead to disastrous consequences in the field of public health. Controlled projects almost never lead to a significant contribution or breakthrough in medicine that will be remembered by future generations. Another illustrative example in this regard is the link shared above to the saga of the worldwide cancer pandemic and its possible real cause: the contamination of drugs with nitrosamines/NDSRIs. The carcinogenic action of nitrosamines in rats under experimental conditions was demonstrated as early as the early 1960s (1954) by Barnes and Magee. The series of subsequent experiments in their numerous research studies was strongly indicative of a pathogenetic role of nitrosamines / dimethylnitrosamine / in the development of liver cancer and kidney cancer. Starting from the fact that contact with nitrosamines is of primary importance for the development of tumours in animals, there is practically no circumstance that would lead us to believe that the intake of the same mutagens in man would have a different carcinogenic effect from that already known to us (as was found under experimental conditions as early as 1954, but in animals). On the contrary, to this day the incidence of cancer is increasing every year and, according to global statistics, it is projected to increase by nearly 50% or 18 million new cases by 2040. The intake of (un)identified nitrosamines found in drugs as contaminants is increasing analogously to the shared breakneck cancer incidence. In addition to the number of identified carcinogens or NDSRIs , the number of affected drug classes is also progressively growing and in mid-2023 this number amounts to over 250 drugs according to the official data of the FDA bulletin of 08.04.2023. In practice, the population/patients have been in a continuous, still ongoing, multicentric prospective study since 1954. The parameters of the ˝experiment˝ are probably pre-set, crystallizing gradually over time and imposed forcefully in the form of hypnotic suggestions and directives by regulators. Encouragingly , the results of the prospective study are also available, are not one-sided and have been published in dozens of international journals as well as in part in the well-known Cancer Journal of the clinicians / Impact factor 254,7. The bad news is that in most of these observations and results, there is no correlation of what is shared between, say, 1) mandatory alternative-free intake of mutagen-contaminated drugs and 2) the breakneck development of heterogeneous cancers/including melanomas, and the scientific vision of the studies is currently rather one-sided. Cancer incidence is skyrocketing (according to Globocan/ Cancer Journal for the Clinicians), and not a single worldwide study has commented on its potential link to actual contamination of the most commonly used drugs worldwide with nitrosamines/ NDSRIs. For the past 5 years, the team of the Bulgarian Society of Dermatological Surgery has been committed to formalizing the final results of these prospective nationwide observational studies and providing full transparency on the relationship between the intake of actual/potential nitrosamine-contaminated drugs and the development of skin cancer. Over 95% of newly reported skin cancers during this period (2016-2023) were associated with prior intake of drugs listed in the 2023 FDA as potentially nitrosamine/NDSRIs contaminated or carcinogens. Melanoma is one of the most significant patterns of tumor arising after contact of the human body with nitrosamines. Whether the drugs affected by the contamination are from the group of sartans, beta blockers, hydrochlorothiazide, calcium antagonists, ACE inhibitors or antidepressants- the ultimate side effect remains the same and is known to the scientific community as or by the frightening and loud name : melanoma. We report the occurrence of another case of nevus associated cutaneous melanoma and multiple dysplastic nevi after taking the antidepressant Sertraline. A drug declared according to the official FDA bulletin of 08.04.2023 as potentially contaminated with class 2 nitrosamines/ NDSRIs: having similar to completely identical carcinogenic potency as that of NDMA and NNK. Or reciprocal to that in valsartan, irbesartan, olmesartan, repeatedly described already as possible melanoma inducers. According to the literature search, this is also the first case in the world of Sertraline-induced nevus associated cutaneous melanoma, and we share the view/ thesis that the real inducer of the tumor is in fact the impurities in the medication in the form of contaminants or nitrosamines: the so-called NDSRIs. The nitrosogenesis of skin cancer is a more than significant concept that has been cleverly concealed by the scientific community until recently. The reason for this concealment could be sought in the paramount importance or central role that the nitrosogenesis occupies at the base of the ʺpyramidʺ guaranteeing billions of dollars of monthly revenue to the regulators of globalism.
... The occurrence of cutaneous tumours in areas exposed to solar radiation should not exclude nitrosamines in drugs as one of the most potent photo-carcinogens for the development of cutaneous melanomas, for example. The reason therefore is that certain nitrosamines appear to be at the same time potent photo-carcinogens that exert part of their genotoxic action after exposure to UVA radiation (similar to n-nitrosomorpholine) [13,14]. ...
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Onco-pharmacogenesis or pharmaco-oncogenesis of skin cancer is a concept , which could also be considered as an ʺend productʺ of drug-mediated Nitrosogenesis or of the permissive regime for carcinogens to be (un)controlled released in drugs. Their controlled distribution remains until 2025 as a forced and non-alternative and there is no indication of any possibility to introduce a full elimination regime against the already mentioned carcinogenic availability. There are three main worrying facts that determine the need for these elimination regimes: 1) the clinicopathological correlations concerning the intake of a heterogeneous class of drugs and the subsequent development of relatively homogeneous tumours/ such as melanoma, 2) the recently proven mutagenic/ carcinogenic action of certain nitrosamines, but this time directly on human DNA, and 3) the fact that some of the nitrosamines are potent photocarcinogens that exert their genotoxic effects only after irradiation with UVA/ also recently proven/. In addition to the rhetoric mentioned above, there is also an overlap in mutational patterns between the genes previously generally accepted to affect melanomas - p53 / RAS oncogenes , with those identified as target genes, but being affected ʺmutationallyʺ, by certain nitrosamines. The processes of photocarcinogenesis, nitrosogenesis and oncopharmacogenesis of skin cancer are inextricably linked and should not be considered and analysed unilaterally or in a semi-invasive manner. Cataloguing the type of nitrosamines and their precise concentration on drug leaflets and prescription/official websites with permanent access to clinicians and end-users remains the only safe and effective weapon in the fight against (un)controlled contamination. The pharmaceutical industry and regulators remain the creators, the ʻparentsʼ of onco-pharmacogenesis, nitrosogenesis, and therefore the processes involved in the generation and progression of skin cancer. The impossibility of establishing elimination regimes for certain mutagens and/or carcinogens already proven to be present in medicines remains a mystery. In practice, end consumers find themselves in a state of enforced tolerance of certain genotoxic substances that are not even declared as available. Clinicians in the face of dermatologists/ dermatological surgeons remain the analysers and identifiers of these globalization processes. Once again, we present a patient who took the antiarrhythmic (nitroso-) drug propafenone and developed a relatively shortterm nodular melanoma with a subsequent fatal outcome. Wecomment on the role of drug-mediated nitrosogenesis and its relationship to photocarcinogenesis and onco-pharmacogenesis.
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The rapid reversal of the direction of thought, of the general attitude, focus and vision on a problem or task, is not new and has been known since biblical times, the Middle Ages or the recent past, but in various forms, such as : ˝The King is dead, long live the King!˝ It is for this reason that abrupt shifts of perception and behaviour or receptor sensitivity in a cell or tissue should not be seen as unusual for the human race either. Similarly, the moral and ethical behavior of the scientific community at the moment has suddenly announced an abrupt change in its outlook, interpretation, and interpretive attitudes-namely: it had another point of view concerning the pathogenesis of skin cancer in general (but so also for prostate cancer, lymphomas, etc.). And the reason for this was the medication intake for high blood pressure. On the intake of the pure medications. Also defined as cancer associative pathogenetic intake. This change, or total metamorphosis, concerning the academic insight, growth, and awareness, is occurring massively and universally only in 2024, linking thiazide diuretic use (according to the most recent German study) to the occurrence of at least 4 heterogeneous forms of skin cancer: basal cell carcinomas, squamous cell carcinomas, atypical fibroxanthoma, and dermal pleomorphic sarcoma. The understanding turns out to be even quite contagious˝, encompassing in parallel an American study (published in the form of a meta-analysis/ 2024), which announces that there is a change of everything mentioned so far as understanding (or concerning Oncopharmacogenesis) and there is a significant association between the intake of most of the known worldwide antihypertensive drugs and the occurrence of keratinocytic tumors and melanomas subsequently. A third study, again by an American collective (2024), linked the intake of photosensitizing drugs in postmenopausal women, again with the development of keratinocytic tumors and melanomas, and found a definite association with the patients' exposure to solar radiation as well (photocarcinogenesis/nitroso-photocarcinogenesis?). And calcium antagonists are associated once again (2024) with the potential generation of prostate cancer, while renin angiotensin antagonists: rather with a lower risk or better prognosis of patients, however, already developed this type of tumor. But let us note that this type of carcinoma occurs within the already mentioned antihypertensive medication , which has been available for years (on sartans or on calcium antagonists) before the tumor even arises! And whether the prognosis of patients is better afterwards depends rather on other factors. Interpretation of clinical as well as certain prognostic data is and remains in practice a play on words or refraction through a particular (different) mental, ideological or ˝light prism˝. But the most general thesis is and remains the following: the intake of these two classes of medication (sartans and calcium antagonists) is followed by the subsequent occurrence of prostate cancer, although this is not clearly expressed in any line of the referenced work. Interesting how even the academic community in Taiwan, only now, in 2024, is ˝suddenly impressed˝ that taking antihypertensives/ and diuretics during pregnancy is associated with a rather high, significantly associated risk of developing acute lymphocytic lymphoma and non-Hodgkin's lymphoma in newborns. Refracting all the mentioned scientific information through the prism of Oncopharmacogenesis and drug-initiated Nitrosogenesis, the following could be shared: it is unlikely that these follow-ups (formalized in 2024) are random, episodic and manipulated. But everything formalized so far finds its reasonable explanation in the following: 1) there is no way that a single drug in the form of a pure/active substance can lead to the development of heterogeneous forms of cancer: be it skin, prostate, blood, lymph gland or a number of others. These drugs are described by regulators as containingheterogeneous nitrosamines/carcinogens or mutagens, each one individually or in combination, capable of inducing heterogeneous cancers! And2) There is no way that in Germany , France, America and Bulgaria for example, the same tumours can be registered after taking the same drugsand this not be catalogued as a carcinogenic side effect for years. Regardless (or even dependent) of whether it is caused by the contaminant inthe form of a particular nitrosamine or the active ingredient, the generic. And 3): the unifier in these publications (concerning cancer) remains tobe the one and only or rather: the drug related Nitrosocontamination, the Oncopharmacogenesis/ Pharmacooncogenesis. Or the contaminationwith a heterogeneous/monomorphic type of carcinogens in the form of nitrosamines and their derivatives, which remain, however, completelyuncommented as a cause of cancer and melanomas in particular, and that too, and very unfortunately, in none of the international publicationspresented.Nitrosamines could also be considered as bicarcinogens or polycarcinogens. A typical example therefore remains NDMA: it activates RAS oncogenesbefore its metabolism, and its metabolites after metabolisation in the liver , are in fact other, radically different mutagens. From another pointof view, contamination of certain preparations is possible with up to several nitrosamines or NDSRIS at the same time (in the context of mono orpolycontamination of one or more drugs).Precisely because of the above-shared facts, the association between the intake of a particular contaminated antihypertensive drug and thesubsequent development of melanoma or other cancers does not require such in-depth analyses or future, prospective follow-up. Polycarcinogenicintake could also lead to the development of melanomas , even if this intake is not formally indicated on drug packaging worldwide. It is this lack offormalisation that casts serious shadows of doubt over the pure substance and could prove to be a subsequent or relatively short-term deterrent tothe spread of even uncontainted drug production and the resulting global drug shortage. The labelling of the Nitroso-component and its completeelimination afterwards, remains the only guarantee for : 1) the protection of the health of patients worldwide , 2) the guarantee of their legal rightto be informed of what products they consume as final consumers and 3) the guarantee of the survival of companies in the conditions of reasonableand fair competition and not on the basis of a hidden distribution of nitrosamines in medicines ensuring 3. 1) the development of melanomas (butalso a high incidence of cancer in general) but also 3.2) government subsidies in the billions by law. Crossing this ̋devil’s circle ̋ would ensure that the ̋much desired progress ̋ is achieved: a rapid and explainable decrease in cancer incidence in general, but also in melanoma incidence in particular.In this context, we report on another or next two patients who were taking a particular antihypertensive medication and developed melanomas againsubsequently. In patient 1 we discuss the role of beta blockers in the face of bisoprolol and the subsequent development of cutaneous melanomas,and discuss the weakness/manipulative aspect of certain international data on the subject: such as a protective effect of beta blockers in melanomas,for example, which does not exist , but is rather attributable. In the second patient described, a nevus associated melanoma developed on thebasis of multimedication with perindopril, amlodipine and moxonidine. Modern scenarios of cancer generation in the context of Nitrosogenesis,Oncopharmacogenesis and Nitroso-photocarcinogenesis are commented. Clearly defined new concepts in medicine would be able to rewrite soonthe history and textbooks concerning skin cancer and melanoma in particular. The vision of new horizons, however, requires a rapid rethinking andimposition of new concepts and standards based on a new perspective rather than on lobbyistic, inadequate in action and design coercive regimensfor universal tolerance of carcinogens in the most commonly distributed antihypertensive (but no only) drugs worldwide. The scientific worldviewand insights remain, to date, the only guiding but also saving light in that direction.
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Although the problem with nitrosamines and their connection to the generation of skin cancer deepens, it is also thoroughly, carefully, and obligingly neglected. The probable reason for this is in all likelihood the lack of a solution or way out of this situation at the regulatory level. There is almost no sartan (on the European market/certain countries) after taking which the development of single or multiple melanomas, as well as melanomas in combination with single/multiple keratinocyte tumors, is not observed. But also, skin tumors (again melanomas) in combination with up to two other tumors - simultaneously or subsequently. These cases are immediately reported to the regional regulatory units, but unfortunately to no avail. Valsartan, irbesartan, olmesartan, and now candesartan is the main "suspect medications" for the development of melanomas, regardless of the dilemma: 1) whether the available nitrosamine remains responsible (for melanoma) as a mono/poly-contaminant (as availability or at a certain dose) or 2) is the generic substance itself also partly to blame? The literature data on the subject are contradictory, but does not exclude the involvement of any of these units in the generation and progression of melanomas. The lack of official results of possible checks for the presence (of nitrosamines) after the side effect reports were submitted to regulatory bodies further deepened the doubts of the clinicians, supporting the possible pathogenetic role of not only nitrosamines as a key link regarding the development of skin cancer. In practice, permissive regimes for the availability of carcinogens/mutagens in minimum permissible amounts, have been established? It is unclear whether this should be interpreted as a powerlessness of the regulatory authorities in the face of powerful pharmaceutical concerns? Or is it rather a lull before the start of general regulatory changes and a forthcoming "shifting of the layers"? The paradox also arises from the fact that many contaminated batches are quickly, quietly withdrawn from the market, despite being declared harmless or dangerous only for animals. We report on a patient who developed thin melanoma and neighbouring melanoma in situ after receiving candesartan, treated via one step melanoma surgery within one surgical session with a complete surgical margin of 2 cm. In parallel with the mentioned, a dysplastic nevus was observed clinically and confirmed dermatoscopically in the area of left scapula, for which surgical treatment is planned. Based on the currently available literature data, a thorough analysis of the role of nitrosamines, as a possible powerful pathogenetic factor for the occurrence and progression of melanomas, was made. The possible role of the generic substance as a cofactor in the carcinogenesis of skin cancer is also discussed.
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Contamination of certain drugs and foods with one of the most potent carcinogens/mutagens- nitrosamines, remains to be an issue and unresolved at present. The increased contamination of these mutagens in the most commonly used drugs in the human population doesn't ceases to baffle clinicians, critics, public scholars, and analysts of the nitrosamine saga. The introduction of permissive determinations of the presence of carcinogens in drugs only reinforces doubts about the powerlessness of regulatory authorities in the face of the influence of powerful pharmaceutical cartels. The FDA's encouraging promises of 2018 for strict control of carcinogens in sartans seems to have been permanently forgotten? By 2021, it was unthinkable that these carcinogens would be present in blood drugs and affected batches were immediately removed. Following alert checks confirming their post-existence in diabetes drugs, anti-smoking drugs, a number of antibiotics, ACE inhibitors, Sartans, thiazide diuretics, ranitidine, but probably a number of others, the decision has been taken to give the green light to their permissible availability. An availability that in all likelihood has the flavour of death. A "flavour" that has been confirmed in hundreds of international publications. Or in data from scientific papers submitted to regulatory regional units for verification and which remain sadly silent to this day. The "silent confirmation" and the lack of any adequate response in favour of public health are a sufficient further indicator of the attitude and position of the regulatory authorities. A position that should be changed. Starting from the mentioned facts and the data announced already in 2016/2017 of all-American data shared originally in American scientific journals, using their statistical estimates, we present the first case in the world literature of nodular melanoma and basal cell carcinoma occurring after taking perindopril. This intake turns out to be confirmatory one with respect to the statistics presented by Beatrice Nardone dating back to 2017. The potential pro-carcinogenic effects of both nitrosamines and the generic substance of perindopril are discussed.
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The pathogenesis of keratinocytic skin cancer has been well-studied over the years, with a main focus on the influence of UV radiation and the subsequent changes in the genome regulator p53, which affects the cell cycle and the programmed cell death, apoptosis. Alarming and relatively new trend is the link between nitrosamines in blood pressure medications (but not only) and the development of both melanocytic and keratinocytic skin tumors. In the recent past, high concentrations (above the so-called daily acceptable intake dose) of nitrosamines in ACE inhibitors and sartans became the reason for some of these medications to be officially withdrawn from the drug market. As of now, and according to the lawsuits filed, contamination with even or just one nitrosamine could be the cause of lawsuits for between 5 to 10 forms of cancer overall. Single case reports, but also large-scale retrospective international studies, find a connection between the intake of possibly nitrosamine contaminated ACE inhibitors/sartans with the subsequent development of basal cell carcinomas. The same studies also found a serious risk of developing melanomas and squamous cell carcinomas after taking ACE inhibitors, thiazide diuretics and sartans. This, in turn, leads clinicians to ponder the following dilemma: Is it possible that the key pathogenetic link concerning the development of skin cancer is due to their radically different mechanism of action (ACEs/ARBs/Thiazides)? Or, more likely, in all three antihypertensive drug classes, such as sartans, ACE inhibitors, and thiazide diuretics, there is another cancer-causing contaminant, the so-called nitrosamines? Systemic intake of potentially nitrosamine-contaminated sartans and ACE inhibitors would logically lead to the generation of relatively uniform skin tumors. Proceeding precisely from this thesis, we present two non-related cases of metatypical basal cell carcinomas in the nasal area, which occurred during the administration of ACE inhibitors/angiotensin receptor blockers and were successfully treated by transpositional reconstructive flap - bilobed flap. Possible contamination with nitrosamines as a pathogenetically significant factor is discussed. Similar articles
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Nitrosamines as contaminants in a wide variety of drugs are also found to be one of the most likely causes of skin cancer. A detailed analysis of this contamination could in the near future solve to a large extent the puzzle of carcinogenesis concerning the keratinocytic forms of cancer and melanoma. But also, probably cancer in general. Over 80% of skin cancer is due to acquired mutations, and nitrosamines, which are contained as contamination in certain batches of the most commonly distributed drugs worldwide (such as sartans, ACE inhibitors, ranitidine, metformin, hydrochlorothiazide, rifampicin, and a number of others.) are considered among the most powerful external mutagens, carcinogens. Carcinogens that until 2021 were not supposed to be present in medicines and carcinogens for which it was subsequently decided to create a regulatory regime for permissible availability. Regardless of whether these contaminants are applied within the so-called daily acceptable intake dose or many times above it, the problem with the availability of nitrosamines continues to be present. It is also caused by the lack of reflection of the concentration of the corresponding nitrosamine in a certain drug. Thus, it is impossible to calculate the ˝permissible daily intake of the total number of mutagens and their concentration based on polymedication˝. In practice, drug manufacturers distribute nitrosamines in parallel with drugs, although they are not listed as a component of the product but are identified and allowed as contamination or substances with permissible availability by the EMA/FDA. From another point of view, the fact that is not commented on is also of interest, namely that not all batches are affected by this contamination. This suggests that the contamination may have been controlled, since in a manufacturing error the contamination should be widespread. The registration of the potential contamination of a heterogeneous type of medicinal products on the European market to the executive agencies for drug control in certain geographical areas has remained for years without any answer and opens a number of questions. The problem with ACE inhibitors is similar to that with sartans, hydrochlorothiazide, metformin, and ranitidine. The ˝special impression˝ of the clinicians is determined by the fact that the patterns of manifestation of the skin tumors during the administration of a heterogeneous class of medications are similar to completely identical. From this it could be concluded that the unifying factor between the pattern of occurrence could not be based on the action of the main substance of each drug class, since it remains to be radically different. The unifying link remains the sole and only contamination or the permissible already availability of a new ingredient known as nitrosamines. We present cases of multiple basal cell carcinomas and dysplastic nevi following enalapril and perindopril administration. The role of potential contamination of ACE inhibitors with nitrosamines for the development of skin cancer is discussed.
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