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Georgian Medical News Mar 2023Contamination 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...
А FLAVOUR OF DEATH: PERINDOPRIL INDUCED THICK MELANOMA AND BCC OF THE BACK. POTENTIAL ROLE OF THE GENERIC SUBSTANCE OR/-AND POSSIBLE NITROSAMINE CONTAMINATION AS SKIN CANCER KEY TRIGGERING FACTORS.
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.
Topics: Humans; Nitrosamines; Perindopril; Angiotensin II Type 1 Receptor Blockers; Skin Neoplasms; Melanoma; Carcinogens; Mutagens; Flavoring Agents
PubMed: 37166894
DOI: No ID Found -
Toxicology and Applied Pharmacology Jun 2023According to some clinical observations, the use of angiotensin-converting enzyme inhibitors (ACEI) may be associated with an increased risk of cancer. The aim of the...
According to some clinical observations, the use of angiotensin-converting enzyme inhibitors (ACEI) may be associated with an increased risk of cancer. The aim of the present study was to screen for the potential carcinogenicity, mutagenicity and genotoxicity of these drugs using in silico methodology. Delapril, enalapril, imidapril, lisinopril, moexipril, perindopril, ramipril, trandolapril, spirapril were thereby analyzed. In parallel, the corresponding degradation impurities, the diketopiperazine (DKP) derivatives, were also investigated. (Q)SAR computer software (VEGA-GUI and Lazar), available in the public domain, was employed. The obtained predictions suggested that none of the compounds tested (from the group of ACE-Is and DKPs) was mutagenic. Moreover, none of the ACE-Is was carcinogenic. The reliability of these predictions was high to moderate. In contrast, in the DKP group, ramipril-DKP and trandolapril-DKP were found to be potentially carcinogenic, but the reliability of this prediction was low. As for the genotoxicity screening, all compounds tested (ACE-I and DKP) were predicted to be active and genotoxic, with moexipril, ramipril, spirapril, and all DKP derivatives within the highest risk group. They were prioritized for experimental verification studies to confirm or exclude their toxic activity. On the other hand, the lowest risk of carcinogenicity was assigned to imidapril and its DKP. Then, a follow-up in vitro micronucleus assay for ramipril was performed. It showed that this drug was genotoxic via aneugenic activity, but only at concentrations exceeding real-life levels. At concentrations found in human blood after standard dose, ramipril was not genotoxic in vitro. Therefore, ramipril was considered safe for human use with a standard dosing regimen. The other compounds of concern (spirapril, moexipril and all DKP derivatives) should be subjected to analogous in vitro studies. We also concluded that the adopted in silico software was applicable for ACE-I toxicity prediction.
Topics: Humans; Angiotensin-Converting Enzyme Inhibitors; Carcinogens; Reproducibility of Results; Ramipril; Tetrahydroisoquinolines
PubMed: 37149094
DOI: 10.1016/j.taap.2023.116541 -
Georgian Medical News Feb 2023Nitrosamines 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...
MULTIPLE BCCS AND DYSPLASTIC NEVI AFTER ACE INHIBITORS (ENALAPRIL/PERINDOPRIL): THE ROLE OF NITROSAMINE CONTAMINATION/AVAILABILITY AS SUBSTANTIAL SKIN CANCER TRIGGERING FACTOR.
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.
Topics: Humans; Nitrosamines; Angiotensin-Converting Enzyme Inhibitors; Perindopril; Enalapril; Angiotensin II Type 1 Receptor Blockers; Dysplastic Nevus Syndrome; Ranitidine; Carcinogens; Pharmaceutical Preparations; Skin Neoplasms; Hydrochlorothiazide; Mutagens
PubMed: 37042596
DOI: No ID Found -
Advances in Therapy Jun 2023This study assessed the real-life effectiveness of a single-pill combination (SPC) of bisoprolol/perindopril for controlling blood pressure (BP) and symptoms of angina... (Observational Study)
Observational Study
Effectiveness and Tolerability of Bisoprolol/Perindopril Single-Pill Combination in Patients with Arterial Hypertension and a History of Myocardial Infarction: The PRIDE Observational Study.
INTRODUCTION
This study assessed the real-life effectiveness of a single-pill combination (SPC) of bisoprolol/perindopril for controlling blood pressure (BP) and symptoms of angina in patients with hypertension and a history of myocardial infarction (MI).
METHODS
Eligible patients with arterial hypertension and a history of MI were aged 18-79 years and had initiated bisoprolol/perindopril SPC within 3 months of study enrollment as part of routine Russian clinical practice. The primary endpoint was mean change in systolic and diastolic BP (SBP/DBP) at week 12 compared with baseline (data collected retrospectively). Secondary endpoints were assessed at weeks 4 and 12 and included mean change in resting heart rate (HR), proportion of patients reaching target level of resting HR, antianginal effectiveness of the SPC, and proportion of patients reaching target BP levels.
RESULTS
A total of 504 patients were enrolled, of whom 481 comprised the full analysis set (mean age 61.4 ± 8.9 years, 68% men). Mean baseline SBP/DBP and HR values were 148.9 ± 16.8/87.7 ± 11.0 mmHg and 77.4 ± 10.5 bpm, respectively. Mean durations of hypertension and CAD were 12.8 ± 8.4 and 6.1 ± 6.3 years, respectively, and time since MI was 3.8 ± 5.3 years. At week 12, SBP/DBP had decreased by 24.9/12.2 mmHg (P < 0.001 vs baseline). Target BP (< 140/90 mmHg) was achieved by 69.8% and 95.9% of patients at weeks 4 and 12, respectively, and target HR (55-60 bpm) by 17.3% and 34.5% at weeks 4 and 12 versus 3.1% at baseline (P < 0.001). Reductions in angina attacks, nitrate consumption, and improvements in HR were statistically significant. Treatment was well tolerated.
CONCLUSION
Treatment of symptomatic patients with CAD, hypertension, and a history of MI with a bisoprolol/perindopril SPC was associated with significant decreases in SBP/DBP and a high proportion of patients achieving BP treatment goals. This was accompanied by improvements in angina symptoms and reductions in HR in a broad patient population representative of those seen in everyday clinical practice.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier NCT04656847.
Topics: Male; Humans; Middle Aged; Aged; Female; Perindopril; Bisoprolol; Antihypertensive Agents; Retrospective Studies; Hypertension; Blood Pressure; Myocardial Infarction; Angina Pectoris; Drug Combinations; Treatment Outcome
PubMed: 37029871
DOI: 10.1007/s12325-023-02462-9 -
Biomedicine & Pharmacotherapy =... May 2023This study investigated the reno-protective effects of a highly selective ATR agonist peptide, β-ProAng III in a mouse model of acute kidney injury (AKI).
BACKGROUND AND PURPOSE
This study investigated the reno-protective effects of a highly selective ATR agonist peptide, β-ProAng III in a mouse model of acute kidney injury (AKI).
METHODS
C57BL/6 J mice underwent either sham surgery or unilateral kidney ischemia-reperfusion injury (IRI) for 40 min. IRI mice were treated with either β-ProAng III or perindopril and at 7 days post-surgery the kidneys analysed for histopathology and the development of fibrosis and matrix metalloproteinase (MMP)-2 and -9 activity. The association of the therapeutic effects of β-ProAng III with macrophage number and phenotype was determined in vivo and in vitro.
KEY RESULTS
Decreased kidney tubular injury, interstitial matrix expansion and reduced interstitial immune cell infiltration in IRI mice receiving β-ProAng III treatment was observed at day 7, compared to IRI mice without treatment. This correlated to reduced collagen accumulation and MMP-2 activity in IRI mice following β-ProAng III treatment. FACS analysis showed a reduced number and proportion of CD45CD11bF4/80 macrophages in IRI kidneys in response to β-ProAng III, correlating with a significant increase in M2 macrophage markers and decreased M1 markers at day 3 and 7 post-IR injury, respectively. In vitro analysis of cultured THP-1 cells showed that β-ProAng III attenuated lipopolysaccharide (LPS)-induced tumour necrosis factor-α (TNF-α) and interleukin (IL)- 6 production but increased IL-10 secretion, compared to LPS alone.
CONCLUSION
Administration of β-ProAng III via mini-pump improved kidney structure and reduced interstitial collagen accumulation, in parallel with an alteration of macrophage phenotype and anti-inflammatory cytokine release, therefore mitigating the downstream progression of ischemic AKI.
Topics: Mice; Animals; Lipopolysaccharides; Mice, Inbred C57BL; Kidney; Acute Kidney Injury; Collagen; Reperfusion Injury; Reperfusion
PubMed: 36948137
DOI: 10.1016/j.biopha.2023.114556 -
World Journal of Clinical Cases Mar 2023Secondary hypertension is a relatively rare condition most commonly caused by renovascular disease due to atherosclerotic vascular disease or fibromuscular dysplasia....
BACKGROUND
Secondary hypertension is a relatively rare condition most commonly caused by renovascular disease due to atherosclerotic vascular disease or fibromuscular dysplasia. Although accessory renal arteries are frequent, to date, only six cases of secondary hypertension determined by their existence have been reported.
CASE SUMMARY
We describe a case of a 39-year-old female who came to the emergency department with an urgent hypertensive crisis and hypertensive encephalopathy. Despite normal renal arteries, the computed tomography angiography revealed an inferior polar artery with 50% stenosis of its diameter. Conservative treatment with amlodipine, indapamide and perindopril was adopted, leading to blood pressure control within one month.
CONCLUSION
To the best of our knowledge, there are controversies regarding accessory renal arteries as a potential etiology for secondary hypertension, but the seven similar cases already described, along with the current case, could reinforce the necessity of more studies concerning this subject.
PubMed: 36926389
DOI: 10.12998/wjcc.v11.i7.1506 -
Frontiers in Pharmacology 2023Hypertension is a major risk factor for cardiovascular diseases and the leading cause of mortality worldwide. Despite the availability of antihypertensive drugs,...
Hypertension is a major risk factor for cardiovascular diseases and the leading cause of mortality worldwide. Despite the availability of antihypertensive drugs, alternative treatments are needed due to the adverse events associated with their use. Previous studies have shown that SABP, a combination of aqueous active metabolites of DSS, Sal-A, Sal-B and PAL, has a significant antihypertensive effect. However, the underlying mechanisms remain unknown. This study aimed to determine the effects of SABP on vascular inflammation, oxidative stress, and vascular remodeling in spontaneously hypertensive rats (SHRs). Additionally, the response of adventitial fibroblasts in SHRs to SABP treatment was also studied, including their proliferation, differentiation, and migration. SABP or perindopril (positive control) were administered intraperitoneally to SHRs, and systolic blood pressure was measured using a tail-cuff approach. The effects of SABP on oxidative stress, inflammation, and vascular remodeling were investigated by transmission electron microscopy, histochemical staining, and Western blot. Adventitial fibroblasts were isolated and cultured from the adventitia of thoracic aorta in SHR and WKY rats. CCK8 assay, wound healing method and immunostaining were used to observe the effect of SABP on fibroblasts proliferation, migration and transformation into myofibroblasts. Moreover, Western blot analysis was also performed to detect the proteins related to oxidative stress, inflammation and fibrosis in adventitial fibroblasts. SHRs displayed higher blood pressure with significant vascular remodeling compared to WKY rats. The thoracic aorta and adventitial fibroblasts of SHRs exhibited significant oxidative stress, inflammation and fibrosis. SABP treatment repressed oxidative stress, inflammatory reaction and vascular remodeling of thoracic aorta in SHR through the ROS/TLR4/NF-κB signaling pathway, and inhibited fibrosis of thoracic aorta. Additionally, SABP inhibited the proliferation and migration of adventitial fibroblasts and their transformation to myofibroblasts through the TGFβ/Smad3 signaling pathway. These findings suggest that SABP have potential as an alternative treatment for hypertension by ameliorating oxidative stress, inflammation and fibrosis. Further research is needed to fully understand the mechanisms underlying the effects of SABP.
PubMed: 36925635
DOI: 10.3389/fphar.2023.1093669 -
Heliyon Mar 2023The fixed-dose combination of Amlodipine Besylate (ADB) with Perindopril Tertbutylamine (PTBA) drug is used to treat patients with mild-to-moderate hypertension. In...
The fixed-dose combination of Amlodipine Besylate (ADB) with Perindopril Tertbutylamine (PTBA) drug is used to treat patients with mild-to-moderate hypertension. In recent times researchers are interested to find the efficient analytical method development and validation for the simultaneous determination of ADB and PTBA in a fixed-dose, film-coated tablet. Therefore, the current study was performed with a reverse-phase liquid chromatography method developed to simultaneously analyze ADB and PTBA in film-coated tablets as fixed-dose combinations. The linearity of the proposed method was calculated by preparing six different mixtures of both ADB and PTBA in the mobile phase. The concentration of both the analytes was analyzed at 56mg/100 mL to 84mg/100 mL and 32mg/100 mL to 48mg/100 mL, respectively. The ratio of acetonitrile and phosphate buffer was 35:65. The flow rate was adjusted to 1.5 ml per minute to reduce the retention time. The validation study was performed for the parameters specificity, linearity, precision, range, limit of detection, limit of quantification, accuracy/biasness, and robustness. The relative percentage standard deviation for Perindopril Tertbutyl amine was 0.148%, and for Amlodipine is 0.312%. These results show that the advanced analysis method for simultaneous analysis of fixed-dose is precise. The theoretical IR spectra were also calculated by Gaussian 9.2 by employing the B3LYP functional at density functional theory (DFT) level study. All these parameters studied in this work authenticate the effectiveness of the developed validation method and ensure its repeatability/reproducibility accordingly. To the best of our knowledge, this is the first time to develop a new fast, and easy method for simultaneous identification and quantification of ADB and PTBA by high-performance liquid chromatography (HPLC) with a time-efficient and cost-effective approach.
PubMed: 36923897
DOI: 10.1016/j.heliyon.2023.e14209 -
Bratislavske Lekarske Listy 2023We performed this meta-analysis determining the antihypertensive effect of telmisartan versus perindopril in patients with essential hypertension. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We performed this meta-analysis determining the antihypertensive effect of telmisartan versus perindopril in patients with essential hypertension.
BACKGROUND
The comparison of antihypertensive effects between telmisartan and perindopril were controversial.
METHODS
Pubmed, Web of Science, and Cochrane Central were searched for all published studies.
RESULTS
The antihypertensive effects were assessed in 753 patients included in 7 trials with a mean follow-up of 20 ± 16 weeks. There was no significant difference between telmisartan and perindopril in reduction of systolic blood pressure (SBP, weighted mean differences (WMD) 0.02 (95% confidence interval (CI), ‒2.78, 2.81) mm Hg, p > 0.05). The reduction of diastolic BP (DBP) treated with telmisartan was greater than perindopril in these patients (WMD ‒2.05 (95% CI, ‒2.60, ‒1.49) mm Hg, p < 0.001). Considering the effects of different doses on BP reduction, a sub-analysis was performed. The reduction of DBP treated with 40 mg/day telmisartan was greater than 4‒5 mg/day perindopril (WMD ‒2.18 (95% CI, ‒2.83, ‒1.53) mm Hg, p 0.05).
CONCLUSION
The reduction of DBP is greater treated with telmisartan than perindopril in patients with essential hypertension (Tab. 2, Fig. 4, Ref. 34). Text in PDF www.elis.sk Keywords: essential hypertension, blood pressure, telmisartan, perindopril, meta-analysis.
Topics: Humans; Antihypertensive Agents; Telmisartan; Perindopril; Benzimidazoles; Hypertension; Essential Hypertension
PubMed: 36876369
DOI: 10.4149/BLL_2023_058 -
European Journal of Pharmacology May 2023Activation of the renin-angiotensin system (RAS), by Angiotensin converting enzyme/Angiotensin II/Angiotensin receptor-1 (ACE/Ang II/AT1 R) axis elicits amyloid...
ACE2/ANG-(1-7)/Mas receptor axis activation prevents inflammation and improves cognitive functions in streptozotocin induced rat model of Alzheimer's disease-like phenotypes.
Activation of the renin-angiotensin system (RAS), by Angiotensin converting enzyme/Angiotensin II/Angiotensin receptor-1 (ACE/Ang II/AT1 R) axis elicits amyloid deposition and cognitive impairment. Furthermore, ACE2 induced release of Ang-(1-7) binds with the Mas receptor and autoinhibits ACE/Ang II/AT1 axis activation. Inhibition of ACE by perindopril has been reported to improve memory in preclinical settings. However, the functional significance and mechanism by which ACE2/Mas receptor regulate cognitive functions and amyloid pathology is not known. The present study is aimed to determine the role of ACE2/Ang-(1-7)/Mas receptor axis in STZ induced rat model of Alzheimer's disease (AD). We have used pharmacological, biochemical and behavioural approaches to identify the role of ACE2/Ang-(1-7)/Mas receptor axis activation on AD-like pathology in both in vitro and invivo models. STZ treatment enhances ROS formation, inflammation markers and NFκB/p65 levels which are associated with reduced ACE2/Mas receptor levels, acetylcholine activity and mitochondrial membrane potential in N2A cells. DIZE mediated ACE2/Ang-(1-7)/Mas receptor axis activation resulted in reduced ROS generation, astrogliosis, NFκB level and inflammatory molecules and improved mitochondrial functions along with Ca influx in STZ treated N2A cells. Interestingly, DIZE induced activation of ACE2/Mas receptor significantly restored acetylcholine levels and reduced amyloid-beta and phospho-tau deposition in cortex and hippocampus that resulted in improved cognitive function in STZ induced rat model of AD-like phenotypes. Our data indicate that ACE2/Mas receptor activation is sufficient to prevented cognitive impairment and progression of amyloid pathology in STZ induced rat model of AD-like phenotypes. These findings suggest the potential role of ACE2/Ang-(1-7)/Mas axis in AD pathophysiology by regulating inflammation cognitive functions.
Topics: Rats; Animals; Alzheimer Disease; Streptozocin; Angiotensin-Converting Enzyme 2; Reactive Oxygen Species; Acetylcholine; Peptidyl-Dipeptidase A; Cognition; Inflammation; Phenotype; Peptide Fragments; Angiotensin I; Receptors, G-Protein-Coupled; Angiotensin II
PubMed: 36871666
DOI: 10.1016/j.ejphar.2023.175623