Chronic mitochondrial dynamic-targeted therapy alleviates left ventricular dysfunction by reducing multiple programmed cell death in post-myocardial infarction rats.

Mitochondrial dysfunction and the activation of multiple programmed cell death (PCD) have been shown to aggravate the severity and mortality associated with the progression of myocardial infarction (MI). Although pharmacological modulation of mitochondrial dynamics, including treatment with the fusion promoter (M1) and the fission inhibitor (Mdivi-1), exerted cardioprotection against several cardiac complications, their roles in the post-MI model have never been investigated. Using a MI rat model instigated by permanent left-anterior descending (LAD) coronary artery occlusion, post-MI rats were randomly assigned to receive one of 4 treatments (n = 10/group): vehicle (DMSO 3%V/V), enalapril (10 mg/kg), Mdivi-1 (1.2 mg/kg) and M1 (2 mg/kg), while a control group of sham operated rats underwent surgery without LAD occlusion (n = 10). After 32-day treatment, cardiac and mitochondrial function, and histopathological morphology were investigated and molecular analysis was performed. Treatment with enalapril, Mdivi-1, and M1 significantly mitigated cardiac pathological remodeling, reduced myocardial injury, and improved left ventricular (LV) function in post-MI rats. Importantly, all interventions also attenuated mitochondrial dynamic imbalance and mitigated activation of apoptosis, necroptosis, and pyroptosis after MI. This investigation demonstrated for the first time that chronic mitochondrial dynamic-targeted therapy mitigated mitochondrial dysfunction and activation of PCD, leading to improved LV function in post-MI rats.

Pharmacogenetic markers of development of angioneurotic edema as a secondary side effect to enalapril in patients with essential arterial hypertension.

BACKGROUND: Angioneurotic edema is the most dangerous complication in angiotensin-converting enzyme inhibitors (ACEIs) therapy. Based on the current data, the clinical and genetic predictors of angioedema development are still understudied, which demonstrates the relevance of this study. OBJECTIVE: To reveal the pharmacogenetic predictors of the angioedema as a secondary side effect to enalapril in patients with essential arterial hypertension. METHODS: The study enrolled 111 subjects randomized into two groups: study group, patients with the angioedema as a secondary side effect to enalapril; and control group, patients without adverse drug reaction. All patients underwent pharmacogenetic testing. RESULTS: An association between the development of the angioneurotic edema and the genotypes AA rs2306283 of gene SLCO1B1, TT rs4459610 of gene ACE, and CC rs1799722 of gene BDKRB2 in patients was revealed. CONCLUSION: The findings justify further investigations of the revealed genetic predictors of angioedema with larger-size patient populations.

Captopril to Lisinopril Conversion in Pediatric Cardiothoracic Surgery Patients Less Than 7 Years of Age (RISE-7).

Hypertension after cardiothoracic surgery is common, often requiring pharmacologic management. The recommended first-line antihypertensives in pediatrics are angiotensin converting enzyme inhibitors. Captopril and enalapril are approved for infants and children; however, lisinopril is only approved for > 7 years of age. This study evaluated safety and efficacy of converting from captopril to lisinopril in patients utilizing a pre-defined conversion of 3 mg captopril to 1 mg lisinopril. This was a single center, retrospective study including patients less than 7 years of age admitted for cardiothoracic surgery who received both captopril and lisinopril from 01/01/2017 to 06/01/2022.The primary outcome was mean change in systolic blood pressure (SBP) from baseline for 72 h after conversion of captopril to lisinopril. A total of 99 patients were enrolled. There was a significant decrease in mean SBP (99.12 mmHg vs 94.86 mmHg; p = 0.007) with no difference in DBP (59.23 mmHg vs 61.95 mmHg; p = 0.07) after conversion to lisinopril. Of the 99 patients who were transitioned to lisinopril, 79 (80%) had controlled SBP, 20 (20%) remained hypertensive, 13 (13%) received an increase in their lisinopril dose, and 2 (2%) required an additional antihypertensive agent. There was a low overall rate of AKI (3%) and hyperkalemia (4%) respectively. This study demonstrates that utilizing lisinopril with a conversion rate of 3 mg of captopril to 1 mg of lisinopril was safe and effective for controlling hypertension in pediatric patients following cardiothoracic surgery.

Impact of a combination of pimobendan, furosemide, and enalapril on heart rate variability in naturally occurring, symptomatic, myxomatous mitral valve degeneration dogs.

BACKGROUND: Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. RESULTS: MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). CONCLUSIONS: It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.

NITROSOGENESIS OF SKIN CANCER: THE NITROSAMINE CONTAMINATION IN THE CALCIUM CHANNEL BLOCKERS (AMLODIPINE), BETA BLOCKERS (BISOPROLOL), SARTANS (VALSARTAN/LOSARTAN), ACE INHIBITORS (PERINDOPRIL/ENALAPRIL), TRICYCLIC ANTIDEPRESSANTS (MELITRACEN), SSRIS (PAROXETINE), SNRIS (VENLAFAXINE) AND METFORMIN: THE MOST PROBABLE EXPLANATION FOR THE RISING SKIN CANCER INCIDENCE.

The Nitrosogenesis of skin cancer is a newly introduced concept in medical science, the significance of which is yet to be the subject of detailed analyses and discussions. Contamination of the most commonly used drugs for systemic treatment worldwide (such as Angiotensin receptor II blockers/ARBs, ACE inhibitors, Beta blockers, Thiazide diuretics, Metformin, Ranitidine, Nizatidine, tricyclic antidepressants, anticoagulants/dabigatran, Rifampicin, calcium channel blockers, SSRIs/ selective serotonin reuptake inhibitors, Varenicline) is already a fact and is more than worrying but also indicative. It is "this relationship" that has been repeatedly described in the medical literature (initially) as an association, and subsequently now increasingly as a causal relationship, a pathogenetic relationship. Observational data from clinicians over the past year increasingly speak in favour of a pathogenetic link and associate every single drug declared as contaminated with the development of heterogeneous forms of skin cancer gradually and surely. New drugs are added monthly that have not yet been declared as actually/potentially contaminated but are probably known to regulatory authorities or are in the process of being clarified. In parallel, the number of nitrosamines identified as contaminants in medicines is growing. This should not be surprising to anyone: ˝You take 3 drugs contaminated with mutagens- you subsequently develop skin cancer˝. Polymorbidity and multimedication against the background of polycontamination with nitrosamines appears to be the most serious problem at present. While until recently polymorbidity was considered to be a key factor in carcinogenesis (generator, trigger, inducer), today this dogma should be re-examined or looked at from another, radically different angle: from the angle of polycontamination to multimedication within polymorbidity. It is this that could provide a good explanation for the pandemic concerning skin cancer, for example. The development of relatively identical patterns of manifestation of skin tumors after concomitant intake of drugs declared as contaminated (drugs from the classes already mentioned above/ with radically different mechanism of action) supports unequivocally the thesis that: the nitrosogenesis of skin cancer is an undeniable fact that should be studied in detail. Studied because it could be eliminated. The analysis presented within this scientific thesis concerns 4 polymorbid patients who developed skin tumors within the framework of the multimedication they were assigned. The concomitant intake of medications declared as contaminated (in the presented patients) led to the manifestation of single or multiple skin neoplasms that were successfully treated surgically. Once again, the importance of potential/actual contamination of beta blockers, ACE inhibitors, oral antidiabetic drugs, and sartans in the generation of 1) non-melanocytic forms of skin cancer, and 2) melanoma precursor lesions or so-called dysplastic moles is established and validated. The possible contamination with nitrosamines of 1) other types of tricyclic antidepressant- Melitracen; 2) antidepressant of the selective serotonin reuptake inhibitor (SSRI) class: Paroxetine; 3) antidepressant of the serotonin and noradrenaline reuptake inhibitor (SNRIs) class: Venlafaxine, as well as of the systemic anticoagulant: apixaban is highlighted for the first time in the world literature.

Hormetic effects of EGC and EGCG on CES1 activity and its rescue from oxidative stress in rat liver S9.

Carboxylesterase 1 (CES1) is a hydrolytic enzyme that plays an important role in the activation or deactivation of many therapeutic agents, thus affecting their pharmacokinetic and pharmacodynamic outcomes. Using rat liver S9 as an enzyme source and enalapril as a CES1 substrate, the present study examined effects of a number of flavonoids on the formation of enalaprilat (the active form of enalapril) produced by CES1-mediated hydrolysis. While a majority of flavonoids tested showed inhibition on CES1, an unexpected hormetic effect was observed for epigallocatechin (EGC) and epigallocatechin gallate (EGCG), i.e., stimulatory effect at low concentrations and enzyme inhibition at high concentrations. Further experiments revealed that oxidative stress caused by hydrogen peroxide, arachidonic acid plus iron, and oxidized low density lipoproteins (oxLOL) reduced CES1 activity in rat liver S9 and the loss of CES1 enzyme activity could be rescued largely by EGC or EGCG. In contrast, such effects were minimal in human liver S9, probably due to the presence of a higher ratio of reduced vs oxidized forms of glutathione. The above findings suggest that the polyphenolic nature of EGC or EGCG might be responsible for rescuing CES1 activity under oxidative stress. Because of the importance of CES1 in drug activation or deactivation and rat liver S9 as a versatile in vitro system used for drug metabolism studies and drug safety assessment, caution should be exercised to avoid potential biases for data interpretation and decision making when CES1 activity in rat liver S9 is evaluated with dependency on experimental conditions.

Pharmacogenetic predictors of development of secondary to enalapril dry cough in hypertensive patients.

OBJECTIVES: Development of the secondary to ACEI cough leads to discontinuation of the drugs of this group. Assessing the safety of the ACEIs with further development of customized approaches for their administration is a major scientific and practical problem. The objective of this study was to assess the association of the genetic markers with the development of the adverse drug reaction in the form of secondary to enalapril dry cough in the patients with essential arterial hypertension. METHODS: Study involved 113 patients with the secondary to enalapril cough and 104 patients without development of the secondary to enalapril adverse drug reaction. RESULTS: The patients carriers of the genotype AA rs2306283 of gene SLCO1B1 had 2-fold higher odds of developing the dry cough than those with the genotypes AG and GG (ОR=2.01, 95%CI=1.10-3.66, р=0.023). Similarly, the patients heterozygous for rs8176746 of gene АВО had 2.3-fold higher odds of developing the ADR in the form of dry cough than the carriers of the genotypes GG and TT (ОR=2.30, 95%CI=1.24-4.29, р=0.008). CONCLUSIONS: Statistically significant association between the development of the ADR in the form of secondary to enalapril dry cough and polymorphisms rs2306283 of gene SLCO1B1 and rs8176746 of gene ABO was revealed.

METATYPICAL BCCS OF THE NOSE TREATED SUCCESSFULLY VIA BILOBED TRANSPOSITION FLAP: NITROSAMINES IN ACES (ENALAPRIL), ARBS (LOSARTAN) AS POSSIBLE SKIN CANCER KEY TRIGGERING FACTOR.

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.

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.

MULTIPLE KERATINOCYTIC CANCERS AFTER ENALAPRIL/LOSARTAN INTAKE: POTENTIAL LINKS TO DRUG MEDIATED NITROSOGENESIS/CARCINOGENESIS: MELOLABIAL ADVANCED FLAP AND UNDERMINING SURGERY AS OPTIMAL THERAPEUTIC APPROACH.

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-year-old 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.

Preventing cardiotoxicity in patients with breast cancer and lymphoma: protocol for a multicentre randomised controlled trial (PROACT).

INTRODUCTION: Anthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin's lymphoma (NHL) receiving anthracycline-based chemotherapy. METHODS AND ANALYSIS: PROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects. ETHICS AND DISSEMINATION: A favourable opinion was given following research ethics committee review by West Midlands-Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03265574.

Effect of the Renin-Angiotensin System Inhibitors on Inflammatory Markers: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To synthesize more conclusive evidence on the anti-inflammatory effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). METHODS: PubMed, Scopus, and Embase were searched from inception until March 1, 2021. We included randomized controlled trials (RCTs) that assessed the effect of ACEIs or ARBs, compared with placebo, on any of the following markers: C-reactive protein (CRP), interleukin 6 (IL-6), or tumor necrosis factor α (TNF-α). Mean changes in the levels of these markers were pooled as a weighted mean difference (WMD) with a 95% CI. RESULTS: Thirty-two RCTs (n=3489 patients) were included in the final analysis. Overall pooled analysis suggested that ACEIs significantly reduced plasma levels of CRP (WMD, -0.54 [95% CI, -0.88 to -0.21]; P=.002; I2=96%), IL-6 (WMD, -0.84 [95% CI, -1.03 to -0.64]; P<.001; I2=0%), and TNF-α (WMD, -12.75 [95% CI, -17.20 to -8.29]; P<.001; I2=99%). Moreover, ARBs showed a significant reduction only in IL-6 (WMD, -1.34 [95% CI, -2.65 to -0.04]; P=.04; I2=85%) and did not significantly affect CRP (P=.15) or TNF-α (P=.97) levels. The lowering effect of ACEIs on CRP levels remained significant with enalapril (P=.006) and perindopril (P=.01) as well as with a treatment duration of less than 24 weeks (WMD, -0.67 [95% CI, -1.07 to -0.27]; P=.001; I2=94%) and in patients with coronary artery disease (WMD, -0.75 [95% CI, -1.17 to -0.33]; P<.001; I2=96%). CONCLUSION: Based on this meta-analysis, ACEIs showed a beneficial lowering effect on CRP, IL-6, and TNF-α, whereas ARBs were effective as a class in reduction of IL-6 only.

Reviewing the Modern Therapeutical Options and the Outcomes of Sacubitril/Valsartan in Heart Failure.

Sacubitril/valsartan (S/V) is a pharmaceutical strategy that increases natriuretic peptide levels by inhibiting neprilysin and regulating the renin-angiotensin-aldosterone pathway, blocking AT1 receptors. The data for this innovative medication are mainly based on the PARADIGM-HF study, which included heart failure with reduced ejection fraction (HFrEF)-diagnosed patients and indicated a major improvement in morbidity and mortality when S/V is administrated compared to enalapril. A large part of the observed favorable results is related to significant reverse cardiac remodeling confirmed in two prospective trials, PROVE-HF and EVALUATE-HF. Furthermore, according to a subgroup analysis from the PARAGON-HF research, S/V shows benefits in HFrEF and in many subjects having preserved ejection fraction (HFpEF), which indicated a decrease in HF hospitalizations among those with a left ventricular ejection fraction (LVEF) < 57%. This review examines the proven benefits of S/V and highlights continuing research in treating individuals with varied HF characteristics. The article analyses published data regarding both the safeness and efficacy of S/V in patients with HF, including decreases in mortality and hospitalization, increased quality of life, and reversible heart remodeling. These benefits led to the HF guidelines recommendations updating and inclusion of S/V combinations a key component of HFrEF treatment.

Acute kidney injury and long-term renal effects of alectinib in anaplastic lymphoma kinase-positive non-small cell lung carcinoma: a case report.

BACKGROUND: Targeted therapy with anaplastic lymphoma kinase inhibitor alectinib has become standard therapy for selected patients with non-small cell lung carcinoma. Few data are available on the renal effects of alectinib. We report on a case of acute kidney injury in a patient using alectinib for less than 2 weeks and on serum sodium and creatinine during long-term use of alectinib. CASE PRESENTATION: A 70-year-old Asian woman was diagnosed with metastasized non-small cell lung carcinoma (cT4N3M1c, stage IV) with echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase gene rearrangement and received alectinib, in two daily doses of 600 mg. Eleven days after the initiation of therapy, she was seen at the emergency department with acute kidney injury. Renal biopsy showed lesions in the proximal tubular epithelial cells. Nine days after alectinib cessation, renal function recovered quickly and reintroduction of alectinib in a reduced dose was tolerated, while withholding metformin, enalapril, and naproxen. In seven other patients, data on estimated glomerular filtration rate showed decreased kidney function at 3 months with stabilization at 6 months. Serum sodium at 3 months increased during alectinib treatment and increased further at 6 months. CONCLUSIONS: Our data suggest direct or indirect toxic (proximal) tubulopathy due to alectinib with a good prognosis after cessation. Adverse acute renal effects of alectinib may be prevented by avoiding other medication influencing renal hemodynamics, in particular nonsteroidal anti-inflammatory drugs. Without these co-medications, alectinib could be reintroduced in our patient.

Huangqi decoction attenuates renal interstitial fibrosis transforming growth factor-ß1/mitogen-activated protein kinase signaling pathways in 5/6 nephrectomy mice.

OBJECTIVE: To investigate the effect of Huangqi decoction on renal interstitial fibrosis and its association with the transforming growth factor-ß1 (TGF-ß1) / mitogen-activated protein kinase (MAPK) signaling pathway. METHODS: 120 C57/BL mice were randomly divided into six groups: sham group, Enalapril (20 mg/kg) group, 5/6 nephrectomy model group, and 5/6 nephrectomy model plus Huangqicoction (0.12, 0.36 and 1.08 g/kg respectively) groups. Detecting 24hours urinary protein, blood pressure, serum creatinine, urea nitrogen content changes. Periodic Acid-Schiff stain (PAS) and Masson's trichrome staining was used to observe the renal tissue pathological changes. Protein expression of TGF-ß1, Phosphorylated P38 mitogen activated protein kinases (P-P38), Phosphorylated c-jun N-terminal kinase (P-JNK), Phosphorylated extracellular regulated proteinhnase (P-ERK), Fibroblast-specific protein-1 (FSP-1), Alpha smooth muscle actin (α-SMA), Type III collagen (Collagen III), Connective tissue growth factor (CTGF), Bcl-2 Assaciated X protein (Bax) and B cell lymphoma 2 (Bcl-2) were measured with western blot and immunohistochemical. RESULTS: Both Huangqi decoction and Enalapril improved the kidney function, 24 h urinary protein and the fibrosis in 5/6 nephrectomy mice, Huangqi decoction downregulated the expressions of TGF-ß1, FSP-1, α-SMA, Collagen III and CTGF in a dose-dependent manner, and it has a significant difference ( 0.01) compared with model group.Huangqi decoction downregulated the expressions of P-P38, P-JNK, P-ERK and Bcl-2 in a dose-dependent manner, while upregulated the expression of Bax. CONCLUSIONS: The protective effect of Huangqi decoction for renal interstitial fibrosis in 5/6 nep-hrectomized mice the inhibition of Epithelial-Mesenchymal Transitions and downregulating the TGF-ß1/ MAPK signaling pathway.

The Relationship between Angiotensin-Neprilysin Treatment, Echocardiographic Parameters, and NT-proBNP Levels in HFpEF Patients with Acute Decompensated Heart Failure.

Background: The valsartan-sacubitril therapy improved the outcomes of patients with acute decompensated heart failure (ADHF) of a reduced ejection fraction (HFrEF). In ADHF patients with preserved ejection fraction (HFpEF), it is not yet clear whether the same treatment regimen may be safely used to treat ADHF. Methods: For this study, HFpEF patients hospitalized due to ADHF were enrolled. Following hemodynamic stabilization, patients were randomized into two groups that were treated with enalapril or sacubitril-valsartan. In this trial, the primary efficacy outcomes were changes in echocardiographic parameters and NT-proBNP levels from baseline to 8 weeks treatment. Results: ARNI treatment resulted in a significant decrease in NT-proBNP levels and an increase in LVEF in patients with HFpEF. However, HFpEF patients that underwent ARNI treatment achieved better outcomes than did patients that underwent ACEI treatment. Conclusion: Sacubitril-valsartan treatment, which lowered NT-proBNP levels and improved cardiac function, was more effective in HFpEF patients with acute decompensated heart failure than enalapril.

Effect of angiotensin II pathway inhibitors on post-surgical adhesion band formation: a potential repurposing of old drugs.

BACKGROUND: In this study we investigated the therapeutic potential of angiotensin II pathway inhibitors in attenuating post-surgical adhesion band formation in tendon injury. METHOD: We assigned 30 Wistar albino rats to 5 groups, including negative control, positive control, sham, Telmisartan- and Enalapril-treated groups (n=6). Telmisartan and Enalapril at a dose of 10 mg/kg were administered intraperitoneally for 21 days. Hematoxylin-Eosin, and Masson's trichrome staining were used to measure the inflammatory cell accumulation and collagen deposition in the Achilles tendon tissue sections. Oxidative stress markers were analyzed in tissue samples by spectrophotometric methods. Properties of Achilles tendon adhesions were compared based on Tang and Ishiyama scoring systems in the presence and absence of angiotensin II pathway inhibitors. RESULTS: Telmisartan and Enalapril reduced severity, length, and density of surgical-induced tendon adhesion at site of injury (***p < 0.001). Our results showed that administration of angiotensin II pathway inhibitors decreased infiltration of inflammatory cells to the injured area (*p < 0.05) and suppressed inflammation by regulating oxidative stress markers including MDA (***p < 0.001), total thiol (***p < 0.001), CAT (***p < 0.001), and SOD (***p < 0.001), in post-operative Achilles tendon tissues. Significant lower collagen deposition and formation of fibrotic tissues was seen in Telmisartan- and Enalapril-treated groups as detected by Masson's trichrome staining which correlated with a decrease in quantity (**p < 0.01) and grading of fibrosis score (***p < 0.001), in adhesive tissues. Moreover, inhibition of angiotensin II pathway could also ameliorate mechanical properties including ultimate load (***p < 0.001), and ultimate stress (*p < 0.05) in injured Tendons. CONCLUSION: Our results showed that ssuppression of inflammation and fibrosis are two mechanisms by which Telmisartan and Enalapril elicit potent protective responses post Achilles tendon injuries.

Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD Model.

Background: Despite widespread use of renin-aldosterone-angiotensin system inhibitors and the benefits of lowering glomerular pressure in patients with CKD, there remains a major unmet need for therapies targeting underlying causes of CKD progression. Apoptosis signal-regulating kinase 1 (ASK1) promotes apoptosis and glomerulosclerosis, and is implicated in the progression of diabetic kidney disease (DKD), a major cause of CKD. Selonsertib is a selective ASK1 inhibitor currently in clinical development for the treatment of DKD. We examined the added benefits of selonsertib on existing glomerulosclerosis and related molecular pathways in the nondiabetic 5/6 nephrectomy (5/6 Nx) rat model in combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril. Methods: Male Sprague Dawley rats underwent 5/6 Nx with kidney biopsy 8 weeks later for assessment of glomerulosclerosis, and were randomized to four treatment groups with equal glomerulosclerosis: selonsertib, enalapril, combination (selonsertib plus enalapril), and untreated controls. Serum creatinine, systolic BP (SBP), and urinary albumin were measured at intervals. Animals were euthanized at week 12 for histologic, biochemical, and molecular analyses. Results: All rats developed hypertension, albuminuria, and glomerulosclerosis by week 8. Kidney function further declined, and glomerulosclerosis and albuminuria progressively increased in controls from week 8 to 12. Enalapril treatment alone from week 8 to 12 reduced SBP versus controls, decreased albuminuria, and resulted in numerically lower glomerulosclerosis. Selonsertib alone had no effect on SBP but preserved kidney function. Combined treatment significantly reduced glomerulosclerosis, with more regression than either monotherapy. Enalapril treatment resulted in fewer interstitial macrophages, whereas selonsertib treatment reduced apoptosis and podocyte loss. RNA-seq revealed that combined treatment influenced pathways related to extracellular matrix and wound healing. Conclusions: Selonsertib targets a novel, nonhemodynamic pathway in CKD. Our data suggest that ASK1 inhibition, when combined with ACEI, has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss.

Within trial comparison of survival time projections from short-term follow-up with long-term follow-up findings.

AIMS: Data on long-term treatment effects are scarce, despite the intent to use new therapies for many years and the need of patients, physicians and payers to have a better understanding of the lifetime benefits of treatments. The restricted mean or median survival time (RMST) calculated using age instead of time, hypothetically enables estimation of long-term gain in event-free or overall survival from the short-term (within-trial) effects of an intervention, compared with its control. Tha aim of the study is to use trials with long-term follow-up available through extension studies to compare the long-term projections estimated using RMST from within-trial follow-up data with the actual long-term outcomes in the extension studies. METHODS AND RESULTS: We estimated the median long-term survival time using age instead of follow-up time and compared these model-based projections with the actual long-term estimates in the (i) SCD-HeFT trial vs. SCD-HeFT long-term outcomes; (ii) SOLVD trial vs. SOLVD 12 year follow-up; (iii) STICH trial vs. STICHES; and (iv) ACCORD study vs. ACCORDION. In the long-term follow-up of SCD-HeFT, gain in survival with ICD vs. placebo over a median of 11.0 years was +1.4 years of life. The RMST model-derived survival projection from the within-trial data (median follow-up of 3.4 years) gave an estimated survival gain of +1.2 years. In STICHES, over a median follow-up of 9.8 years, coronary artery bypass grafting (CABG) vs. medical care led to a survival extension of +1.4 years in favour of CABG. RMST projections using within-trial data from STICH (median follow-up of 4.9 years), gave an extended survival of +2.4 years in favour of CABG in younger patients. In the long-term follow-up of SOLVD, enalapril vs. placebo led to a survival gain of +0.8 years over a median follow-up of 12.1 years. The RMST projections from the within-trial data (median follow-up of 2.8 years) gave a survival extension of +0.3 years in favour of enalapril. In the long-term follow-up ACCORDION study, with a median follow-up of 8.8 years, intensive vs. a standard anti-hyperglycaemic treatment did not influence long-term survival, which was concordant with the RMST projections from the short-term ACCORD study with median follow-up of 4.9 years. CONCLUSIONS: Age-based survival projections using within-trial data generally provided concordant results with the actual survival measured in long-term follow-up extension studies. Our findings suggest that age-based lifetime projections may be used as means to assess the long-term treatment effects.

Endothelial expression of the receptor for advanced glycation end products in experimental diabetes / Expresión endotelial del receptor para productos finales de glicación avanzada en diabetes experimental

The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of several chronic diseases including diabetes. The interaction between RAGE and advanced glycation end products (AGEs) promotes gene expression, enhances the release of proinflammatory molecules and causes the generation of oxidative stress in numerous cell types. The aim of this investigation was to evaluate the effect of enalapril and losartan on RAGE expression in abdominal aortic endothelium of rats with experimentally induced diabetes. Male Sprague-Dawley rats, weighing approximately 150 - 200 g, were used. Diabetes was induced in 30 rats by intravenous administration of a single dose of 55 mg/kg body weight of streptozotocin (ETZ). The following groups were studied: control (n=10), diabetic (n=10), losartan-treated diabetic (n=10) and enalapril-treated diabetic (n=10) rats. RAGE expression in aortic endothelium was determined by indirect immunofluorescence. A significant increase in RAGE expression was observed in diabetic animals versus controls (p<0.001), there was a decrease in RAGE expression, in animals treated with losartan versus controls (p<0.01) and in those treated with enalapril (p<0.05) versus control and versus diabetes + vehicle. In conclusion, in the experimental model of ETZ-induced diabetes, there is an increase in RAGE expression at the level of the abdominal aortic endothelium, which can be reversed by treatment with losartan and/or enalapril, two drugs that block the renin-angiotensin system, suggesting its involvement in the molecular events related to vascular damage during diabetes.

El receptor para productos finales de glicación avanzada (RAGE) está implicado en la patogénesis de varias enfermedades crónicas incluyendo la diabetes. La interacción entre RAGE y los productos finales de glicación avanzada (AGEs), promueve la expresión génica, potencia la liberación de moléculas proinflamatorias y provoca la generación de estrés oxidativo en numerosos tipos de células. El objetivo de esta investigación fue evaluar el efecto del enalapril y el losartán sobre la expresión de RAGE en el endotelio de la aorta abdominal de ratas con diabetes inducida experimentalmente. Se utilizaron ratas Sprague-Dawley machos, con un peso aproximado de entre 150 - 200 g. La diabetes se indujo en 30 ratas mediante la administración intravenosa de una sola dosis de 55 mg/Kg de peso corporal de estreptozotocina (ETZ). Se estudiaron los siguientes grupos: ratas control (n=10), diabéticas (n=10), diabéticas tratadas con losartán (n=10) y diabéticas tratadas con enalapril (n=10). La expresión de RAGE en el endotelio aórtico se determinó por inmunofluorescencia indirecta. Se observó un incremento significativo en la expresión de RAGE en los animales diabéticos versus los controles (p<0.001), hubo una disminución en la expresión de RAGE, en los animales tratados con losartán versus los controles (p<0.01) y en los tratados con enalapril (p<0.05) versus control y versus diabetes + vehículo. En conclusión, en el modelo experimental de diabetes inducida por ETZ, existe un incremento en la expresión de RAGE a nivel del endotelio de la aorta abdominal, la cual puede revertirse mediante el tratamiento con losartán y/o enalapril, dos fármacos bloqueadores del sistema renina-angiotensina, lo cual sugiere la participación del mismo en los acontecimientos moleculares relacionados con el daño vascular durante la diabetes.