Drug-mediated phototoxicity and photocarcinogenicity have long remained poorly understood. One of the most significant dilemmas surrounding this issue is the sporadic nature of these reactions. This sporadic occurrence may be explained by modern and newly introduced concepts such as drug-mediated nitrosogenesis of skin cancer, as well as nitroso-photocarcinogenesis of skin cancer. Regardless of their carcinogenic potential, all nitrosamines may exhibit phototoxic properties and may therefore act as photocarcinogenic substances, because of the instability of the nitroso group under UV radiation. Drug-related Nitroso Photocarcinogenesis represents a new and innovative concept that seeks to provide a logical explanation for the phenomenon of nitroso-photocarcinogenicity. Various groups of medications, including antihypertensive agents (beta-blockers, ACE inhibitors, calcium antagonists, centrally acting sympatholytics, and sartans), anticoagulants, antidiabetic drugs, and several other classes, possess secondary amino groups. Under gastric conditions - an acidic environment and in the presence of nitrite-rich food - these amino groups may lead to the formation of nitrosamines, which are well known carcinogens and established photocarcinogens. The subsequent resorption of these drug-mediated nitroso compounds may result in their subsequent deposition in the skin. The decomposition of nitrosamines under the influence of ultraviolet radiation may lead to the release of nitric oxide and/or procarcinogenic mediators capable of damaging DNA of keratinocytes and melanocytes. Thus, in practice, malignant cellular branches may be initiated even when the relevant groups of medications are not externally contaminated with nitrosamines. In this sense, generic drugs from heterogenous classes may effectively act as donors of photocarcinogenic compounds to the human skin. In this context, and in support of the aforementioned modern concept of skin cancer, we present another case of keratinocyte cancer (basal cell carcinoma) that developed relatively shortly after combined intake of four drugs (apixaban, flecainide, amlodipine, and perindopril), each containing a secondary amino group in its structure - serving as a potential precursor for the generation of photocarcinogens in the stomach. The skin cancer has been removed surgically without "!" The defect has been treated via nasal tip rotation flap as dermatosurgical approach. The role of endogenous, gastric related Nitrosogenesis during intake of potentially completely uncontaminated drugs (containing secondary amino groups in their chemical structure), in relation to nitroso-photocacinogenesis and the subsequent development of skin cancer, is discussed.

Profound hyponatremia (<110 mmol/L) represents a critical electrolyte disturbance associated with significant neurological risk, particularly when rapid correction precipitates osmotic demyelination syndrome. Therapeutic management becomes especially complex when severe hyponatremia coexists with anuric acute kidney injury (AKI) requiring urgent renal replacement therapy, as intermittent hemodialysis may induce abrupt sodium shifts. We describe the case of a 66-year-old hypertensive woman receiving hydrochlorothiazide and perindopril who presented 10 days after cataract surgery with severe anuric AKI, profound asymptomatic hyponatremia (104 mmol/L), hyperkalemia (6.6 mmol/L), elevated creatinine (143 mg/L), and urea (2.6 g/L). Despite the severity of biochemical abnormalities, the patient remained conscious, hemodynamically stable, and neurologically intact, with normal thyroid and adrenal function. Given the urgency of treating hyperkalemia and uremia while avoiding overcorrection of sodium, a carefully individualized intermittent hemodialysis strategy was implemented using ultra-short initial sessions, controlled blood flow (220 mL/min), gradual dialysate sodium adjustment, and concomitant dextrose infusion. This approach enabled progressive correction of serum sodium to 126 mmol/L over four consecutive sessions without exceeding recommended safety thresholds and without neurological complications. This case highlights that meticulously tailored short-duration intermittent hemodialysis can achieve safe sodium correction while addressing life-threatening metabolic indications, suggesting a potential alternative when continuous renal replacement therapy is unavailable.

In patients, extraintestinal manifestations of inflammatory bowel disease (IBD) are attenuated ventricular contractile function and arrhythmia. To determine the mechanism of IBD-induced changes in ventricular function, we used a mouse model of dextran sodium sulfate (3.5% weight/volume; 7 days)-induced colitis. Changes in cardiac function were quantified in isolated ventricular myocytes (VM) by cell shortening, imaging of [Ca[2+]]i, reactive oxygen species (ROS), and t-tubular density. During colitis, VMs exhibited attenuated cell-shortening and altered Ca[2+]-handling properties. A prolonged Ca[2+] transient (CaT) rise time correlated with an increased coefficient of variation in the subcellular Ca[2+] release and an attenuated t-tubular density. T-tubular loss was accompanied by increased ROS production, calpain-2 (CAPN2) expression, junctophilin-2 (JPH-2) cleavage, and autophagy. Inhibition of Angiotensin-converting enzyme during colitis (Perindopril: 3 mg/kg/day) prevented the increase in CAPN2, ROS production, autophagy, and t-tubular remodeling. It failed, however, to restore full length JPH-2. We conclude that, during IBD, the angiotensin II (AngII)-induced loss of t-tubular integrity and altered cellular Ca[2+] handling can be prevented by suppression of the AngII-dependent increase in CAPN2 and autophagy and thus suppression of AngII signaling might benefit IBD patients with cardiac manifestations of the disease.

Background/Objectives: While doxorubicin (DOX) and trastuzumab (TRZ) improve overall survival in women with breast cancer, these two anti-cancer drugs increase the risk of developing heart failure. As a novel and largely unexplored approach, our aim was to evaluate whether the prophylactic use of the sodium-glucose co-transporter 2 inhibitor empagliflozin (EMPA), with and without the angiotensin converting enzyme inhibitor perindopril (PER), is cardioprotective in preventing DOX + TRZ-mediated cardiotoxicity. Methods: In a chronic in vivo murine model, female mice received prophylactic treatment with PER (3 mg/kg), EMPA (10 mg/kg), or EMPA + PER via oral gavage for a total of 3 weeks as a run-in period prior to weekly administration of DOX + TRZ (8 mg/kg and 3 mg/kg, respectively) intraperitoneally for an additional 3 weeks (total of 6 weeks). Results: In mice treated with DOX + TRZ, the left ventricular ejection fraction (LVEF) decreased from 75 ± 2% at baseline to 40 ± 4% at week 6. Prophylactic treatment with either PER, EMPA, or EMPA+PER improved LVEF to 58 ± 3%, 66 ± 3%, and 67 ± 4% at week 6, respectively (p < 0.05). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX + TRZ-treated mice. Prophylactic administration with PER, EMPA, or EMPA + PER, however, improved myofibril integrity at week 6 in mice receiving DOX + TRZ. Finally, although the Bax/Bcl-xL ratio was significantly elevated by 1.5-fold in mice treated with DOX + TRZ, this marker of apoptosis was attenuated by prophylactic treatment with either PER, EMPA, or EMPA + PER. Conclusions: Prophylactic administration of EMPA mitigated adverse cardiovascular remodeling in a chronic in vivo model of DOX + TRZ-mediated cardiotoxicity.

Migraine is commonly regarded as a primary neurovascular disorder; however, systemic endothelial and autonomic factors may modulate its expression and course. A 41-year-old male with a 10-year history of migraine without aura and vasomotor rhinitis experienced sustained remission after initiation of nebivolol 5 mg and (perindopril 5 mg/indapamide 1.25 mg/amlodipine 5 mg) once daily for mild hypertension. Attacks occurred 3-4 times per month-often on Saturdays-were triggered by strong odors such as perfume, and occasionally accompanied by nausea or vomiting. Headaches fulfilled ICHD-3 criteria for migraine without aura and initially responded to triptans. Within two weeks of therapy, blood pressure normalized and both migraine and nasal symptoms resolved. Remission persisted for 12 months. The temporal sequence and clinical pattern appear consistent with a clinical improvement that may involve endothelial and autonomic modulation, among several plausible contributors, including combined antihypertensive therapy. The patient's blood pressure remained within the physiological range throughout the observation period, indicating that the sustained remission extended beyond antihypertensive control per se. This case illustrates a hypothesis-generating clinical pattern potentially involving endothelial and autonomic modulation and highlights how vascular homeostasis and circadian autonomic factors may influence migraine chronification and remission.

Background and Clinical Significance: Angiotensin-converting enzyme inhibitors (ACE-Is) are commonly used for treatment of hypertension and are well known among primary care specialists. ACE-I-induced angioedema is a rare, yet possible side effect. It should not be taken lightly, as it can be life-threatening. It is characterized by erythematous or skin-coloured, self-limiting, localized, non-pitting swelling of the submucosal and/or subcutaneous layers of tissue. Usually, it develops in the first year of using the medication, although it can also start several years after using it. Herein, we describe a late-onset ACE-I-induced angioedema, which developed 7 years after using the ACE-I. This case report depicts the challenges of diagnosing ACE-I-induced angioedema, especially if it is late-onset. It highlights the importance of actively asking patients questions about possible side effects of medication even several years after using it and the patients themselves not having any complaints. Case Presentation: We present a 61-year-old Caucasian male with recurring swelling of the lips, tongue and an uncomfortable feeling in the throat, which started 7 years after using an ACE-I: perindopril. There was no airway obstruction or urticaria in any of the episodes. Hereditary angioedema was ruled out by blood analysis. Based on the clinical presentation, images and blood analysis, it was diagnosed as late-onset ACE-I-induced angioedema. After discontinuing the ACE-I, there were two more episodes of angioedema reported, which were a lot milder in symptoms and lasted a shorter time period. Since then, there have been no other episodes of angioedema. Conclusions: It is important to keep in mind angioedema as a possible side effect for patients on ACE-Is. Patients should be regularly and actively questioned about side effects, even if the medication has been started several years ago and no complaints are brought up by the patient.

We sought to investigate whether remnant cholesterol (RC) modified the effect of intensive blood pressure (BP) lowering treatment. This study was a post hoc analysis of ESPRIT. In this trial, hypertensive patients with high cardiovascular risk were randomly assigned to intensive (systolic BP < 120 mmHg) or standard (systolic BP < 140 mmHg) treatment. Cox regression analysis was used to examine heterogeneity of treatment effect on the primary composite outcome (myocardial infarction, heart failure, stroke, coronary or non-coronary revascularization, or death from cardiovascular causes), individual components, and death from any cause in participants grouped by RC tertiles or the cut-off value (0.8 mmol/L). A total of 11,221 participants with complete data of baseline RC were included for analysis (females 41.3%, mean age 64.6 years). During a median follow-up of 3.3 years, 1163 primary outcomes occurred, and hazard ratios (HR) for the primary outcome were 0.98 (95% CI 0.80-1.20), 0.90 (95% CI 0.74-1.11), and 0.77 (95% CI 0.64-0.94) in the lowest, middle, and highest RC tertiles, respectively (P for interaction: 0.11). Additionally, intensive treatment only reduced the risk of myocardial infarction in the highest RC tertile (HR 0.56, 95% CI 0.36-0.89, P for interaction: 0.01). When grouping by RC level of 0.8 mmol/L, significant interactions were also noted for the primary outcome, myocardial infarction, death from cardiovascular causes, and death from any cause (all P for interaction <0.05). These results showed that effects of intensive treatment were shown to be modified by baseline RC level, and further research is needed to confirm our findings.

Arsenic trioxide (ATO) remains vital in acute promyelocytic leukemia therapy, yet its clinical use is limited by cumulative organ toxicities, particularly neurotoxicity, which compromise tolerability and outcomes. Perindopril and L‑Arginine exert cytoprotective effects through antioxidant and anti‑inflammatory mechanisms. This study evaluated their neuroprotective efficacy against ATO‑induced neurotoxicity, emphasizing mechanistic pathways. Male rats were assigned to five groups: Control, ATO‑only (7.5 mg/kg, intraperitoneally, 14 days), Perindopril (2 mg/kg, orally), L‑Arginine (200 mg/kg, orally), and combined therapy. Interventions commenced seven days prior to the ATO challenge and continued for 21 days. Body weight was documented at baseline and endpoint; survival indices were monitored. Biochemical, histopathological, and molecular evaluations examined oxidative stress, inflammatory mediators, and apoptotic signaling. ATO exposure increased malondialdehyde (MDA) and nitric oxide derivatives (NOx), while reducing glutathione (GSH), superoxide dismutase (SOD), and catalase activities. It elevated tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β), and interleukin‑6 (IL‑6), while suppressing brain‑derived neurotrophic factor (BDNF) and nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 (Nrf2/HO‑1) signaling. Upregulation of Kelch‑like ECH‑associated protein 1/Nuclear factor kappa‑light‑chain‑enhancer of activated B cells (Keap1/NF‑κB), cleaved caspase‑3, and caspase‑3, alongside downregulation of B cell lymphoma‑2 (Bcl‑2), was evident. Histopathological lesions substantiated neurotoxicity. Perindopril and L‑Arginine markedly reversed these perturbations, reinstating molecular and structural homeostasis. Their combination afforded superior neuroprotection compared with monotherapies. Both agents mitigate ATO‑induced neurotoxicity through antioxidant, anti‑inflammatory, and anti‑apoptotic mechanisms, with their co‑administration surpassing individual efficacy. The Keap‑1/Nrf2/HO‑1 axis emerges as a critical therapeutic node, underscoring the translational potential of combined intervention.

It is still unclear whether hypertensive patients using angiotensin II receptor blockers (ARBs) have a different risk of developing dementia compared with those taking angiotensin-converting enzyme inhibitors (ACEIs). We conducted a prospective cohort study using the 45 and Up Study Cohort in patients aged ≥ 45 years with hypertension who initiated ARB or ACEI therapy between 2004 and June 30, 2022. ARB/ACEI exposure was defined as having a supply that covered at least 80% of their follow-up period. Propensity score matching was used to balance baseline characteristics. We used the Cox proportional hazards model to estimate the risk of incident dementia. We included 51,574 patients with hypertension (mean age 66.3 (9.0) years; 48.2% women), with a mean follow-up of 11.3 (5.2) years. After controlling for major modifiable lifestyle factors such as diet and physical activity, ARB use was linked to a significantly reduced risk of dementia compared with ACEI use (hazard ratio [HR] = 0.72; 95% confidence interval [CI]: 0.65-0.80, p < 0.001). In exploratory agent-level analyses, compared with lisinopril, olmesartan (HR = 0.32; 95% CI: 0.16-0.62), candesartan (HR = 0.41; 95% CI: 0.24-0.69), telmisartan (HR = 0.42; 95% CI: 0.25-0.71), irbesartan (HR = 0.45; 95% CI: 0.27-0.75), and perindopril (HR = 0.52; 95% CI: 0.31-0.87) were associated with a significantly lower risk of dementia, while captopril showed a significantly increased risk (HR = 4.9; 95% CI: 1.04-23.4). The findings were consistent across subgroup analyses (sex, head-to-head ARBs vs ACEIs) and sensitivity analyses (excluding hypertension defined only by antihypertensive medication use, adjusting for competing risk of death or inverse probability of treatment weighting analysis). Among hypertensive patients, ARB use was linked to a reduced risk of dementia compared with ACEI treatment, regardless of diet and physical activity, and the effect varied across specific agents. These findings highlight the potential role of ARBs in dementia prevention; however, further randomised controlled trials are needed to confirm them.