Accumulation of pre-mutagenic 8-oxoguanine and impaired DNA repair can lead to poly(ADP-ribose) (PAR) accumulation and parthanatos in Alzheimer's disease, the leading cause of age-dependent dementia. However, the occurrence of parthanatos has not been well established in other types of dementia, including juvenile neuronal ceroid lipofuscinosis (JNCL), a major form of juvenile dementia. In this study, we investigated parthanatos-associated pathology in JNCL using patient-derived lymphoblasts (PDLs). Quantitative immunofluorescence microscopy revealed increased accumulation of 8-oxoguanine and PAR in JNCL-PDLs. JNCL is known to exhibit elevated intracellular calcium, which activates PAR polymerase - 1 (PARP1). The L-type calcium channel blocker diltiazem effectively suppressed PAR accumulation in JNCL-PDLs, even under co-treatment with a calcium ionophore. Diltiazem also reduced 8-oxoG accumulation in JNCL-PDLs, although this effect was largely calcium independent. Subcellular fractionation followed by immunoblotting showed that diltiazem enhanced nuclear recruitment of OGG1 and its partner proteins. These protective effects were abolished by OGG1 knockdown, suggesting a dual role of diltiazem in regulating both calcium signaling and OGG1 activity. Collectively, our data identify that parthanatos as novel therapeutic target for JNCL and propose diltiazem as a potential therapeutic agent. KEY MESSAGES: Increased poly(ADP-ribose) accumulation represents a novel therapeutic target in juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations. Increased PARP1 expression and decreased PARP1 cleavage lead to elevated poly(ADP-ribose) accumulation in juvenile neuronal ceroid lipofuscinosis. Diltiazem ameliorates poly(ADP-ribose) accumulation in patient-derived cell models of juvenile neuronal ceroid lipofuscinosis by suppressing PARP1 expression and 8-oxoguanine accumulation.

POLGA, the catalytic subunit of the mitochondrial DNA polymerase, is essential for mitochondrial DNA (mtDNA) replication and maintenance. Mutations in POLGA cause progressive external ophthalmoplegia (PEO), but the underlying pathogenic mechanisms remain unclear. Here, we show that the mitochondrial E3 ligase MITOL hyperubiquitylates PEO-associated POLGA mutants at lysine 1060, triggering conformational changes and formation of insoluble aggregates that impair their mitochondrial import and consequently compromise mtDNA replication and mitochondrial homeostasis. To identify compounds that disrupt POLGA aggregates and restore mutant POLGA function, we screened an FDA/EMA/PMDA-approved drug library using a split-GFP system. We identified two clinically approved compounds, diltiazem hydrochloride (C1) and sulbactam (C4), that disrupted POLGA aggregates, prevented aberrant MITOL recognition, restored mitochondrial import, and rescued mtDNA replication and mitochondrial function. Importantly, treatment with either compound significantly improved motor performance in a knock-in mouse model carrying the disease-relevant A467T-equivalent POLGA mutation. These findings establish pathogenic aggregation as a previously underrecognized disease mechanism and demonstrate that disrupting POLGA aggregates with repurposed drugs can restore mitochondrial function in vivo, providing a potential therapeutic strategy for POLGA-associated mitochondrial disease.

This study aimed to develop an innovative wound dressing by loading Chelidonium majus L. extract into an alginate hydrogel matrix and to assess its efficacy in wound healing. The extract of C. majus, famous for its anti-inflammatory and antioxidant features, was obtained from plant material collected in Mazandaran Province, Iran, and incorporated into sodium alginate hydrogels at concentrations of 2% and 5% w/w. The hydrogel formulations were characterized in terms of their morphological, thermal, and swelling properties, demonstrating interconnected porous structures, altered thermal behavior indicating increased amorphous content, and high moisture absorption capacity. To evaluate biological activity, the antioxidant and flavonoid content of the extract were measured, showing notable free radical scavenging ability and high levels of flavonoids. An in vivo wound healing model using adult male Wistar rats compared the effectiveness of control, bare hydrogel, C. majus-loaded hydrogels (2% and 5%), and diltiazem treatments. Wounds treated with the 5% C. majus hydrogel showed accelerated closure rates and improved tissue regeneration, as confirmed by histological examination and enhanced expression of proliferative and regenerative genes (TGF-β) alongside decreased inflammatory markers (TNF-α and IL-1β), in comparison with the control group. These results indicate that C. majus-loaded alginate hydrogel, especially at a 5% concentration, promotes wound healing through offering a wet environment, supporting cell proliferation, and modulating inflammation. This hydrogel may represent a promising topical therapeutic option for treating skin wounds.

Rabies is an almost always fatal disease caused by rabies virus (RABV). Once RABV enters the central nervous system, the mortality rate is almost 100%. Therefore, preventing RABV from entering the nervous system is crucial for the development of anti-RABV therapeutics. Here, we found that the L-type calcium channel Cav1.2 pore-forming subunit (Cav1.2) and potassium calcium-activated channel subfamily M alpha 1 (KCa1.1) are involved in the internalization of RABV using an siRNA approach. RABV glycoprotein interacts with Cav1.2, a process that is required for the subsequent activation of the channel. The activated Cav1.2 then interacts with and activates KCa1.1 to regulate the endocytosis of RABV by promoting the F-actin polymerization. Importantly, diltiazem, a blocker of Cav1.2 and an FDA-approved drug, has been shown to substantially reduce mortality in mice infected with RABV. Approximately 70% of mice survived following treatment with diltiazem at 50 mg/kg, whereas the 25 mg/kg dose resulted in 26% survival. Our findings suggest that Cav1.2 is a promising target for the development of antiviral drugs against rabies and enhances our comprehension of the RABV entry mechanism.

Calcium channel blockers are first-line medications for the treatment of hypertension, angina pectoris, and arrhythmias, and are generally well-tolerated. However, in recent years, there have been reports indicating that CCBs may cause severe pulmonary toxicity, such as non-cardiogenic pulmonary edema and acute respiratory distress syndrome. This article employs a comprehensive review methodology to systematically summarize the clinical types, incidence, risk factors, mechanisms of injury, and management strategies for CCB-related pulmonary toxicity. Current evidence indicates that pulmonary toxicity is extremely rare at standard therapeutic doses; however, the incidence increases significantly in cases of acute overdose and among specific populations (pregnant women, patients with underlying cardiopulmonary diseases). Pharmacovigilance studies have identified significant signals suggesting an association between nifedipine, diltiazem, and verapamil to pulmonary edema, with amlodipine having the highest number of related clinical reports. Major risk factors include drug overdose, pregnancy, underlying cardiopulmonary disease, and differences among CCB subclasses. Toxicity associated with dihydropyridine CCBs is primarily characterized by vasodilatory shock, whereas non-dihydropyridine CCBs exhibit a combination of cardiac depressant and vasodilatory effects. Mechanisms involve hemodynamic changes, increased capillary permeability, inflammatory activation, and alveolar epithelial dysfunction. Early recognition, drug discontinuation, selection of vasoactive agents based on the type of shock, and life support are key to improving prognosis.

Cardiovascular medications used in coronary artery disease (CAD) can potentially modulate the risk of incident atrial fibrillation (AF). However, comprehensive data regarding medication-specific AF risk in the CAD population remain limited. This study aimed to identify prevalent medications prescribed to patients with CAD and evaluate their independent associations with AF risk. In this retrospective cohort study of 157,750 patients with CAD and related comorbidities, CAD-predominant medications were identified based on a frequency analysis of prescriptions in the overall cohort. Among 99,370 patients who received at least one such medication, associations with incident AF were evaluated using extended Cox proportional hazards models with time-varying covariates. Overall, 30 CAD-predominant medications were identified across nine pharmacological classes. In multivariable Cox proportional hazards models, six medications were significantly associated with AF risk, of which one was associated with a lower risk and five with a higher risk. Ezetimibe/rosuvastatin was associated with reduced AF risk, whereas diltiazem HCl, torasemide, heparin sodium, bisoprolol fumarate, and norepinephrine were associated with increased risk. Torasemide showed the strongest positive association. AF risk demonstrated heterogeneity across different CAD medications. Antilipidemic agents were associated with a lower AF risk, whereas certain diuretics, antianginal agents, antihypertensive, and vasoactive agents were associated with a higher risk. These results may have implications for individualized pharmacotherapy and AF prevention in patients with CAD.

Background/Objectives: Interindividual pharmacokinetic (PK) variability remains a daunting challenge for effective and safe drug therapy. Despite the widespread use of direct oral anticoagulants (DOACs) and calcium channel blockers (CCBs), a substantial number of adverse drug reactions have been reported for both classes. Herein, this study aimed to assess and analyze the PK variability of DOACs and CCBs across diverse clinical and demographic profiles under both single- and multiple-dose conditions. Methods: A PubMed search identified clinical PK studies reporting maximum plasma concentration (Cmax) and/or area under the concentration-time curve (AUC). The coefficient of variation (CV%) was calculated and used as a measure of PK variability. A CV% < 40% indicated low-to-moderate variability, and a CV% > 40% was defined as high variability. Results: A total of 264 studies were included following systematic screening, and the dataset was further characterized according to population features and clinical context. Among DOACs, edoxaban exhibited the lowest PK variability, whereas dabigatran showed the highest. CCBs demonstrated a broad variability spectrum, ranging from predictable agents (amlodipine and felodipine) to highly variable compounds (nisoldipine, isradipine, nimodipine, diltiazem, and verapamil). Studies evaluating drug-drug interactions, ethnicity, and specific drug-related factors were associated with increased PK variability. Conclusions: These findings suggest that fixed-dose strategies may not be universally appropriate for DOACs and CCBs, particularly in high-risk subgroups where altered exposure may lead to sub- or supratherapeutic concentrations and compromise clinical outcomes. Therefore, clinicians should avoid evaluating individual risk factors in isolation and instead consider the patient's complete profile when selecting and adjusting pharmacotherapy.

Enclomiphene citrate is increasingly prescribed off-label for secondary male hypogonadism, and its cardiovascular safety profile remains poorly characterised. We report a 46-year-old man with a mitral valve repair performed 20 years earlier and chronic immune thrombocytopenia (ITP) in whom atrial flutter was first documented shortly after he inadvertently increased his enclomiphene dose, taking 50 mg daily in place of 25 mg daily. Laboratory evaluation demonstrated chronic thrombocytopenia with a platelet count of 36 × 10[9]/L, while thyroid function, cardiac biomarkers, and electrolytes were normal. Transthoracic echocardiography showed preserved left ventricular systolic function with mild asymmetric left ventricular hypertrophy, mild left atrial enlargement, and mildly reduced right ventricular systolic function. Computed tomography pulmonary angiography (CTPA) excluded pulmonary embolism. Rate control was achieved with metoprolol and diltiazem. Anticoagulation was deferred because of severe thrombocytopenia, and high-dose prednisone was initiated to raise the platelet count before planned anticoagulation and elective cardioversion. Testosterone was elevated at presentation and the arrhythmia was detected soon after the dose increase, but causality cannot be established. The patient had a remote atriotomy and echocardiographic evidence of chronic atrial and ventricular remodelling, a substrate sufficient on its own to sustain macro-reentrant atrial flutter, and earlier asymptomatic or self-limiting episodes could not be excluded. Formal causality assessment using the Naranjo scale placed the association in the possible category only. The case is presented for two reasons: as an illustration of how a hormonal agent should be weighed against a pre-existing structural substrate rather than assumed to be causal, and as an example of the difficulty of balancing thromboembolic and bleeding risk when atrial flutter coexists with severe ITP.

Several studies have supported Dr Gideon Koren’s 1993 landmark article, “Medications Which Can Kill a Toddler with One Tablet or Teaspoonful.” Although each study has its own merits, most focus solely on pediatric overdoses, and few provide an exhaustive reference list for real-time evaluation of ingestions in children and adults. The following xenobiotics warrant special attention because of their potential to cause serious outcomes, even after exposure to small volumes. This list does not imply that all pediatric exposures to these agents result in fatality, and the absence of a xenobiotic from this list does not indicate that it is necessarily safe. α1-Adrenergic agonists and imidazoline receptor agonists: Clonidine, guanfacine, naphazoline, oxymetazoline, tetrahydrozoline, xylazine (veterinary). Sulfonylureas: Chlorpropamide, glyburide, glipizide, glimepiride. Calcium channel blockers: Verapamil, diltiazem, nifedipine, amlodipine, nicardipine, nimodipine; β-Blockers: Metoprolol, labetalol, propranolol, sotalol. Tricyclic antidepressants: Imipramine, desipramine, amitriptyline, nortriptyline. Opioids: Codeine, hydrocodone, methadone, morphine, heroin. Antidiarrheals: Diphenoxylate plus atropine, loperamide. Salicylates and methyl salicylate: Oil of wintergreen, bismuth subsalicylate, mentholated balms, paramao or lawang root oil . Antipsychotics: Loxapine, thioridazine, chlorpromazine. Antimalarials: Chloroquine, hydroxychloroquine, quinine, primaquine. Antiarrhythmics: Quinidine, disopyramide, procainamide, flecainide, amiodarone. Camphor: A terpenoid used as an analgesic, antipruritic agent, and component of cooling gels, ointments, balms, mothballs, household fragrances, and essential oils. Oral camphor use occurs in some regions for religious ceremonies, traditional remedies, aphrodisiacs, or lactation suppression. Nonalkaloid toxic lignan: Podophyllin, podofilox. Unique plant toxins: Colchicine. Oral acetylcholinesterase inhibitors: Rivastigmine, donepezil, galantamine, carbamate pesticides. Methylxanthines: Theophylline, 1,3-dimethylxanthine, caffeine. Other opioids: Buprenorphine, fentanyl. Toxic alcohols: Methanol, ethylene glycol, diethylene glycol. Caustics and other household products: Acidic or alkaline household products, hydrofluoric acid, selenious acid, acetonitrile, methylene chloride. Accidental overdoses continue to occur regularly despite the implementation of various safety measures, including widespread public education, the use of childproof containers, and easy access to poison control centers. In the US, poison control centers receive more than 2.4 million calls annually, with more than 50% involving children younger than 6 years. Most pediatric accidental ingestions involve household cleaning products and analgesics, followed by cosmetics, foreign objects, and dietary supplements. Adult overdoses may be unintentional but often involve larger total doses or high-risk medications, including opioids and sedative-hypnotics. America's Poison Centers identify the 5 most common substance classes as analgesics, household cleaners, antidepressants, cosmetic or personal care items, and cardiovascular drugs. The number of ingestions involving cleaning products increased sharply during the COVID-19 pandemic but has since declined.

We describe a 35-year-old male patient who had acute inferior myocardial infarction based on clinical signs and electrocardiographic abnormalities after experiencing sudden chest pain for 2 h. An abnormal origin of the right coronary artery (RCA) from the left coronary sinus was discovered by emergency coronary angiography, along with mild stenosis in the mid-RCA segment that persisted even after intracoronary nitroglycerin was administered. The mid-RCA lesion was identified by intravascular ultrasonography (IVUS) as a 48% stenotic fibro-lipid plaque with a lipid core and thin fibrous top. A minimum luminal diameter of 2.14 mm was found at the deformed RCA ostium with concomitant myocardial bridging. The patient experienced total symptom alleviation and an uneventful recovery after receiving dual antiplatelet therapy, intense lipid-lowering treatment, diltiazem for myocardial bridging, and stringent risk factor control. For long-term risk reduction, a multidisciplinary evaluation is planned for surgical of the coronary abnormality. In addition to highlighting the significance of tailored management approaches for congenital coronary anomalies combined with acquired vulnerable plaques, this case underscores the crucial role of multimodality imaging, particularly IVUS, in accurate etiological diagnosis and treatment decision-making for young patients with acute myocardial infarction (AMI) caused by complex coronary lesions.

Introduction: syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of euvolemic hyponatremia in older adults. Case report: we report the case of a 72-year-old woman with chronic SIADH, probably secondary to sertraline, in the setting of polyp harmacy and chronic liver disease. Initially, serum sodium normalized with fluid restriction guided by the Furst formula under caregiver supervision. Following the death of her primary caregiver and admission to a long-term care facility, an increase in sertraline dosage and the inability to maintain fluid restriction led to recurrent hyponatremia (serum sodium 126 mEq/l). Tolvaptan was avoided because of the risk of interaction with diltiazem (CYP3A4 inhibitor) and underlying liver disease. Oral urea was initiated and titrated to 30 g/day, achieving gradual and sustained normalization of serum sodium (134-135 mEq/l) without adverse effects or changes to her psychotropic treatment. Six months later, the patient remains clinically stable on 15 g/day of oral urea with progressive sertraline dose reduction. Discussion: this case highlights oral urea as a safe, effective, and cost-effective therapeutic option for SIADH when fluid restriction is not feasible and vaptans are unsuitable, particularly in frail older adults with polypharmacy and complex social circumstances.

This study investigates whether Luhong Formula (LHF) inhibits hypoxia/reoxygenation (H/R)-induced ferroptosis in cardiomyocytes and the underlying mechanism. H9c2 cells were subjected to H/R injury and treated with LHF extract, diltiazem (positive control), or Fer-1 (ferroptosis inhibitor). CCK-8, colorimetric assays, and transmission electron microscopy showed that LHF significantly increased cell viability, reduced LDH release, restored SOD activity and GSH content, and alleviated mitochondrial damage. FerOrange staining and C11-BODIPY flow cytometry revealed that LHF decreased intracellular Fe[2+] levels and lipid ROS accumulation. Immunofluorescence and Western blot demonstrated that LHF up-regulated GPX4 expression, showing effects comparable to those of Fer-1 and diltiazem in this in vitro system. Using SLC7A11-overexpressing and -silencing stable cell lines, we found that SLC7A11 overexpression mimicked LHF's protective effects, while SLC7A11 silencing partially reversed them. Co-immunoprecipitation confirmed that H/R increased SLC7A11 ubiquitination, whereas LHF reduced this modification, thereby stabilizing SLC7A11 protein. Collectively, LHF is associated with reduced SLC7A11 ubiquitination, which correlates with up-regulated GPX4 and blocked ferroptosis, alleviating H/R injury in cardiomyocytes. These findings provide preliminary evidence for a potential regulatory effect of LHF on SLC7A11 protein stability, although direct measurements of protein half-life and detailed ubiquitin topology require further investigation. These findings suggest that LHF inhibits H/R-induced ferroptosis in H9c2 cells, at least in part, through the SLC7A11/GPX4 pathway, which may contribute to its cardioprotective effect.