Background: Sex hormones play crucial functions in the body via the genomic and non-genomic pathways. 5α- and 5β-dihydrotestosterone (5α- and 5β-DHT) are 5-reduced testosterone metabolites. We aimed to investigate the non-genomic effect of 5α- and 5β-DHT on uterine muscle contractility in vitro and in vivo for non-pregnant and 22-day-pregnant rats. Methods: The rapid in vitro action of 5α-DHT and 5β-DHT (10[-9]-10[-3] M) on KCl (25 mM)-stimulated contractions was examined in an organ bath in the presence of several blockers and after endometrium removal. The actions of DHTs (10[-4] M) and nifedipine (10[-7] M) were also examined in contractions stimulated by KCl (40 mM) with a cumulative addition of CaCl2 (3-120 mM). Plasma DHT levels were measured by ELISA after a single intraperitoneal (i.p.) administration of DHT (10 mg/kg), and kinetic curves were obtained. The in vivo relaxing action of DHTs was detected by strain-gauge sensors. The animals received 5α- or 5β-DHT alone (3/10/30/100/300 mg/kg i.p.) or with flutamide (100 mg/kg i.p.). Results: DHT showed concentration-dependent relaxation of uterine muscle in vitro, with a higher potency observed for 5β-DHT. Among the blockers used, G15 and L-NAME reduced the potency of 5α-DHT in pregnant rats only. Both DHTs inhibited the contraction-increasing effect of CaCl2, proving their Ca[2+] inhibiting effects. DHTs had similar cmax and tmax values in both non-pregnant and pregnant rats. DHT plasma levels before and 30 min after administration were proportional to the administered doses. Their single doses (30/100/300 mg/kg) elicited a flutamide-resistant uterine relaxing effect in vivo. Conclusions: DHTs or their analogs are candidates for further studies in the human uterus to establish their potential to treat conditions associated with uterine hyperactivity.

Functional dyspepsia (FD) is a disorder of gut-brain interaction involving heterogeneous motor, sensory, immune, and oxidative stress-related mechanisms. Simotang oral liquid (SMT), a traditional Chinese medicine formulation used for dyspeptic and gastrointestinal motility-related symptoms, has not been evaluated with an integrated clinical, functional, and molecular framework. This single-arm prospective pre-post study assessed gastric emptying by the 13C-octanoic acid breath test, gastric electrical activity by electrogastrography, postprandial tolerance by nutrient drink testing, symptom scores, serum biomarkers, and gastric antral tissue markers in patients with FD. FD-like mice were used for charcoal meal transit, smooth muscle strip tension, calcium channel blockade, and mucosal RNA sequencing. Public transcriptomic data from GSE169304 were analyzed to characterize FD-associated duodenal mucosal molecular features. SMT treatment was associated with reduced gastric emptying half-time, improved 3-cpm stability, lower gastric dysrhythmia, reduced Nepean Dyspepsia Index and Gastroparesis Cardinal Symptom Index scores, increased motilin and gastrin levels, lower malondialdehyde, higher superoxide dismutase activity, and lower tumor necrosis factor alpha and interleukin-6 levels. Paired gastric antral biopsy analyses showed increased α-smooth muscle actin and higher phosphorylation ratios of myosin light chain kinase and myosin light chain after SMT treatment. In mice, SMT increased intestinal transit, acetylcholine-induced smooth muscle tension, Cav1.2 abundance, calmodulin fluorescence, and p-MLCK/p-MLC signaling, while nifedipine reduced the SMT-associated phosphorylation changes. Transcriptomic analyses showed enrichment of smooth muscle contraction, calcium signaling, oxidative stress response, and Nrf2-related antioxidant pathways, while protein analyses showed reduced canonical NF-κB activation markers. The data are consistent with Ca[2+]-dependent smooth muscle contraction as the central motor pathway associated with SMT- related functional improvement in FD, with Nrf2/NF-κB modulation as a microenvironmental regulatory component.

Hypertensive disorders of pregnancy (HDP) are associated with maternal and neonatal morbidity. Although delivery is the definitive treatment, antihypertensive agents are often prescribed to control blood pressure to facilitate safe prolongation of pregnancy. International guidelines vary in their treatment recommendations and preferences for methyldopa, labetalol and nifedipine. Within the field of HDP, randomised trials are often underpowered and observational studies are limited in causal inference due to confounding. Therefore, we propose a target trial emulation with hospital-based electronic health record (EHR) data to compare methyldopa, labetalol and nifedipine in pregnancies complicated by HDP, focusing on maternal and perinatal outcomes.

Administration of finerenone during perfusion of isolated rabbit lungs caused a decrease in pulmonary artery pressure, capillary hydrostatic pressure, and pulmonary vascular, precapillary, and postcapillary resistances. These parameters decreased approximately to the same extent as in case of administration of L‑type Ca[2+] channels blocker nifedipine. Under conditions of intact systemic circulation, intravenous injection of finerenone elicited a more pronounced decrease in pulmonary arterial pressure and pulmonary vascular resistance relative to nifedipine treatment. Concurrently, blood flow in the caudal vena cava increased to a greater extent than after nifedipine administration. The increased cranial and caudal vena cava flows after intravenous injection of finerenone were a result of vasodilatation of arterial vessels in the respective regions.

The clinical efficacy of many antihypertensive medications is constrained by their poor water solubility, low membrane permeability, significant first-pass metabolism, and uncertain oral bioavailability, even though hypertension is still a major worldwide health concern. For BCS Class II and IV medications like telmisartan, amlodipine, nifedipine, and carvedilol, these restrictions are especially important and call for creative delivery methods. Because of their unique dual hydrophilic-hydrophobic structure, amphiphilic chitosan derivatives have emerged as adaptable nanocarriers that may overcome these limitations. Chitosan can self-assemble into micelles, nanoparticles, nanoemulsions, and hybrid systems, with high encapsulation efficiency for lipophilic drugs when chemically modified with alkyl chains, fatty acids, bile acids, sterols, or synthetic polymer segments. By keeping medications in an amorphous, molecularly dispersed state and providing protection against gastrointestinal degradation, these nanostructures improve solubility. In addition to increasing solubility, amphiphilic chitosan improves drug permeation and systemic absorption by providing strong mucoadhesion, extended intestinal residence, and temporary modulation of tight junctions. Combined oral delivery with these carriers often results in a 2- to 3- fold increase in bioavailability and extended antihypertensive action in preclinical studies. Moreover, amphiphilic chitosan systems can provide sustained and extended release, with reduced peak-trough fluctuations and enhanced therapeutic stability. Their natural origin, biodegradability, acceptable safety profile, and regulatory acceptability strengthen their translation potential. This review carefully scrutinizes the chemistry and self-assembly processes, formulation strategies, pharmacokinetic advantages, safety-related issues, and potential uses of amphiphilic chitosan-based nanocarriers. All things considered, these technologies represent an interesting emerging delivery approach that may improve the oral bioavailability and therapeutic efficacy of poorly soluble antihypertensive drugs.

Renal arteriovenous malformations (AVMs) are uncommon vascular abnormalities that may present a diagnostic challenge, particularly in young patients undergoing evaluation for persistent hypertension. We present the case of a 20-year-old woman with hypertension that remained elevated despite treatment with lisinopril and extended-release nifedipine. During outpatient cardiology follow-up, her blood pressure was 163/91 mmHg, prompting further evaluation for a secondary cause. Renal ultrasonography demonstrated asymmetric kidney size, with the left kidney smaller than the right. Subsequent computed tomography angiography of the chest, abdomen, and pelvis demonstrated a normal aorta without evidence of coarctation and no significant stenosis of the main renal arteries. Despite unrevealing noninvasive vascular imaging, persistent clinical suspicion for an underlying renal vascular abnormality prompted selective renal angiography. Angiography revealed a hypervascular nidus in the lower pole of the left kidney supplied by a tortuous branch of the left main renal artery, consistent with a slow-flow renal AVM. Superselective embolization of the feeding vessel was performed through right distal radial access using a detachable microcoil. Final angiography demonstrated successful occlusion of the targeted AVM while preserving perfusion to the surrounding renal parenchyma. The procedure was completed without immediate complications. At four-month follow-up, hypertension persisted and required intensification of antihypertensive therapy, suggesting that the AVM could not be established as the sole cause of the patient's hypertension. This case highlights the importance of considering uncommon renal vascular abnormalities in young patients with severe hypertension and renal asymmetry when the initial evaluation is inconclusive. Selective renal angiography can provide detailed anatomic characterization while simultaneously offering an opportunity for targeted endovascular therapy.

Eucommia ulmoides leaves, a traditional edible and medicinal resource, are a rich source of bioactive polyphenols. In this study, male Wistar rats served as the normal control, while spontaneously hypertensive rats were randomized into model, positive control (nifedipine, 6.0 mg/kg/d), and low-, medium-, and high-dose groups receiving 1.25, 2.50, and 3.75 mL/kg/d of the polyphenol extract (n = 8/group) via intragastric gavage for 4 weeks. The extract supplementation significantly reduced systolic and diastolic blood pressure to approximately 166.33 mmHg and 113.93 mmHg, respectively, thereby improving vascular function (p < 0.05), accompanied by alleviation of lipid metabolism disorders and oxidative stress. In addition, it mitigated intestinal injury and enhanced gut barrier integrity. Notably, it reshaped the gut microbiota by enriching beneficial bacteria and suppressing harmful taxa, which is associated with increased production of short-chain fatty acids. Integrated metabolomics analysis further demonstrated that it modulated multiple metabolic pathways, particularly arachidonic acid and tryptophan metabolism, which are closely linked to vascular homeostasis, inflammation, and oxidative stress. Collectively, these findings indicate that the antihypertensive effects of the polyphenol extract are potentially linked to the regulation of the gut microbiota-metabolite axis, highlighting its promising application as a functional food ingredient for cardiovascular health.

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.

The cardiotoxicity of doxorubicin significantly restricts its effectiveness, even though it remains a crucial element of breast cancer chemotherapy. Nifedipine (NFP) offers multi-mechanistic therapeutic benefits, including vasodilation, anti-proliferative activities, suppression of cellular apoptosis, and potent anti-inflammatory and antioxidant properties. However, the translation of oral NFP into an effective cardioprotective adjuvant is hindered by its poor solubility, first-pass hepatic metabolism, and poor bioavailability. Hence, this study aimed to develop a nasal NFP-loaded ufasomes (NLU) spray formulation to enhance the permeation, bioavailability, sustained release, and cardiac accumulation of NFP when co-administered with doxorubicin. Various NLU formulations were developed and optimised employing Design-Expert[®] software. The in vivo cardioprotective efficacy of the nasal NLU was comprehensively evaluated in a doxorubicin-induced cardiotoxicity rat model. The optimal NLU substantially prolonged drug sustainability and amplified mucosal permeability by 69.07% and 6.47-fold, respectively, compared to the free NFP suspension. Furthermore, nasal NLU formulation achieved a remarkable 7.33-fold enhancement in bioavailability and a 5.40-fold increase in cardiac tissue accumulation when contrasted with conventional oral NFP administration. Furthermore, the nasal NLU spray exhibited superior cardioprotective and antioxidant performance over the oral NFP. In conclusion, these findings establish the nasal NLU formulation as a promising therapeutic platform to mitigate doxorubicin-induced cardiotoxicity.

Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital vascular disorder characterized by persistent, violaceous, reticulated skin changes that may be complicated by painful ulcerations. Although localized disease often improves with age, generalized CMTC can persist into adulthood and may be associated with limb asymmetry, ocular abnormalities, and neurologic sequelae. Diagnosis can be challenging in atypical adult presentations despite established major and minor criteria. We report a case of a 50-year-old woman with congenital livedo reticularis and Raynaud syndrome who presented with lifelong unilateral left lower-extremity hypoplasia and fixed lacy violaceous patches. Over the preceding decade, she developed recurrent, spontaneous, painful ulcerations exacerbated by cold exposure. Examination revealed a hypoplastic left leg with reticulated violaceous patches and tender, crusted erosions without venectasia; biopsy findings ruled out vasculitis, and the overall clinicopathologic picture met all three major and multiple minor Kienast-Hoeger criteria for CMTC. Multiple therapies targeting vasospasm and microvascular flow (including sildenafil, pentoxifylline, diosmiplex, nifedipine, and aspirin) failed to improve symptoms. Initiation of once-daily topical sirolimus (1 mg/mL) resulted in marked pain reduction within four weeks and cessation of new ulcerations, with visible improvement and healed erosions by two months. This case supports topical sirolimus as a promising off-label option for adult CMTC with chronic ulcerative disease.

To address the low predictability (92% clinical failure rate) and high costs associated with species differences in traditional animal testing, this research advocates for New Approach Methodologies (NAMs) in alignment with the US FDA Modernization Act 2.0. The central achievement presented is the development of a "human Heart-on-a-chip." This microfluidic device co-cultures human iPS-derived cardiomyocytes, fibroblasts, and vascular endothelial cells to mimic living 3D tissue structures and fluid environments. The system demonstrated superior physiological reproducibility compared to conventional methods in evaluating drug responses (e.g., nifedipine) and detecting fatal side effects like QT prolongation. In addition to the heart, applications are advancing across diverse organ and disease models, including the construction of ischemia-reperfusion injury models using kidney chips and pulmonary fibrosis models using lung chips, the evaluation of barrier functions via blood-brain barrier (BBB) chips, and the analysis of interactions between cancer cells and immune cells using cancer chips. It is concluded that these technologies enable high-precision in vitro reproduction of human physiology and pathology, thereby improving the efficiency of drug screening, reducing economic losses, and accelerating the paradigm shift toward the 3Rs (Replacement, Reduction, and Refinement) in animal experimentation.