Preterm birth occurs in approximately 10% of all pregnancies, and is not only the leading cause of neonatal mortality but also a major contributor to short- and long-term morbidities due to immaturity. Preterm birth has also been linked to an increased risk of maternal cardiovascular and cerebrovascular diseases, making it a critical concern in both perinatal medicine and women's lifelong health. Effective treatment requires interventions during threatened preterm labor, and several tocolytic agents have been developed and used in clinical practice. However, no pharmacological agent has been shown to prolong gestation and improve neonatal outcomes. Nifedipine, a calcium channel blocker, is widely used as a first-line tocolytic agent because of its oral administration route and relatively favorable safety profile compared with other drugs. Evidence from randomized controlled trials, meta-analyses, and Cochrane reviews suggests that nifedipine can delay delivery for a short period; however, robust evidence demonstrating sustained prolongation of pregnancy or improved neonatal survival is still lacking. Moreover, data on maternal hemodynamic changes and fetal effects are limited, highlighting the need for optimal dosing strategies and monitoring protocols. In this study, we discuss the clinical significance and limitations of nifedipine in the management of threatened preterm labor and outlined future directions. Future studies should involve large and homogeneous populations, continuous assessment of maternal hemodynamics, and application of novel biomarkers to support individualized therapy. Accumulation of such evidence is expected to optimize the management of threatened preterm labor and ultimately improve outcomes for mothers and infants.

Hypertension is leading non communicable disease associated with high morbidity and mortality. There is uncertainty about the superiority of angiotensin receptor blocker (ARB)-diuretic versus ARB-calcium channel blocker (CCB) combination for the treatment of hypertension. This meta-analysis compares the effectiveness of angiotensin receptor blocker (ARB)-diuretic versus ARB-calcium channel blocker (CCB) combination therapies in adults with hypertension. RCTs were identified through PubMed, Embase, Scopus, and Cochrane Central; data were analyzed using RevMan 5.4.1 with a random-effects model. Primary outcomes were mortality, systolic blood pressure (SBP), and diastolic blood pressure (DBP); secondary outcomes included serum electrolytes and renal function. 3549 studies were identified based on database searches. 19 studies were included for analyses. Meta-analysis revealed no significant difference between both the combination therapies for primary outcomes: all-cause mortality [RR: 1.19 (95% CI: 0.85 to 1.65; p = 0.31)], SBP [MD: 1.24 mmHg (95% CI: - 0.48 to 2.96; p = 0.16; I² = 59%)], and DBP [MD: 0.62 mmHg (95% CI: - 0.15 to 1.38; p = 0.11; I² = 0%)]. The diuretic group showed significant changes in serum sodium, chloride, creatinine, e-GFR, and increased uric acid. Risk of bias was mostly low, with moderate to high evidence certainty. Both ARB + CCB and ARB + diuretic combinations showed comparable effectiveness in lowering blood pressure and all-cause mortality in hypertensive adults. ARB + CCB seems to be having good safety profile, with better renal functions based on biomarkers.

This real-world, non-interventional, retrospective cohort study evaluated the achievement rate of guideline-recommended target blood pressure (BP) and representative safety profile of the treatment incorporating sacubitril/valsartan (Sac/Val) in Japanese patients with essential hypertension. Data were collected from electronic health records from ~4700 clinics across Japan, covering ~11.4% of the nationwide population. Of the 1405 eligible patients, 1247 were included in the effectiveness analysis. The primary endpoint investigated the proportion of patients achieving the Japanese Society of Hypertension 2019-recommended antihypertensive goals within 8 weeks of initial Sac/Val administration (index date). Secondary endpoints included description of baseline characteristics and their relative contribution to BP goal attainment, description of prescription patterns, and safety. A total of 29.8% of patients achieved individual estimated BP goals, with significant mean reductions in systolic and diastolic BPs (-15.6 mmHg and -6.1 mmHg, respectively, p < 0.0001). Patients aged ≥75 years, those with cerebrovascular disease, and those classified as Grade I hypertension were more likely to meet BP goals. Among patients with BP reduction of ≥10 mmHg, the most common prescription pattern at index date was a combination of calcium channel blocker (CCB) and Sac/Val, and a majority switched from CCB and angiotensin receptor blocker combination or were on CCB monotherapy. The most common signs of adverse events were hypotension and diuresis-related events, particularly during summer. The discontinuation rates following these signs were 1.0% and 0.8%. This real-world study demonstrated the clinical utility and representative safety profile of treatments involving Sac/Val in Japanese patients with essential hypertension.

Patients with chronic kidney disease (CKD) frequently experience cardiovascular events, and as per current therapeutic guidelines, renin-angiotensin system inhibitors (RASi) can protect the cardiovascular system in those with proteinuric CKD. Effectiveness of RASi in treating non-proteinuric CKD is still unknown, yet. In order to evaluate the impact of RASi on cardiovascular morbidity and mortality in patients with non-proteinuric CKD, we performed a post-hoc analysis of the Frontier of Renal Outcome Modification-Japan study. A urine protein-to-creatinine ratio less than 0.15 g/g or negative/trace protein on urinalysis was considered as non-proteinuric CKD. Those who have undergone dialysis, kidney transplant recipients, and patients who refused to give their consent were excluded. A composite of cardiovascular events, initiation of renal replacement therapy, and all-cause mortality was studied as the primary outcome. Of 2379 patients with CKD, 630 met the criteria for non-proteinuric CKD. Among them, 490 used RASi, and 140 did not. Although the RASi group was considerably younger and had a higher prevalence of hypertension and calcium channel blocker use, baseline characteristics were comparable. 12.1% of the control group and 16.7% of the RASi group experienced the primary outcome during follow-up, with no significant difference (adjusted HR: 1.37; 95% CI: 0.81-2.31). Secondary outcomes and analyses of RASi use for the whole observation period did not show any significant differences (adjusted HR: 0.81; 95% CI: 0.43-1.56). These results imply that RASi was not linked to a decreased risk of mortality or long-term events in those with nonproteinuric CKD.

Pharmaceutical excipients have traditionally been regarded as pharmacologically inert carriers, serving merely as vehicles for active pharmaceutical ingredients. However, this conventional paradigm is increasingly challenged by emerging evidence revealing clinically significant drug-excipient interactions that can profoundly influence therapeutic outcomes. This study investigates a previously unrecognized pharmacokinetic interaction between nimodipine, a dihydropyridine calcium channel blocker, and polysorbate 80, a commonly used solubilizing excipient in nimodipine formulations. A novel HPLC-MS/MS method for simultaneous quantification of nimodipine and polysorbate 80 was developed and validated, achieving excellent analytical performance with linearity (r > 0.995), precision (RSD < 15%), and accuracy (RE < 15%). Pharmacokinetic studies in rats revealed that polysorbate 80 co-administration dramatically enhanced nimodipine systemic exposure, increasing AUC by 51.1%, decreasing clearance by 36.5%, and prolonging half-life by 16.1%. Mechanistic investigations using rat liver microsomes demonstrated that polysorbate 80 competitively inhibited nimodipine metabolism with an IC50 of 103.30 μmol/L and Ki of 94.35 μmol/L, while remaining minimally metabolized itself. These findings provide the first evidence of a clinically significant pharmacokinetic interaction between nimodipine and polysorbate 80, challenging the assumption of excipient inertness and highlighting the critical importance of evaluating excipient-drug interactions in pharmaceutical development and clinical practice.

Fluorescence-based assay for rapid screening of GABAA receptor modulating steroid antagonists (GAMSA).

Heart rate control is one of the cornerstones of atrial fibrillation (AF) management and is recommended in all AF patients, even as background therapy for rhythm control. Both non-dihydropyridine calcium channel blockers and beta blockers are recommended as first choice rate control drugs, but no preference is given. Even though there are important differences in pharmacological mechanisms and side effects between these drugs, large randomized controlled trials are lacking. We aim to critically evaluate and synthesize the scientific evidence comparing calcium channel blockers and beta blockers. A systematic review is conducted in four databases: MEDLINE, Embase, Web of Science, and Cochrane Central, collecting all original research published up until March 2025. Studies including patients with AF (P) treated with non-dihydropyridine calcium channel blockers (I) or beta blockers (C) reporting heart rate (O) or other key secondary outcomes such as major adverse cardiac and cerebrovascular events or mortality will be included. Titles and abstracts, as well as full texts, will be screened by two reviewers, and results will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Assessment of risk of bias is evaluated using the Cochrane Risk-of-Bias (RoB 2) tool for randomized controlled trials and the Risk Of Bias In Non-Randomized Studies - of Interventions (ROBINS-I) tool for non-randomized studies. If sufficient homogeneous data are available, meta-analyses are performed. Current systematic reviews on rate control in AF have primarily focused on acute rate control using the intravenous administration of calcium channel blockers and beta blockers. However, systematic reviews comparing these two drug classes for long-term rate control are lacking, and current guidelines offer little guidance for choosing one drug over the other. This systematic review with meta-analysis will compare the effects of calcium channel blockers and beta blockers on heart rate and provide a comprehensive overview of clinical outcomes and side effects in the treatment of AF. It aims to provide a comprehensive overview, helping clinicians tailor rate control for individual patients. PROSPERO CRD42024526695.

The adult human heart is incapable of regeneration after myocardial infarction (MI) injury. One potential therapeutic strategy is to enhance the proliferation of resident cardiomyocytes (CMs). In this study, we developed a high-content screening assay based on DNA synthesis in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) to identify small molecules that could promote CM proliferation. In the primary screening, we found that L-type calcium channel (LTCC) blockers induced DNA synthesis of hPSC-CMs. Among the 6 clinically approved calcium channel blockers tested in secondary screening and confirmatory experiments, nimodipine (NM) consistently enhanced CM proliferation both in vitro and in vivo. RNA-Seq analysis revealed that NM activated the canonical Wnt signaling pathway, while inhibiting Wnt signaling blunted the proliferative effect of NM. Lrp5, a co-receptor for Wnt ligands known to interact with LTCC, was found to mediate the effect of NM to promote nuclear localization of β-catenin and CM proliferation. In the MI mouse model established by ligating the left anterior descending coronary artery, administration of NM (10 mg/kg, i.p.) for 7 consecutive days significantly improved cardiac contractile function and enhanced resident CM proliferation, which was attenuated by co-treatment with Wnt inhibitor Wnt-C59 (10 mg/kg, i.p.). Our data suggest that L-type calcium channel blockers that induce CM proliferation may be potentially used in the treatment of MI and heart failure to promote cardiac regeneration.

For patients with persistent atrial fibrillation (PersAF), initial treatment strategies often involve rate or rhythm control before offering ablation. This study compared two approaches: (1) catheter ablation without prior medication (referred to as direct-to-catheter ablation, DTCA) and (2) catheter ablation after initial rate control with either diltiazem or metoprolol. This study included two independentanalyses of patients with persistent atrial fibrillation (PersAF) undergoing catheter ablation. Aimed at evaluating the potential impact of pre-ablation rate control medications including beta blockers and calcium channel blockers on post-ablation outcomes. Comparison 1: DTCA without prior beta-blocker use (n = 209) vs. metoprolol use prior to ablation (n = 260). Comparison 2: DTCA without prior calcium channel blocker use (n = 639) vs. diltiazem use prior to ablation (n = 55). Patients were followed for 18 months to evaluate primary outcome: recurrence of atrial fibrillation (AF) and secondary outcomes: Pre-ablation and Post-ablation left atrial percent fibrosis as seen on LGE MRI and Quality of life (QoL), measured with the SF-36 questionnaire. The Wilcoxon tests were conducted to compare the QoL and fibrosis among groups. Time to recurrence among the groups post ablation was assessed via Kaplan-Meier curves. Multivariable Cox models were developed to adjust for other confounders of AF recurrence. In the beta-blocker analysis (n = 469), no significant difference in AF recurrence was observed between patients without prior beta-blocker use (DTCA group) and those treated with metoprolol (Kaplan-Meier, p > 0.05). Similarly, in the calcium channel blocker analysis (n = 694), no difference in recurrence was found between the DTCA group and those with prior diltiazem use (p > 0.05). Multivariable Cox models confirmed that neither metoprolol (p = 0.44) nor diltiazem (p = 0.34) independently predicted AF recurrence. Additionally, no significant differences were found in imaging metrics or QoL between the groups in either comparison (all p > 0.05). Prior treatment with diltiazem or metoprolol before ablation of PersAF did not show additional benefits in reducing patient outcomes such as AF recurrence, fibrosis, or improving QoL.

Acute anal fissure is a common cause of severe pain in the anorectal region. The standard treatment is the topical application of a calcium channel blocker or glyceryl trinitrate. Despite acute anal fissure being a common proctologic condition, data on the healing rates and long-term outcomes remain scarce. This study aimed to evaluate data from our centre, with a special focus on long-term follow-up and recurrent disease. All consecutive patients who presented with acute anal fissure between January 2016 and December 2016 were retrospectively identified. Patients were included if their clinical symptoms lasted for less than 6weeks, secondary changes to fissure morphology were absent, and data from follow-up examinations were available. Clinical features, symptoms, therapy and long-term outcomes were evaluated. A total of 623 patients with a median age of 45years were included; 342/623 patients were female (54.9%). The median follow-up period was 41months (range 6weeks-89months), and 39.5% of the patients had a follow-up duration exceeding 5years. Most fissures occurred in the 6o'clock lithotomy position (63.7%), in the 12o'clock position (21.0%), or in both (4.5%). In 67/623 patients, the fissure was in an atypical region (10.8%). In 439/623 patients, the fissure healed completely (70.5%). A total of 8.7% of the patients underwent fissurectomy, and 180/623 patients experienced recurrence (28.9%). The management of acute anal fissure can be challenging because recurrence is common. Conservative management is successful in the majority of cases. Surgery is necessary only for a minority of patients.

Vasoplegia, Cardiac Dysfunction, and Hypoxia: The Complicated Use of Extra Corporeal Membrane Oxygenation in Calcium Channel Blocker Toxicity.

Hypertension affects over one billion individuals worldwide and remains the leading modifiable risk factor for cardiovascular disease. While first-line therapies including thiazide-type diuretics, angiotensin converting enzyme inhibitors / angiotensin receptor blockers, and calcium channel blockers can effectively control blood pressure in many patients, 10-20% develop resistant hypertension requiring additional therapeutic approaches. Steroidal mineralocorticoid receptor antagonists (MRAs) have emerged as essential fourth-line agents for resistant hypertension, with spironolactone demonstrating superior efficacy compared to other add-on therapies in the landmark PATHWAY-2 trial. The pathophysiological rationale for MRAs includes natriuretic effects, vasodilatory properties and target organ protection through anti-fibrotic mechanisms. Novel non-steroidal MRAs offer improved selectivity and reduced endocrine side effects compared to traditional agents, potentially expanding the therapeutic window for mineralocorticoid receptor blockade. In this review, we discuss the established role of MRAs in primary and resistant hypertension management and discuss consideration of MRAs in certain hypertension patient populations. We also briefly review patient selection strategies and future directions for this important therapeutic class.

Background: Cannabidiol (CBD) is a major non-psychoactive phytocannabinoid that exerts multiple biological effects in the body. It has been shown to exert anti-cancer effects in a variety of cancer cells, including acute lymphoblastic leukemia of pre-T cell origin (T-ALL), a highly aggressive hematological malignancy. However, the mechanisms underlying CBD’s anti-cancer effects are not fully understood. Furthermore, cancer cells abundantly express surface CD47, which is a negative regulator of phagocytosis and linked with cell survival/death. Little is known about CBD effects on the expression of CD47 in T-ALL cells. The objectives of this study were to address these issues. Methods: Studies were conducted in vitro using Jurkat cells and human peripheral blood mononuclear cells in different culture conditions, CBD concentrations, and in the presence or absence of different reagents. Results: CBD downregulates CD47 expression and induces apoptosis in Jurkat cells. Similar biological effects of CBD were also observed in primary human CD4+ T cells, albeit at reduced levels. The CBD’s effects on CD47 expression and apoptosis were not rescued by a cannabinoid receptor (CBR)-2 agonist, a CBR-2 antagonist, or an anion channel blocker. However, these effects on CD47 expression and apoptosis were significantly rescued by a Voltage-Dependent Anion Channel (VDAC)-1 oligomerization inhibitor. Conclusions: Overall, we conclude that CBD downregulates CD47 expression and induces apoptosis involving VDAC-1 oligomerization. Furthermore, they also suggest that CBD’s pro-apoptotic effects on primary human T cells should also be monitored if it is used as an anti-cancer adjuvant or neo-adjuvant therapeutic in cancer patients.

We present a novel plasmonic imaging technique for real-time, label-free tracking of bioelectrical interactions in live pancreatic beta-cell networks. Surface plasmon resonance microscopy (SPRM) is utilized to reveal synchronized glucose-induced intensity oscillations that are suppressed by calcium channel blockers. These oscillations are observed at the subcellular scale with a resolution of 1 μm. The technique can also uncover the extracellular spread of these oscillations beyond the cells. We further combine SPRM with network analysis to quantify coordinated electrical activity within the living cell network using both amplitude and phase-based metrics. Our results demonstrate a new method for studying electrical communication in pancreatic beta-cells, which could be crucial for understanding dysregulation in diabetes and advancing treatment development. This technique holds promise for investigating electrical connectivity in biological cell networks with applications in neuroscience, cardiac science, and bioelectricity in cancer, microbiology, development and regeneration.

To investigate cerebral vasorelaxation of total flavonoids of Chuzhou chrysanthemum (TFCC) in rats and its mechanism. Cerebral basilar arteries (CBA) of rats were isolated, and the vasodilation induced by TFCC (10-2,560 mg/L) following pretension with 100 nmol/L U46619 or 30 mmol/L KCl were measured using a pressure myograph system. Addition of H2S synthase cystathionine-γ-lyase (CSE) inhibitor dl-propargylglycine (PPG, 100 µ mol/L), a large-conductance Ca2+-activated potassium (BKCa) channel blocker iberiotoxin (IBTX,100 nmol/L) and L-type Ca2+ channel blocker nifedipine (100 nmol/L) were added to determine the effect of pretreatment with the inhibitors on TFCC-induced vasorelaxation. KCl (30 mmol/L) was used as a contractile agent, TFCC (3.3-270 mg/L)-induced relaxation was detected by measuring the length of the long axis of rat cerebral vascular smooth muscle cells (VSMCs). Determination of the effect of pretreatment of VSMCs by IBTX or nifedipine on TFCC-induced cellular relaxation, and intracellular free Ca2+ concentration ([Ca2+]i) was detected by fluorescent method. Endothelial cells (ECs) were co-cultured with VSMCs to observe the effect of endogenous H2S on TFCC-induced relaxation in VSMCs. TFCC caused a concentration-dependent vasorelaxation in the rat CBA precontracted with KCl or U46619 (P<0.01). Endothelial removal markedly attenuated this vasodilation, but the remaining vasorelaxation was still significant (P<0.01). The TFCC-induced cerebral vasorelaxation was remarkably inhibited by PPG, IBTX and nifedipine (P<0.01). TFCC caused a significant relaxation of rat CBA VSMCs (P<0.01). Co-culture with wild-type cerebral ECs but not with cystathionine-γ-lyase- or 3-mercaptosulfotransferase-knockout ECs markedly enhanced TFCC-induced relaxation of VSMCs (P<0.05) and increased H2S content (P<0.01). TFCC decreased the [Ca2+]i in VSMCs (P<0.01), which was attenuated by PPG and IBTX. TFCC dilated rat CBA in both endothelium-dependent and -independent manner. Its endothelium-dependent dilation was probably involved in the blockade of L-type Ca2+ channels caused by endothelial H2S activating BKCa channels in VSMCs; its endothelium-independent relaxation was primarily from the direct blockade of the L-type Ca2+ channels in VSMCs.

GsMTx-4 reduces mechanical allodynia in a model of schwannomatosis-related pain.

Fentanyl is widely used perioperatively and illicitly as a drug of abuse. As a potent μ-opioid receptor agonist, fentanyl canonically inhibits excitability through Gαi/o intracellular signalling pathways resulting in analgesia and respiratory depression. However, fentanyl also paradoxically activates respiratory muscles causing a potentially lethal effect termed wooden chest syndrome. Here we show that fentanyl, but not morphine, causes a persistent tonic component of diaphragmatic muscle activity. Voltage-clamp studies reveal that fentanyl directly blocks a subset of ether-à-go-go-class potassium (K+) channels. These channels are widely expressed in spinal motoneurons, including those innervating the diaphragm. A significant fraction of these motoneurons are excited by fentanyl, concomitant with blockade of K+ currents. Taken together we identified a novel off-target mechanism for fentanyl action, independent of μ-opioid receptor activation. Our findings may inform the design of safer analgesics and generalize beyond the activation of motoneurons to other neuronal circuits implicated in fentanyl-related maladaptive behaviours. KEY POINTS: High doses of fentanyl can cause a lethal phenotype termed 'wooden chest syndrome' (WCS) resulting from tonic contractions of respiratory-associated musculature, precluding the ability to mechanically inflate the lungs. In vivo murine diaphragmatic electromyograms reveal a tonic component of muscle activity elicited by fentanyl, but not morphine. Fentanyl reversibly blocks a subset of ether-à-go-go (EAG)-class potassium channels (EAG/Kv10 and ERG/Kv11 subclasses) expressed in HEK293 cells. Computational docking of fentanyl into cryogenic electron microscopy structures of these potassium channels predicts a binding site beneath the K+ selectivity filter. RT-PCR and RNA-scope in situ experiments reveal widespread expression of EAG/Kv10 (Kcnh1, Kcnh5) and ERG/Kv11 (Kcnh2, Kcnh6, Kcnh7) transcripts in cervical motoneurons, including phrenic motoneurons retrogradely labelled from the diaphragm. In vitro patch-clamp recordings from cervical spinal sections identifies a significant fraction of phrenic motoneurons (44%) electrically excited by fentanyl, concomitant with the blockade of a non-inactivating voltage-gated potassium current. Direct block of EAG potassium channels by fentanyl may contribute to WCS.

Magnoliae Officinalis Cortex volatile oil alleviated asthma via dual cAMP-mediated pathways: Anti-Inflammation and Bronchodilation.

Hypertension is a global health burden and a major risk factor for cardiovascular disease, necessitating lifelong pharmacological intervention. While antihypertensive agents such as ACE inhibitors, ARBs, calcium channel blockers, and diuretics are essential for blood pressure control, their use is frequently accompanied by adverse drug reactions (ADRs) that can lead to poor adherence, treatment discontinuation, or life-threatening complications. With the emergence of novel therapeutics targeting aldosterone synthase, neprilysin, and central renin-angiotensin pathways, the landscape of hypertension management is evolving, bringing new safety challenges that demand rigorous post-marketing surveillance. Pharmacovigilance—through systematic ADR detection, reporting, and analysis—serves as a cornerstone in safeguarding patient safety, optimizing therapy, and guiding clinical decision-making. Embedding pharmacovigilance into hypertension care pathways, supported by timely reporting from healthcare professionals, is essential for reducing preventable harm and enhancing long-term treatment outcomes.

Hypertension (HTN) is both a cause and effect of Chronic kidney disease (CKD) and affects the vast majority of CKD patients. HTN control is important for those patients who are suffering from CKD. The risk and progression of CKD may reduce by controlling HTN. Now a days CKD is globally increasingly prevalent condition and is strongly associated with circumstance of cardiovascular disease (CVD). CKD is a rising health problem and one of the major causes of mortality. Control of HTN plays a major role in preventing its progression to end stage kidney disease and death. The objectives of the study were to evaluate the class, dosing schedule of antihypertensive prescribed in CKD and the percentage of monotherapy and combination therapy. This cross-sectional, observational study was conducted in the Department of Pharmacology in collaboration with the Department of Nephrology out patients' Department in Mymensingh Medical College Hospital, Bangladesh from January 2021 to December 2021. Most commonly used single drug is Calcium channel blocker (13.27%) and most commonly used combination therapy is Calcium channel blocker (CCB) and Angiotensin II receptor blockers (ARBs). It is concluded that in CKD with HTN, majority of patients were treated with combination therapy. CCB was found to be the commonest prescribed antihypertensive in monotherapy and in combination therapy. According to JNC8 guideline majority of the BP goals were achieved.