The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome (BrS), characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used for the treatment of type 2 diabetes. Here, we report a novel role of gliquidone in inhibiting Kv4.3 and Kv4.3/KChIP2 channels that encode the cardiac transient outward K+ currents responsible for the initial phase of action potential repolarization. Gliquidone results in concentration-dependent inhibition of both Kv4.3 and Kv4.3/KChIP2 fast or steady-state inactivation currents with an IC50 of approximately 8 μM. Gliquidone also accelerates Kv4.3 channel inactivation and shifts the steady-state activation to a more depolarizing direction. Site-directed mutagenesis and molecular docking reveal that the residues S301 in the S4 and Y312A and L321A in the S4-S5 linker are critical for gliquidone-mediated inhibition of Kv4.3 currents, as mutating those residues to alanine significantly reduces the potency for gliquidone-mediated inhibition. Furthermore, gliquidone also inhibits a gain-of-function Kv4.3 V392I mutant identified in BrS patients in voltage- and concentration-dependent manner. Taken together, our findings demonstrate that gliquidone inhibits Kv4.3 channels by acting on the residues in the S4 and the S4-S5 linker. Therefore, gliquidone may hold repurposing potential for the therapy of Brugada syndrome. SIGNIFICANCE STATEMENT: We describe a novel role of gliquidone in inhibiting cardiac Kv4.3 currents and the channel gain-of-function mutation identified from patients with Brugada syndrome, suggesting its repurposing potential for therapy for the heart disease.

As a novel acid-suppressing drug, vonoprazan shows the potential to replace traditional proton-pump inhibitors. With its widespread use, some adverse effects that require further study have emerged due to drug-drug interactions. Our study is the first experiment that evaluated the drug-drug interactions of eleven common cardiovascular drugs that inhibit vonoprazan metabolism in vitro and in vivo. Rat liver microsome incubation and molecular simulation docking were applied to explore the inhibition mechanism. Amlodipine and nifedipine showed inhibitory effects on vonoprazan metabolism in both rat and human liver microsomes in the first evaluation part in vitro. The inhibition mechanism analysis results demonstrated that amlodipine and nifedipine might inhibit the metabolism of vonoprazan by a mixed type of competitive and non-competitive inhibition. However, the pharmacokinetic data of the vonoprazan prototype revealed that amlodipine affected vonoprazan in vivo while nifedipine did not. Thus, more attention should be paid when amlodipine is prescribed with vonoprazan. Furthermore, the changes in its carboxylic acid metabolites MI hinted at a complex situation. Molecular simulation suggested the CYP2B6 enzyme may contribute more to this than CYP3A4, and further inhibitory experiments preliminarily verified this speculation. In conclusion, the use of vonoprazan with cardiovascular drugs, especially amlodipine, should receive particular attention in clinical prescriptions.

The residues of pharmaceuticals in surface waters of megacities and ecotoxicological implications are of particular concern. In this study, we combined field investigations and model simulations to explore the contamination of cardiovascular and lipid-lowering drugs, one group of the most prescribed medications globally, in surface waters of a typical megacity, Shanghai, with a high wastewater treatment ratio (≈96%). Among 26 target substances, 19 drugs were detected with aqueous concentrations ranging from 0.2 (ketanserin) to 715 ng/L (telmisartan). Of them, angiotensin II receptor antagonists, telmisartan and irbesartan, were dominant besides β-blockers. Spatial distribution analysis demonstrated their much higher levels in tributaries compared to the mainstream. The results of model simulations and field investigation revealed relatively low concentrations of cardiovascular and lipid-lowering drugs in surface waters of Shanghai compared to other cities in highly developed countries, which is associated with low per capita usage in China. Ecotoxicological studies in zebrafish embryos further revealed developmental effects, including altered hatching success and heart rate, by irbesartan, telmisartan, lidocaine, and their mixtures at ng/L concentrations, which are typical levels in surface waters. Overall, the present results suggest that the high wastewater treatment ratio was not sufficient to protect fish species in the aquatic ecosystem of Shanghai. Exposure to cardiovascular and lipid-lowering drugs and associated risks will further increase in the future due to healthcare improvements and population aging.

This study aimed to investigate the association between cardiovascular drugs and depression/anxiety in patients with cardiovascular disease (CVD). This meta-analysis was registered in PROSPERO (International Prospective Register of Systematic Reviews; CRD42020197839) and conducted in accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. The PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP databases were systematically searched to identify all available studies on this topic. Random-effects multivariate meta-regression was performed to investigate the sources of study heterogeneity. Review Manager version 5.3 and Stata 12.0 were used for data analyses. This meta-analysis included 54 studies with a total number of 212651 patients. Overall, in patients with CVD, aspirin (odds ratio [OR]:0.91, 95% confidence interval [CI]:0.86-0.96, P=0.02) was associated with a lower risk of depression, while calcium channel blockers (CCB) (OR:1.21, 95%CI:1.05-1.38, P=0.008), diuretics (OR:1.34, 95%CI:1.14-1.58, P=0.0005), and nitrate esters (OR:1.32, 95%CI:1.08-1.61, P=0.006) were associated with a higher risk of depression, additionally, statin (OR:0.79, 95%CI:0.71-0.88, P<0.0001) was associated with a lower risk of anxiety, but diuretics (OR:1.39, 95%CI:1.26-1.52, P<0.00001) was associated with a higher risk of anxiety. Subgroup analysis presented that, in patients with hypertension, β-blockers were associated with a higher risk of depression (OR:1.45, 95%CI:1.26-1.67, P<0.00001); in patients with coronary artery disease (CAD), statin (OR:0.77, 95%CI:0.59-0.99, P=0.04), and aspirin (OR:0.85, 95%CI:0.75-0.97, P=0.02) were associated with a lower risk of depression, while CCB (OR:1.32, 95%CI:1.15-1.51, P<0.0001) and diuretics (OR:1.36, 95%CI:1.12-1.64, P=0.002) were associated with a higher risk of depression, additionally, diuretics was associated with a higher risk of anxiety (OR:1.41, 95%CI:1.28-1.55, P<0.00001); in patients with heart failure, nitrate esters (OR:1.93, 95%CI:1.19-3.13, P=0.007), and diuretics (OR:1.58, 95%CI: 1.02-2.43, P=0.04) were associated with a higher risk of depression. The use of cardiovascular drugs should be considered when evaluating depression or anxiety in patients with CVD to improve the care and treatment of these patients.

Osteoarthritis (OA) and cardiovascular diseases (CVD) share many similar features, including similar risk factors and molecular mechanisms. A great number of cardiovascular drugs act via different ion channels and change ion balance, thus modulating cell metabolism, osmotic responses, turnover of cartilage extracellular matrix and inflammation. These drugs are consumed by patients with CVD for many years; however, information about their effects on the joint tissues has not been fully clarified. Nevertheless, it is becoming increasingly likely that different cardiovascular drugs may have an impact on articular tissues in OA. Here, we discuss the potential effects of direct and indirect ion channel modulating drugs, including inhibitors of voltage gated calcium and sodium channels, hyperpolarization-activated cyclic nucleotide-gated channels, β-adrenoreceptor inhibitors and angiotensin-aldosterone system affecting drugs. The aim of this review was to summarize the information about activities of cardiovascular drugs on cartilage and subchondral bone and to discuss their possible consequences on the progression of OA, focusing on the modulation of ion channels in chondrocytes and other joint cells, pain control and regulation of inflammation. The implication of cardiovascular drug consumption in aetiopathogenesis of OA should be considered when prescribing ion channel modulators, particularly in long-term therapy protocols.

Objective: This national survey was aimed at measuring the access to cardiovascular disease (CVD) medicines in terms of their availability, price, and affordability in Pakistan. This was done by using the standard WHO/Health Action International (HAI) methodology. Methods: The price and availability data for 18 CVD medicines were collected from public sector hospitals (n = 40) and private sector retail pharmacies (n = 40) in eight cities of Pakistan. The outcome measures were availability (calculated as percentage of health facilities stocked with listed medicines), medicine price to the international reference price ratio (i.e., median price ratio (MPR)), and affordability (calculated as number of days\' wages (NDWs) of the lowest paid unskilled government worker required to afford one-month treatment of a chronic disease). The affordability of standard treatment in Pakistan with four CVD drugs was compared with data from six other low and middle income countries (LMICs) using HAI database. Findings: The mean percent availability of CVD medicines was significantly low (p < 0.001) in the public sector as compared to the private sector, that is, 25.5% vs. 54.6% for originator brands (OBs) and 30.4% vs. 34.9% for lowest price generics (LPGs), respectively. For all OBs and LPGs, the inflation-adjusted mean MPR was 2.72 and 1, respectively. CVD medicines were found to be unaffordable with average NDWs of 6.4 and 2.2 for OBs and LPGs, respectively, that is, NDWs of more than 1. In international comparison with countries such as Sudan, Lebanon, Egypt, India, Afghanistan, and China, the affordability of standard treatment with selected CVD medicines (atenolol, amlodipine, captopril, and simvastatin) in Pakistan was found to be low. Overall, all four OBs and three out of four LPGs of selected CVD drugs were found unaffordable in Pakistan. Conclusion: This data indicated that the availability of selected CVD medicines was low in both public and private sector medicine outlets. Both OBs and LPGs were found unaffordable in the private sector, necessitating the redressal of pricing policies, structuring, and their implementation.

Cardiovascular risk factors and related disorders are common among older adults, and use of various classes of cardiovascular (CV) drugs could reduce the risk of cardiovascular disease (CVD). However, data are sparse with regard to the use of CV drugs among rural-dwelling older adults in China. Therefore, this population-based study aimed to describe use of CV drugs among older adults living in the rural communities in China, while taking into account the use of CV drugs for primary and secondary prevention of CVDs. This study included 5,246 participants (age ≥65 years; 57.17% women; 40.68% illiteracy) in the baseline examination of the MIND-China study. In March-September 2018, data on health-related factors, CVDs (ischemic heart disease, atrial fibrillation, heart failure, and stroke), and CV drug use were collected via face-to-face survey, clinical examination, and laboratory tests. We classified CV drugs according to the Anatomical Therapeutic Chemical classification system for western medications and specific cardiovascular effects for the products of traditional Chinese medicine (TCM). We conducted descriptive analysis. The overall prevalence of major cardiovascular risk factors ranged from 14.30% in diabetes and 23.81% in dyslipidemia to 66.70% in hypertension, and CVDs affected 35.07% of all participants (36.28% in women vs. 33.47% in men, p = 0.035). In the total sample, calcium channel blockers (C08) were most commonly used (10.39%), followed by TCM products (7.64%), hypoglycemic agents (A10, 4.73%), renin-angiotensin system (RAS)-acting agents (C09, 4.61%), and lipid-lowering agents (C10, 4.17%). The proportions of CV drugs for primary prevention (i.e., use of CV drugs among people without CVD) were 3.14% for antithrombotic agents (mainly aspirin), 1.38% for lipid-lowering agents, and 3.11% for RAS-acting agents; the corresponding figures for secondary prevention (i.e., use of CV drugs among people with CVD) were 13.97%, 9.35%, and 7.39%. In conclusion, despite highly prevalent cardiovascular risk factors and CVDs, a fairly low proportion of the rural-dwelling older adults take CV medications for primary and secondary prevention. Notably, TCM products are among the most commonly used CV drugs. These results call for additional efforts to promote implementation of the evidence-based recommendations for prevention of CVDs in the primary care settings.

Cardiovascular drugs and lipid regulating agents have emerged as major groups of environmental contaminants over the past decades. However, knowledge about their occurrence in freshwaters and their ecotoxicity is still limited. Here, we critically summarize the presence of 82 cardiovascular drugs and lipid regulating agents at a global-scale and represent their effects on aquatic organisms. Only about 71% of these pharmaceuticals in use have been analyzed for their residues in aquatic ecosystems and only about 24% for their effects. When detected in surface waters, they occurred at concentrations of dozens to hundreds of ng/L. In wastewaters, they reached up to several μg/L. Effects of cardiovascular drugs and lipid regulating agents have been extensively studied in fish and a few in invertebrates, such as Daphnia magna and mussels. These pharmaceuticals affect cardiac physiology, lipid metabolism, growth and reproduction. Besides, effects on spermatogenesis and neurobehavior are observed. Environmental risks are associated with beta-blockers propranolol, metoprolol, and lipid lowering agents bezafibrate and atorvastatin, where adverse effects (biochemical and transcriptional) occurred partially at surface water concentrations. In some cases, reproductive effects occurred at environmentally relevant concentrations. This review summarizes the state of the art on the occurrence of cardiovascular drugs and lipid regulating agents at a global-scale and highlights their risks to fish. Further research is needed to include more subtle changes on heart function and to explore non-investigated drugs. Their occurrence in freshwaters and impact on a diverse array of aquatic organisms are particularly needed to fully assess their environmental hazards and risks.

An effective dual preconcentration method involving off-line membrane supported liquid-liquid-liquid microextraction (MS-LLLME) and on-line field-amplified sample injection (FASI) was proposed for the extraction of six cardiovascular drugs, including mexiletine, xylocaine, propafenone, propranolol, metoprolol, and carvedilol from aqueous solution prior to CE-UV. In MS-LLLME, the analytes were extracted from 9 mL sample solution into toluene, and then back extracted into a drop of acceptor phase of 10 μL 20 mmol/L acetic acid. After that, the acceptor phase was directly introduced into CE for FASI without any modification. In FASI process, water plug was hydrodynamically injected (50 mbar, 3 s) into the capillary prior to sample injection (+6 kV, 18 s). Six target analytes were separated in less than 10 min at 25°C with a BGE consisting of 70 mmol/L Tris-H3 PO4 (pH 2.2) containing 10% v/v methanol. Under the optimized conditions, LODs obtained by the proposed MS-LLLME-FASI-CE-UV method were in the range of 0.02-0.82 μg/L (based on S/N = 3) with enrichment factors of 546- to 7300-fold for the target analytes. The RSDs of the developed method were in the range of 6.7-12.9% (n = 7). Good linearity (R(2) = 0.9928-0.9997) was obtained in concentration range of 0.1-100 μg/L for mexiletine and propranolol, 0.2-100 μg/L for xylocaine and metoprolol, 0.5-100 μg/L for propafenone and 2.0-100 μg/L for carvedilol, respectively. The developed method was successfully applied for real-time determination of metoprolol in human urine samples within 26 h after uptake.

BACKGROUND: Pharmaceutical expenditure has grown by 16% per annum in China, enhanced by incentives for physicians and hospitals. Hospital pharmacies dispense 80% of medicines in China, accounting for 46% of total hospital expenditure. Principal measures to moderate drug expenditure growth include pricing initiatives as limited demand-side measures.
OBJECTIVE: Assess current utilization and expenditure including traditional Chinese medicines (TCMs) between 2006 and 2012.
METHODS: Uncontrolled retrospective study of medicines to treat cardiovascular and cerebrovascular diseases in one of the largest hospitals in southwest China.
RESULTS: Utilization increased 3.3-fold for cerebrovascular medicines, greatest for TCMs, with expenditure increasing 4.85-fold. Low prices for generics were seen, similar to Europe. However, there was variable utilization of generics at 29-31% of total product volumes in recent years. There continued to be irrationality in prescribing with high use of TCMs, and the utilization of different medicines dropping significantly once they achieved low prices.
CONCLUSIONS: Prices still have an appreciable impact on utilization in China. Potential measures similar to those implemented among western European countries could improve prescribing rationality and conserve resources.