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Background Vitamin K 2 contributes to bone and cardiovascular health. Therefore, two vitamin K 2 homologues, menaquinone-4 (MK-4) and menaquinone-7 (MK-7), have been used as nutrients by the food industry and as nutritional supplements to support bone and cardiovascular health. However, little is known about the bioavailability of nutritional MK-4. To investigate MK-4 and MK-7 bioavailability, nutritional doses were administered to healthy Japanese women. Findings Single dose administration of MK-4 (420 μg; 945 nmol) or MK-7 (420 μg; 647 nmol) was given in the morning together with standardized breakfast. MK-7 was well absorbed and reached maximal serum level at 6 h after intake and was detected up to 48 h after intake. MK-4 was not detectable in the serum of all subjects at any time point. Consecutive administration of MK-4 (60 μg; 135 nmol) or MK-7 (60 μg; 92 nmol) for 7 days demonstrated that MK-4 supplementation did not increase serum MK-4 levels. However, consecutive administration of MK-7 increased serum MK-7 levels significantly in all subjects. Conclusions We conclude that MK-4 present in food does not contribute to the vitamin K status as measured by serum vitamin K levels. MK-7, however significantly increases serum MK-7 levels and therefore may be of particular importance for extrahepatic tissues.

A sustained-release (SR) formulation of cilostazol was recently developed in Korea and was expected to yield a lower C max and a similar AUC to the immediate-release (IR) formulation. The goal of the present study was to compare the pharmacokinetic profiles of a newly developed SR formulation and an IR formulation of cilostazol after single- and multiple-dose administration and to evaluate the influence of food in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. This was a randomized, 3-part, sequential, open-label, 2-period crossover study. Each part consisted of different subjects between the ages of 19 and 55 years. In part 1, each subject received a single dose of SR (200 mg × 1 tablet, once daily) and IR (100 mg × 2 tablets, BID) formulations of cilostazol orally 7 days apart in a fasted state. In part 2, each subject received a single dose of the SR (200 mg × 1 tablet, once daily) formulation of cilostazol 7 days apart in a fasted and a fed state. In part 3, each subject received multiple doses of the 2 formulations for 8 consecutive days 21 days apart. Blood samples were taken for 72 hours after the dose. Cilostazol pharmacokinetics were determined for both the parent drug and its metabolites (OPC-13015 and OPC-13213). Adverse events were evaluated through interviews and physical examinations. Among the 92 enrolled subjects (66 men, 26 women; part 1, n = 26; part 2, n = 26; part 3, n = 40), 87 completed the study. In part 1, all the primary pharmacokinetic parameters satisfied the criterion for assumed bioequivalence both in cilostazol and its metabolites, yielding 90% CI ratios of 0.9624 to 1.2323, 0.8873 to 1.1208, and 0.8919 to 1.1283 for C max and 0.8370 to 1.0134, 0.8204 to 0.9807, and 0.8134 to 0.9699 for AUC 0–last of cilostazol, OPC-13015, and OPC-13213, respectively. In part 2, food intake increased C max and AUC significantly ( P < 0.0001), yielding geometric mean ratios of 3.2879, 2.9894, and 3.0592 for C max and 1.7001, 1.7689, and 1.6976 for AUC 0–last of cilostazol, OPC-13015, and OPC-13213. In part 3, only the C ssmax of clilostazol in the reference formulation did not satisfy the criterion for assumed bioequivalence, yielding 90% CI ratios of 1.2693 to 1.4238 and 1.2038 to 1.3441, respectively. When each dose was normalized, the C max for the SR formulation was significantly lower ( P < 0.005 for cilostazol). Headache was the most frequently noted adverse effect (part 1, a total of 14 subjects with the IR formulation and 14 with the SR formulation; part 2, a total of 10 without food and 23 with a high-fat meal; part 3, a total of 10 with the IR formulation and 24 with the SR formulation), followed by nausea (part 1, none; part 2, only 1 without food and 3 with a high-fat meal; part 3, a total of 3 with the IR formulation and 3 with the SR formulation), and then dizziness (parts 1 and 2, none; part 3, a total of 4 with the IR formulation and 5 with the SR formulation). All other AEs, including fever, cough, vomiting, palpitation, diarrhea, and epigastric pain, occurred in <3 subjects. These findings suggest that in this select group of healthy Korean volunteers, the SR formulation of cilostazol was not significantly different in AUC compared with that of the IR formulation, although it did display a significantly lower C max per dose in both the single- and multiple-dose groups. Food significantly increased the bioavailability of the SR formulation. The cilostazol SR and IR formulations were well tolerated in all parts of the study, with no serious adverse events reported. ClinicalTrials.gov identifier: NCT01455558.

This study evaluated the adherence to prescribed cardiovascular therapy medications among cardiovascular disease patients attending clinics in Misan, Amara, Iraq. Mixed methods were used to assess medication adherence comprising the Arabic version of the eight-item Morisky Medication Adherence Scale (MMAS-8) and determination of drug concentrations in patient dried blood spot (DBS) samples by liquid chromatography-high resolution mass spectrometry. Three hundred and three Iraqi patients (median age 53 years, 50.5% female) who had been taking one or more of the nine commonly prescribed cardiovascular medications (amlodipine, atenolol, atorvastatin, bisoprolol, diltiazem, lisinopril, losartan, simvastatin and valsartan) for at least six months were enrolled. For each patient MMAS-8 scores were determined alongside drug concentrations in their dried blood spot samples. Results from the standardized questionnaire showed that adherence was 81.8% in comparison with 50.8% obtained using the laboratory-based microsample analysis. The agreement between the indirect (MMAS-8) and direct (DBS analysis) assessment approaches to assessing medication adherence showed significantly poor agreement (kappa = 0.28, P = 0.001). The indirect and direct assessment approaches showed no significant correlation between nonadherence to prescribed cardiovascular pharmacotherapy and age and gender, but were significantly associated with the number of medications in the patient’s treatment regimen (MMAS-8: Odds Ratio (OR) 1.947, 95% CI, P = 0.001; DBS analysis: OR 2.164, 95% CI, P = 0.001). The MMAS-8 results highlighted reasons for nonadherence to prescribed cardiovascular pharmacotherapy in this patient population whilst the objective DBS analysis approach gave valuable information about nonadherence to each medication in the patient’s treatment regimen. DBS sampling, due its minimally invasive nature, convenience and ease of transport is a useful alternative matrix to monitor adherence objectively in Iraq to cardiovascular pharmacotherapy. This information combined with MMAS-8 can provide clinicians with an evidence-based novel approach to implement intervention strategies to optimise and personalise cardiovascular pharmacotherapy in the Iraqi population and thereby improve patient health outcomes.

Cardiovascular diseases are the major cause of global mortality, and often require the concomitant use of a number of drugs to prevent and reduce these deaths. The challenge is to find effective and accurate methods for analyzing these drugs in plasma. This research introduces an innovative, sustainable HPLC-FLD method for the concurrent determination of bisoprolol (BIS), amlodipine besylate (AML), telmisartan (TEL), and atorvastatin (ATV) within human plasma. Chromatographic separation was achieved using an isocratic elution mode on a Thermo Hypersil BDS C18 column (150 × 4.6 mm, 5.0 μm), while the mobile phase comprised of ethanol and 0.03 M potassium phosphate buffer (pH 5.2) in a 40:60 ratio, with a flow rate of 0.6 mL/min. The eluate was analyzed using UV detection within the wavelength range of 210–260 nm to confirm effective separation of the four cardiovascular drugs. For enhanced specificity, a fluorescence detector was set to 227ex/298em for BIS, 294ex/365em for TEL, 274ex/378em for ATV, and 361ex/442em for amlodipine. The method was validated following the International Council for Harmonisation (ICH) guidelines. Linearity was established within the ranges of 5–100 ng/mL for BIS and AML, 0.1–5 ng/mL for TEL, and 10–200 ng/mL for ATV, ensuring accuracy and precision. The significant of the current work represented in introduction of a highly sensitive, and selective analytical method, utilizing an economical sample preparation strategy, for the simultaneous determination of four different cardiovascular drugs (bisoprolol, amlodipine, telmisartan, and atorvastatin) in spiked human plasma. The extraction of sample was carried by liquid-liquid extraction (LLE) and analyzed by LC-fluorescence detector. The chromatographic run was short (less than10 min) which is a greet economical value.

The pharmacokinetics and the effects of a single intramuscular (IM) dose of alfaxalone on sedation and cardiopulmonary and echocardiographic variables was studied in dogs. Twelve healthy adult Beagles (3 females, 9 males) were used in this prospective controlled cross-over trial. Echocardiography was performed with and without 4 mg kg(-1) alfaxalone IM with a week wash-out interval. Sedation (19-point scale; 0 = no sedation), cardiopulmonary parameters, blood gas analysis and plasma concentration of alfaxalone were assessed every 5 minutes following the injection (T0). The influence of the alfaxalone plasma concentration and time on physiological variables was tested using a linear model whereas echocardiographic measurements were compared between conscious and alfaxalone-administered dogs using paired t-tests. Compared to baseline, alfaxalone administration was followed by an increase in heart rate (HR) from T5 to T30 and a decrease in mean arterial pressure (MAP) at T10, T25 and T30, in stroke volume (SV; 15 +/- 5 to 11 +/- 3 ml; P<0.0001), and end-diastolic volume (EDV; 24.7 +/- 5.7 to 19.4 +/- 4.9 ml). Cardiac output (CO) and blood gas analysis did not change significantly throughout. Mean plasma half-life was 29 +/- 8 minutes, volume of distribution was 1.94 +/- 0.63 L kg(-1), and plasma clearance was 47.7 +/- 14.1 ml kg(-1) minute(-1). Moderate to deep sedation was observed from T5 to T35. Ten dogs showed paddling, trembling, nystagmus and strong reaction to sound during the procedure. Although there were no significant changes in CO and oxygenation, the impact of HR, MAP, SV, EDV alterations requires further investigations in dogs with cardiac disease.

Background Heart failure is a major cause of morbidity and mortality in society. Current medical therapy centres on neurohormonal modulation with angiotensin converting enzyme inhibitors and β-blockers. There is growing evidence for the use of metabolic manipulating agents as adjunctive therapy in patients with heart failure. We aim to determine the effect of perhexiline on cardiac energetics and alterations in substrate utilisation in patients with non-ischaemic dilated cardiomyopathy. Methods A multi-centre, prospective, randomised double-blind, placebo-controlled trial of 50 subjects with non-ischaemic dilated cardiomyopathy recruited from University Hospital Birmingham NHS Foundation Trust and Cardiff and Vale NHS Trust. Baseline investigations include magnetic resonance spectroscopy to assess cardiac energetic status, echocardiography to assess left ventricular function and assessment of symptomatic status. Subjects are then randomised to receive 200 mg perhexiline maleate or placebo daily for 4 weeks with serum drug level monitoring. All baseline investigations will be repeated at the end of the treatment period. A subgroup of patients will undergo invasive investigations with right and left heart catheterisation to calculate respiratory quotient, and mechanical efficiency. The primary endpoint is an improvement in the phosphocreatine to adenosine triphosphate ratio at 4 weeks. Secondary end points are: i) respiratory quotient; ii) mechanical efficiency; iii) change in left ventricular (LV) function. Trial Registration ClinicalTrials.gov: NCT00841139 ISRCTN: ISRCTN2887836

A dried blood spot (DBS) sampling method was exploited to extract cardiovascular drugs using a small volume of whole blood of human and rodent. Thereafter, an analytical method using liquid chromatography with tandem mass spectrometry (LC-MS/MS) was developed and validated for the determination of 12 cardiovascular drugs. A 6 mm internal diameter disc containing 10 μL of blood was punched from a specifically designed card and analyzed by LC-MS/MS using a gradient elution method with a total run time of 16 min. For sample separation, a universal octadecyl-silica column was used with a flow rate of 0.2 mL/min. The developed method was validated in terms of linearity, accuracy, and precision, which showed satisfactory results. In addition, the matrix effects were closely investigated to confirm the extraction efficiency. Additionally, the stability was tested by storing DBSs at room temperature; the results showed that these drugs were stable for at least 30 days. Accordingly, the proposed LC-MS/MS method is capable to analyze several cardiovascular drugs in a single analysis. It can be applied to therapeutic drug monitoring in patients as well as in the in vivo settings. [Display omitted] •Multiclass cardiovascular drugs were determined in dried blood spot samples.•Several extraction methods were compared to determine the most efficient method.•A simple and fast LC-MS/MS method was developed and validated.•The developed method was successfully applied to quantify drugs in real samples.

Background: Treatment options for the closure of a hemodynamically significant patent ductus arteriosus (hsPDA) include medical therapy such as ibuprofen and indomethacin and surgical ligation. Objective: To evaluate the efficacy of intravenous paracetamol in preterm infants with hsPDA whose feeding was contraindicated or had feeding intolerance. Methods: Preterm infants with hsPDA were started on intravenous paracetamol treatment with parental consent. Paracetamol was administered at a dose of 60 mg/kg/day, in four divided doses, for a period of 3 days. In the absence of closure of hsPDA, treatment was extended up to 6 days, after which echocardiographic examination was performed. Results: A total of 10 preterm infants were included in the study with a median gestational age of 27 4/7 weeks (minimum–maximum: 24–29) and a median birth weight of 775 g (590–990). The first dose of intravenous paracetamol was given after a median of 6 days (2–15). On echocardiographic examination, median internal ductal diameter was 2 mm (1.5–3), with a median left atrium-to-aortic root ratio of 1.95 (1.6–2.2). Intravenous paracetamol resulted in successful closure of hsPDA in all patients. Conclusions: This study is the first case series in the literature which used intravenous paracetamol treatment for hsPDA. We believe that intravenous paracetamol could be used as an alternative drug for infants. Further prospective randomized-controlled trials are needed to evaluate the efficacy of intravenous paracetamol for the closure of hsPDA.

Background Levamlodipine, a calcium channel blocker, has been show act as a cardiovascular drug. To compare the pharmacokinetic parameters between levamlodipine (test formulation) at a single dose of 5 mg and amlodipine (reference formulation) at a single dose of 10 mg, the bioequivalence study was carried out. Methods A single-dose randomized, open-label, two-period crossover study was designed in healthy Chinese subjects. 48 subjects were divided into fasted and fed groups equally. The subjects randomly received the test or reference formulations at the rate of 1:1. Following a 21-day washout period, the alternative formulations were received. The blood samples were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168 h later. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentrations of levamlodipine. Adverse events were recorded. Results The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of C max , AUC 0-t , and AUC 0-∞ under both fasted and fed conditions were within the prespecified bioequivalence limits between 80 ~ 125%. Under fasted conditions, 24 subjects were enrolled and completed the study. The mean C max was (2.70 ± 0.49) ng/mL, AUC 0-t was (141.32 ± 36.24) ng × h/mL and AUC 0-∞ was (157.14 ± 45.65) ng × h/mL after a single dose of 5 mg levamlodipine. The mean C max was (2.83 ± 0.52) ng/mL, AUC 0-t was (153.62 ± 33.96) ng × h/mL and AUC 0-∞ was (173.05 ± 41.78) ng × h/mL after a single dose of 10 mg amlodipine. Under fed conditions, 24 subjects were enrolled and completed the study. The mean C max was (2.73 ± 0.55) ng/mL, AUC 0-t was (166.93 ± 49.96) ng × h/mL and AUC 0-∞ was (190.99 ± 70.89) ng × h/mL after a single dose of 5 mg levamlodipine. The mean C max was (2.87 ± 0.81) ng/mL AUC 0-t was (165.46 ± 43.58) ng × h/mL and AUC 0-∞ was (189.51 ± 64.70) ng × h/mL after a single dose of 10 mg amlodipine. Serious adverse event was not observed. Conclusion The trial confirmed that levamlodipine at a single dose of 5 mg and amlodipine at a single dose of 10 mg were bioequivalent under both fasted condition and fed condition. Trial registration Cinicaltrials, NCT04411875 . Registered 3 June 2020 - Retrospectively registered

microRNAs (miRNAs) are a class of conserved, short, non-coding RNAs that have important and potent capacities to regulate gene expression at the posttranscriptional level. In the past several years, the aberrant expressions of miRNAs in the cardiovascular system have been widely reported, and the crucial roles of some special miRNAs in heart development and pathophysiology of various cardiovascular diseases have been gradually recognized. Recently, it was discovered that miRNAs are presented in peripheral circulation abundantly and stably. This has raised the possibility of using circulating miRNAs as biomarkers for diseases. Furthermore, some studies demonstrated that circulating miRNAs may serve as novel extracellular communicators of cell-cell communication. These discoveries not only reveal the functions of circulating miRNAs in cardiovascular system but also inform the development of miRNAs therapeutic strategies. In this review, we discuss the potential roles of circulating miRNAs in a variety of cardiovascular diseases from biomarkers to therapeutic targets to clearly understand the roles of circulating miRNAs in cardiovascular system.