Renal Function Protection as an Important Component of a Comprehensive Approach to the Management of Patients with Atrial Fibrillation

The increase in the life expectancy of the population is accompanied by an increase in the prevalence of diseases for which old and senile age are risk factors. Atrial fibrillation (AF) and chronic kidney disease (CKD) are two diseases that can coexist in a patient. The risk of ac thromboembolic and hemorrhagic events in this case increases due to the mutual aggravating influence of these diseases. In addition, these patients have a high incidence of coronary events, and cardiovascular complications are the main cause of death in patients with AF and CKD. Consequently, such patients require an integrated approach to treatment, and their management is a complex clinical task. The direct oral anticoagulant rivaroxaban has been most studied in a population of comorbid AF and CKD patients and has proven a high efficacy and safety profile in these patients in randomized controlled trials. In addition, rivaroxaban has shown a significant reduction in the risk of myocardial infarction in various patients, as well as the possibility of preserving renal function to a greater extent compared with warfarin therapy, and a possible positive effect on reducing the risk of cognitive impairment. A single dosing regimen can improve adherence to treatment, which is one of the key conditions for achieving the above effects. Thus, these factors make it possible to achieve comprehensive protection of comorbid patients with AF and CKD.

Unmet needs and evolving treatment for limb girdle muscular dystrophies

Limb-girdle muscular dystrophies (LGMDs) represent a major group of muscle disorders. Treatment is sorely needed and currently expanding based on safety and efficacy adopting principles of single-dosing gene therapy for monogenic autosomal recessive disorders. Gene therapy has made in-roads for LGMD and this review describes progress that has been achieved for these conditions. This review first provides a background on the definition and classification of LGMDs. The major effort focuses on progress in LGMD gene therapy, from experimental studies to clinical trials. The disorders discussed include the LGMDs where the most work has been done including calpainopathies (LGMD2A/R1), dysferlinopathies (LGMD2B/R2) and sarcoglycanopathies (LGMD2C/R5, LGMD2D/R3, LGMD2E/R4). Early success in clinical trials provides a template to move the field forward and potentially apply emerging technology like CRISPR/Cas9 that may enhance the scope and efficacy of gene therapy applied to patient care.

Pharmacokinetics Evaluation of Acamprosate Tablets in Healthy Human Volunteers

Pharmacokinetic data of acamprosate tablets was not accessible on large number of human. Rationale to examine the pharmacokinetic properties of acamprosate calcium in healthy male subject, on single or multiple dosage administration, to evaluate the bioequivalence of two formulations of acamprosate calcium tablets in fast or fed environment. This work engross the study of pharmacokinetic property of Acamprosate calcium tablets in single dosing under fasting condition. Methods: Bioequivalence study of delayed release acamprosate tablets 333 mg for a randomized, single dose, open label, two treatment, two periods, two sequences and crossover design in 12 healthy, adult human subjects under fasting condition was conducted. The wash out period within the each treatment and each stage was 1 week. The quantification of acamprosate was done by LCMS/MS method. Accessibility was evaluated by monitoring adverse events, physical examinations and ECG and laboratory tests. Results: The entire study was conducted by using 12 male subjects to fulfill all stages in the study. The pharmacokinetic calculations for test and reference formulations are as follows: single dosing, Tmax 8.54 ± 5.24 and 10.71 ± 5.41 h, Cmax 146.06 ± 99.73 and 115.01 ±86.26 ng · mL−1, AUC0-t 1391.95 ± 731.24 and 1557.03 ± 960.98 ng·mL−1·h, AUC0–∞ 1987.40 ± 962.84 and 2720.21 ± 1931.79 ng·mL−1·h, respectively. In all three stages, 90% CIs for the test/reference ratio of AUC0–t and AUC0–∞ was to be found within 80% –125% of acamprosate calcium. Conclusions: As per regulatory guidelines, pharmacokinetics parameters for acamprosate calcium were found to be within the acceptance criteria.

A novel n-3 glyceride mixture enhances enrichment of EPA and DHA after single dosing in healthy older adults: results from a double-blind crossover trial

A glyceride mixture of monoglyceride, diglyceride and TAG increases solubilisation and enhances emulsification of n-3 fatty acid (FA)-containing lipids in the stomach. This allows for better access of digestive enzymes, pivotal for the release of bioactive n-3 FA. The objective was to compare the effect of a glyceride formulation and an ethyl ester formulation of EPA + DHA on concentrations of EPA and DHA in plasma following single dosing. We conducted a double-blind crossover trial in which twenty healthy adults aged 50–70 years consumed a single dose (2·8 g EPA + DHA) of each EPA + DHA formulation without a meal in random order separated by a 2-week washout period. EPA and DHA were measured in plasma total lipid over the following 12 h. EPA and DHA in plasma total lipid increased over 12 h with both formulations. A 10-fold greater Δ concentration of EPA, 3-fold greater Δ concentration of DHA and 5-fold greater Δ concentration of EPA + DHA were seen with the glyceride-EPA + DHA. The time at which the maximal concentrations of n-3 FA occurred was 4 h earlier for EPA, 1 h earlier for DHA and 2 h earlier for EPA + DHA when consuming glyceride-EPA + DHA. A mixture of monoglyceride, diglyceride and TAG results in greater and faster incorporation of EPA and DHA into blood plasma lipid in the absence of a fatty meal. This may provide benefit to individuals on a low-fat diet or with digestive impairments and could result in greater efficacy in clinical trials using n-3 FA.

NOM removal and residual Al minimization by enhanced coagulation: roles of sequence dosing with PACl–FeCl3

To remove higher proportions of natural organic matter (NOM) in water treatment plants, over dosing of Al-based coagulant is frequently applied. However, this leads to the risk of an excess of coagulant residue in the clean water. In this study, sequential coagulation with polyaluminum chloride (PACl) and FeCl3 was proposed to improve the removal of NOM as well as to minimize residual Al. Single dosing with either PACl or FeCl3 in particular was compared with sequential coagulation, with different dosing sequences of PACl–FeCl3 (P–F) or FeCl3–PACl (F–P). At optimum dosage, sequential coagulation P–F showed twice as much dissolved organic carbon (DOC) removal from water containing algogenic organic matter, compared to single dosing of PACl and sequential coagulation F–P. However, sequential coagulation F–P was the most effective approach for humic substance removal that improved DOC removal up to >70% compared to other dosing approaches (<60%). Practical treatment with real water also showed the advantages of sequential coagulation with P–F in improving the removal of low SUVA NOM by 18% compared to the traditional single dosing of PACl. As expected, the Al residues found in both sequential coagulation (0.07 mg/L) were significantly reduced compared to single dosing with PACl (0.15 mg/L), indicating the promising application of sequential coagulation for future safe water treatment.

The use of Multi-compartment Compliance Aids (MCAs) in Pharmacies in England and North Wales

Multicompartment compliance aids (MCAs) are devices with each discrete section denoting a single dosing occasion. The purpose of an MCA is to maximize patient adherence and thereby optimize the treatment benefits. These devices are widely employed throughout western Europe and UK and use appears to be rapidly increasing (2) although the RPS as moved away from these devices as a means to improve adherence. We analysed MCAs from various pharmacies over a wide geographic area in England and North Wales. We concluded that most MCA users are elderly patients. Also, most of the patients suffer of combined cardiovascular disease. However, a significant proportion of patients falls in the mental/ neurological disease category. Additionally, most of the externals added to MCAs are inhalers and painkillers. Moreover, SDIs are more frequent in female patients and these SDI are mainly related with mental health medication, cardiovascular disease medication and neurological medication. In conclusion, a directive for dispensing of MCAs in pharmacies by pharmacists through an enhanced service should be elaborated having in consideration PIMs, SDIs, drug stability and use of externals and MCA design and brand.

Del Nido cardioplegia in coronary surgery: a propensity-matched analysis

OBJECTIVES Del Nido cardioplegia (DNC) has been shown to be safe in adults with normal coronary arteries who are undergoing valve surgery. This study compared the effects of DNC versus traditional blood-based cardioplegia on postoperative complications in patients who underwent coronary artery bypass grafting (CABG). METHODS A retrospective analysis was performed on 863 patients who underwent CABG with DNC (n = 420) or control cardioplegia (CC) (n = 443) between 2014 and 2017. The full cohort of DNC and CC recipients, as well as propensity score-matched pairs, was compared regarding preoperative risk variables and outcomes. RESULTS The DNC and CC groups showed no significant differences in mean cardiopulmonary bypass time (53.09 vs 52.10 min, P = 0.206) or aortic cross-clamp time (32.82 vs 33.28 min, P = 0.967). The groups also showed no difference in operative mortality (2.1% vs 2.5%, P = 0.734); however, DNC use resulted in lower rates of overall infections (1.7% vs 4.3%, P = 0.024), total sternal infections (0.9% vs 3.2%, P = 0.023), postoperative atrial fibrillation (23.8% vs 30.7%, P = 0.023) and postoperative ventricular tachycardia (0.5% vs 3.4%, P = 0.002). A propensity-matching analysis (n = 335 pairs) showed similar statistically significant decreases with DNC. CONCLUSIONS In this large cohort of CABG patients, DNC was shown as a safe alternative to CC and was associated with lower postoperative dysrhythmia and infection rates. These findings show that DNC is safe and effective in patients whose operative interventions may require only single-dosing cardioplegia; its use in longer cases should be further explored given its low complication rate.

1343. Prophylactic Dosing of Baloxavir Acid Eliminates Mortality in Mice Lethal Influenza A Virus Infection Model

Background Baloxavir acid (BXA), an active form of orally available prodrug baloxavir marboxil (BXM, formerly S-033188), is a novel small molecule inhibitor of cap-dependent endonuclease (CEN) of influenza A and B virus, and was recently launched for the treatment of acute and uncomplicated influenza with single dosing of BXM (the trade name XOFLUZA™) in Japan in March 2018. Here, we evaluated the prophylactic efficacy of BXA in mice lethally infected with influenza A virus. Methods T1/2 of BXA in human is more than 10 times longer than that in mice. Therefore, suspension of BXA was subcutaneously administered at 0.8 or 1.6 mg/kg in mice to maintain the plasma concentration of BXA as seen in humans, and then mice were intranasally inoculated with a lethal dose of A/PR/8/34 strain at 48, 72, or 96 hours after the administration of BXA. Survival time and body weight change were then monitored through a 28-day period after virus infection. Mice were euthanized and regarded as dead if their body weights were lower than 70% of the initial body weights according to humane endpoints. Results Single dosing of BXA (1.6 mg/kg) completely eliminated mortality in mice, when the mice were administrated the drug at 48, 72, or 96 hours before virus infection (Figure 1). BXA treatment also significantly prevented body weight loss, consistent with the prolonged survival. Conclusion Prophylactic dosing of BXA exhibited significant protective efficacy against mortality and body weight loss in mice following a lethal infection with influenza A virus. The significant prophylactic efficacy observed in our mouse model suggests the potential utility of BXM for the prophylaxis of influenza in human. Disclosures S. Shano, Shionogi & Co., Ltd.: Employee, Salary. K. Fukao, Shionogi & Co., Ltd.: Employee, Salary. T. Noshi, Shionogi & Co., Ltd.: Employee, Salary. K. Sato, Shionogi & Co., Ltd.: Employee, Salary. M. Sakuramoto, Shionogi & Co., Ltd.: Employee, Salary. K. Baba, Shionogi TechnoAdvance Research & Co., Ltd.: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary. A. Naito, Shionogi & Co., Ltd.: Employee, Salary.