Clinical correlates and pharmacological management of Asian patients with concomitant diabetes mellitus and heart failure.

Asia is the center of convergence of the twin epidemics of diabetes mellitus (DM) and heart failure (HF). The regional and ethnic diversity across Asia, along with a high prevalence of a young, lean diabetic phenotype, emphasizes the importance of targeted public health strategies that address the unique needs of Asian patients with DM and HF. This review discusses the epidemiology, clinical correlates, pharmacological management, and outcomes of Asian patients with concomitant DM and HF.

Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone and N-Desbutyl Dronedarone.

Dronedarone is an antiarrhythmic agent approved in 2009 for the treatment of atrial fibrillation. An in-house preliminary study demonstrated that dronedarone inhibits cytochrome P450 (CYP) 3A4 and 3A5 in a time-dependent manner. This study aimed to investigate the inactivation of CYP450 by dronedarone. We demonstrated for the first time that both dronedarone and its main metabolite N-desbutyl dronedarone (NDBD) inactivate CYP3A4 and CYP3A5 in a time-, concentration-, and NADPH-dependent manner. For the inactivation of CYP3A4, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 0.87 µM and 0.039 minute(-1), respectively, for dronedarone, and 6.24 µM and 0.099 minute(-1), respectively, for NDBD. For CYP3A5 inactivation, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 2.19 µM and 0.0056 minute(-1) for dronedarone and 5.45 µM and 0.056 minute(-1) for NDBD. The partition ratios for the inactivation of CYP3A4 and CYP3A5 by dronedarone are 51.1 and 32.2, and the partition ratios for the inactivation of CYP3A4 and CYP3A5 by NDBD are 35.3 and 36.6. Testosterone protected both CYP3A4 and CYP3A5 from inactivation by dronedarone and NDBD. Although the presence of Soret peak confirmed the formation of a quasi-irreversible metabolite-intermediate complex between dronedarone/NDBD and CYP3A4/CYP3A5, partial recovery of enzyme activity by potassium ferricyanide illuminated an alternative irreversible mechanism-based inactivation (MBI). MBI of CYP3A4 and CYP3A5 was further supported by the discovery of glutathione adducts derived from the quinone oxime intermediates of dronedarone and NDBD. In conclusion, dronedarone and NDBD inactivate CYP3A4 and CYP3A5 via unique dual mechanisms of MBI and formation of the metabolite-intermediate complex. Our novel findings contribute new knowledge for future investigation of the underlying mechanisms associated with dronedarone-induced hepatotoxicity and clinical drug-drug interactions.

Technological preferences of aging cancer patients for delivery services and devices to solve drug-related problems in oncology.

AIM: To identify the technological preferences of aging cancer patients with regard to the delivery services and devices for preventing/solving three common drug-related problems (DRPs): medication nonadherence, lack of knowledge in medications, and side effects management. METHODS: A survey was conducted at a cancer center from May to August 2011. Delivery services included in the interviewer-administered questionnaire included voice-activated dispensing, voice reminders, electronic messages, helplines, and mobile phone applications, among others. Three devices were proposed-watches, bracelets, and mobile phones. Descriptive statistics and chi-square tests were performed. RESULTS: A total of 361 surveys were analyzed. Median age of respondents was 61 years. The majority of respondents were female (57.3 %), Chinese (88.9 %), and 65 years and younger (73.4 %). More than half (59.0-63.2 %) were receptive to the use of the delivery services. Patients preferred voice reminder alerts (28.0 %) and electronic messages (17.7 %) to help with their medication nonadherence, and helplines for medications (52.6 %) and side effects management (47.4 %). Higher educated patients were more likely to want delivery services to improve their medication adherence (p = 0.045) and knowledge in medications management (p = 0.050). Middle age patients (age 50-65) were also more likely to want delivery services for the latter DRP (p = 0.009). Among those who wanted delivery services, most preferred mobile phones. CONCLUSION: Middle age and elderly cancer patients are accepting of delivery services to help them with their DRPs. With middle aged patients being more receptive of the delivery services, technology can potentially play an important role in minimizing DRPs.

Inherited chromosomally-integrated human herpes virus 6 confounding test results in a patient with myelitis and optic neuritis - A case report.

A case of the 'perfect storm' of myelin oligodendrocyte glycoprotein (MOG) antibody-mediated myelitis, human herpesvirus 6 (HHV-6) reactivation, and COVID-19 infection was reported in 2021. This article reports a case of a similarly observed clinical triad, but with a different conclusion and explanation supported by laboratory test results and evidence from our literature review.

Stem Cell Therapy for Neurodegenerative Diseases: How Do Stem Cells Bypass the Blood-Brain Barrier and Home to the Brain?

Blood-brain barrier (BBB) is a term describing the highly selective barrier formed by the endothelial cells (ECs) of the central nervous system (CNS) homeostasis by restricting movement across the BBB. An intact BBB is critical for normal brain functions as it maintains brain homeostasis, modulates immune cell transport, and provides protection against pathogens and other foreign substances. However, it also prevents drugs from entering the CNS to treat neurodegenerative diseases. Stem cells, on the other hand, have been reported to bypass the BBB and successfully home to their target in the brain and initiate repair, making them a promising approach in cellular therapy, especially those related to neurodegenerative disease. This review article discusses the mechanism behind the successful homing of stem cells to the brain, their potential role as a drug delivery vehicle, and their applications in neurodegenerative diseases.

Immunomodulatory potential of anti-idiotypic antibodies for the treatment of autoimmune diseases.

The immune system is a complex network of specialized cells and organs that recognises and reacts against foreign pathogens while remaining unresponsive to host tissues. This ability to self-tolerate is known as immunological tolerance. Autoimmune disease occurs when the immune system fails to differentiate between self and non-self antigens and releases autoantibodies to attack our own cells. Anti-idiotypic (anti-ID) antibodies are important in maintaining a balanced idiotypic regulatory network by neutralising and inhibiting the secretion of autoantibodies. Recently, anti-ID antibodies have been advanced as an alternative form of immunotherapy as they can specifically target autoantibodies, cause less toxicity and side effects, and could provide long-lasting immunity. This review article discusses the immunomodulatory potential of anti-ID antibodies for the treatment of autoimmune diseases.

Prescribing patterns of evidence-based heart failure pharmacotherapy and outcomes in the ASIAN-HF registry: a cohort study.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), ß blockers, and mineralocorticoid receptor antagonists (MRAs) are of proven benefit and are recommended by guidelines for management of patients with heart failure and reduced ejection fraction (HFrEF). We aimed to examine the first prospective multinational data from Asia on prescribing patterns of guideline-directed medical therapies and analyse its effect on outcomes. METHODS: In the prospective multinational ASIAN-HF registry (with enrolment from 46 centres in 11 countries in Asia), we enrolled patients aged 18 years or older, with symptomatic heart failure (stage C, with at least one episode of decompensated heart failure in the past 6 months that resulted in admission to hospital or was treated in an outpatient clinic) and left ventricular systolic dysfunction (ejection fraction ≤40% on baseline echocardiography, consistent with 2016 European Society of Cardiology guidelines). We excluded patients with heart failure caused by severe valvular heart disease, life-threatening comorbidity with a life expectancy of less than 1 year, who were unable or unwilling to give consent, or who had concurrent participation in a clinical trial. Patients were followed up for 3 years for the outcomes of death and cause-specific admittance to hospital. Primary outcomes were uptake of guideline-directed medical therapies (as proportions) by therapeutic class, achieved doses as proportions of guideline-recommended doses, and their association with 1-year composite outcome of all-cause death or admittance to hospital because of heart failure. This study is registered with ClinicalTrials.gov, number NCT01633398. FINDINGS: Between Oct 1, 2012, and Dec 31, 2015, we enrolled 5276 patients with HFrEF (mean age 59·6 years [SD 13·2], 77% men, body-mass index 24·9 kg/m2 [5·1], 33% New York Heart Association class III or IV). Follow-up data were available for 4544 (90%) of 5061 eligible patients taking medication for heart failure, with median follow-up of 417 days (IQR 214-735). ACE inhibitors or ARBs were prescribed to 3868 (77%) of 5005 patients, ß blockers to 3975 (79%) of 5061, and MRAs to 2998 (58%) of 5205, with substantial regional variation. Guideline-recommended dose was achieved in only 17% of cases for ACE inhibitors or ARB, 13% for ß blockers, and 29% for MRAs. Country (all three drug classes), increasing body-mass index (ACE inhibitors or ARBs and MRAs), and in-patient recruitment (ACE inhibitors or ARBs and ß blockers) were associated with attainment of guideline-recommended dose (all p<0·05). When adjusted for indication bias, increasing drug doses, from low dose (1-<25% of guideline-recommended dose) upwards were associated with lower hazards of a 1-year composite outcome for ACE inhibitors or ARBs and ß blockers compared with non-users. The lowest adjusted hazards were in the group that attained guideline-recommended doses above 50% (hazard ratio [HR] 0·54, 95% CI 0·50-0·58 for ACE inhibitors or ARBs [50-99·9%]; HR 0·47, 0·46-0·50 for ß blockers, and HR 0·77, 0·72-0·81 for MRAs [≥100%]). INTERPRETATION: Guideline-directed medical therapies at recommended doses are underutilised in patients with HFrEF. Improved uptake and uptitration of guideline-directed medical therapies are needed for better patient outcomes. FUNDING: National Medical Research Council (Singapore), A*STAR Biomedical Research Council ATTRaCT program, Boston Scientific Investigator Sponsored Research program, and Bayer.

Disparity Between Indications for and Utilization of Implantable Cardioverter Defibrillators in Asian Patients With Heart Failure.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) are lifesaving devices for patients with heart failure (HF) and reduced ejection fraction. However, utilization and determinants of ICD insertion in Asia are poorly defined. We determined the utilization, associations of ICD uptake, patient-perceived barriers to device therapy and, impact of ICDs on mortality in Asian patients with HF. METHODS AND RESULTS: Using the prospective ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry, 5276 patients with symptomatic HF and reduced ejection fraction (HFrEF) from 11 Asian regions and across 3 income regions (high: Hong Kong, Japan, Korea, Singapore, and Taiwan; middle: China, Malaysia, and Thailand; and low: India, Indonesia, and Philippines) were studied. ICD utilization, clinical characteristics, as well as device perception and knowledge, were assessed at baseline among ICD-eligible patients (EF ≤35% and New York Heart Association Class II-III). Patients were followed for the primary outcome of all-cause mortality. Among 3240 ICD-eligible patients (mean age 58.9±12.9 years, 79.1% men), 389 (12%) were ICD recipients. Utilization varied across Asia (from 1.5% in Indonesia to 52.5% in Japan) with a trend toward greater uptake in regions with government reimbursement for ICDs and lower out-of-pocket healthcare expenditure. ICD (versus non-ICD) recipients were more likely to be older (63±11 versus 58±13 year; P<0.001), have tertiary (versus ≤primary) education (34.9% versus 18.1%; P<0.001) and be residing in a high (versus low) income region (64.5% versus 36.5%; P<0.001). Among 2000 ICD nonrecipients surveyed, 55% were either unaware of the benefits of, or needed more information on, device therapy. ICD implantation reduced risks of all-cause mortality (hazard ratio, 0.71; 95% confidence interval, 0.52-0.97) and sudden cardiac deaths (hazard ratio, 0.33; 95% confidence interval, 0.14-0.79) over a median follow-up of 417 days. CONCLUSIONS: ICDs reduce mortality risk, yet utilization in Asia is low; with disparity across geographic regions and socioeconomic status. Better patient education and targeted healthcare reforms in extending ICD reimbursement may improve access. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT01633398. Unique identifier: NCT01633398.

Impact of Community-Based Cardiac Rehabilitation on Clinical Parameters of Patients with Cardiovascular Diseases.

BACKGROUND: Cardiac rehabilitation (CR) programmes have been shown to improve patient outcomes, but vary widely in their components. The impact of Singapore's CR programme on clinical outcomes is currently not known. OBJECTIVE: To evaluate the effects of a community-based CR programme on important clinical parameters in patients with cardiovascular disease in Singapore. METHOD: A retrospective cohort study was conducted. Cardiovascular patients who had completed a hospital-based CR programme were included. Patients who continued with community-based CR (n = 94) during the period of 2009-2013 were compared with patients who received regular care (n = 157). Changes in clinical and physical examination parameters between baseline and one-year post follow-up were analyzed. Within-group differences were compared using the paired t-test, while multivariate linear regression was used to compare the changes in the various parameters between the intervention and control groups. The primary outcome measure was low density lipoprotein (LDL) levels. RESULTS: Patients in the intervention group had significant lowering of LDL (2.5 to 2.2 mmol/L, p<0.01), while the control group's LDL increased (2.2 to 2.4 mmol/L, p<0.01). The intervention group had greater improvements in LDL (-0.3 vs. +0.2 mmol/L, p<0.01), triglycerides (-0.1 vs. +0.1 mmol/L, p=0.01), total cholesterol (-0.3 vs. +0.3 mmol/L, p<0.01), fasting blood glucose (-0.5 vs. +0.3 mmol/L, p<0.01), systolic blood pressure (-3.2 vs. +5 mmHg, p<0.01) and diastolic blood pressure (-2.6 vs. +2.8 mmHg, p<0.01). CONCLUSION: The community-based CR programme in Singapore is associated with improvements in several cardiovascular clinical parameters and may be of benefit to cardiovascular patients.