Possibility of Multiple Drug-Drug Interactions in Patients Treated with Statins: Analysis of Data from the Japanese Adverse Drug Event Report (JADER) Database and Verification by Animal Experiments.

Adverse drug events due to drug-drug interactions can be prevented by avoiding concomitant use of causative drugs; therefore, it is important to understand drug combinations that cause drug-drug interactions. Although many attempts to identify drug-drug interactions from real-world databases such as spontaneous reporting systems have been performed, little is known about drug-drug interactions caused by three or more drugs in polypharmacy, i.e., multiple drug-drug interactions. Therefore, we attempted to detect multiple drug-drug interactions using decision tree analysis using the Japanese Adverse Drug Event Report (JADER) database, a Japanese spontaneous reporting system. First, we used decision tree analysis to detect drug combinations that increase the risk of rhabdomyolysis in cases registered in the JADER database that used six statins. Next, the risk of three or more drug combinations that significantly increased the risk of rhabdomyolysis was validated with in vivo experiments in rats. The analysis identified a multiple drug-drug interaction signal only for pitavastatin. The reporting rate of rhabdomyolysis for pitavastatin in the JADER database was 0.09, and it increased to 0.16 in combination with allopurinol. Furthermore, the rate was even higher (0.40) in combination with valsartan. Additionally, necrosis of leg muscles was observed in some rats simultaneously treated with these three drugs, and their creatine kinase and myoglobin levels were elevated. The combination of pitavastatin, allopurinol, and valsartan should be treated with caution as a multiple drug-drug interaction. Since multiple drug-drug interactions were detected with decision tree analysis and the increased risk was verified in animal experiments, decision tree analysis is considered to be an effective method for detecting multiple drug-drug interactions.

Adverse Drug Events Caused by Drugs Contraindicated for Coadministration Reported in the Japanese Adverse Drug Event Report Database and Recognized by Reporters.

The "INTERACTIONS" section of package inserts aims to provide alert-type warnings in clinical practice; however, these also include many drug-drug interactions that occur rarely. Moreover, considering that drug-drug interaction alert systems were created based on package inserts, repeated alerts can lead to alert fatigue. Although investigations have been conducted to determine prescriptions that induce drug-drug interactions, no studies have focused explicitly on the adverse events induced by drug-drug interactions. We, therefore, sought to investigate the true occurrence of adverse events caused by drug pair contraindications for coadministration in routine clinical practice. Toward this, we created a list of drug combinations that were designated as "contraindications for coadministration" and extracted the cases of adverse drug events from the Japanese Adverse Drug Event Report database that occurred due to combined drug usage. We then calculated the reporters' recognition rate of the drug-drug interactions. Out of the 2121 investigated drug pairs, drug-drug interactions were reported in 43 pairs, 23 of which included an injected drug and many included catecholamines. Warfarin potassium and miconazole (19 reports), azathioprine and febuxostat (11 reports), and warfarin potassium and iguratimod (six reports) were among the 20 most-commonly reported oral medication pairs that were contraindicated for coadministration, for which recognition rates of drug-drug interactions were high. Although these results indicate that only a few drug pair contraindications for coadministration were associated with adverse drug events (43 pairs out of 2121 pairs), it remains necessary to translate these findings into clinical practice.

Admission Heart Rate Is a Determinant of Effectiveness of Beta-Blockers in Acute Myocardial Infarction Patients.

BACKGROUND: Beta-blockers are standard therapy for acute myocardial infarction (AMI). However, despite current advances in the management of AMI, it remains unclear whether all AMI patients benefit from ß-blockers. We investigated whether admission heart rate (HR) is a determinant of the effectiveness of ß-blockers for AMI patients. Methods and Results: We enrolled 3,283 consecutive AMI patients who were admitted to 28 participating institutions in the Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) study. According to admission HR, we divided patients into 3 groups: bradycardia (HR <60 beats/min, n=444), normocardia (HR 60 to ≤100 beats/min, n=2,013), and tachycardia (HR >100 beats/min, n=342). The primary endpoint was major adverse cardiac events (MACE), including all-cause death, non-fatal MI, non-fatal stroke, heart failure (HF), and urgent revascularization for unstable angina, at 3-year follow-up. Beta-blocker at discharge was significantly associated with a lower risk of MACE in the tachycardia group (23.6% vs. 33.0%; P=0.033), but it did not affect rates of MACE in the normocardia group (17.8% vs. 18.4%; P=0.681). In the bradycardia group, ß-blocker use at discharge was significantly associated with a higher risk of MACE (21.6% vs. 12.7%; P=0.026). Results were consistent for multivariable regression and stepwise multivariable regression. CONCLUSIONS: Admission HR might determine the efficacy of ß-blockers for current AMI patients.

Association of onset-season with characteristics and long-term outcomes in acute myocardial infarction patients: results from the Japanese registry of acute myocardial infarction diagnosed by universal definition (J-MINUET) substudy.

It is known that incidence and short-term mortality rate of acute myocardial infarction (AMI) tend to be higher in the cold season. The aim of our study was to investigate the association of onset-season with patient characteristics and long-term prognosis of AMI. This was a prospective, multicenter, Japanese investigation of 3,283 patients with AMI who were hospitalized within 48 h of symptom onset between July 2012 and March 2014. Patients were divided into 3 seasonal groups according to admission date: cold season group (December-March), hot season group (June-September), and moderate season group (April, May, October, and November). We identified 1356 patients (41.3%) admitted during the cold season, 901 (27.4%) during the hot season, and 1026 (31.3%) during the moderate season. We investigated the seasonal effect on patient characteristics and clinical outcomes. Baseline characteristics of each seasonal group were comparable, with the exception of age, Killip class, and conduction disturbances. The rates of higher Killip class and complete atrioventricular block were significantly higher in the cold season group. The 3-year cumulative survival free from major adverse cardiac events (MACE) rate was the lowest in the cold season (67.1%), showing a significant difference, followed by the moderate (70.0%) and hot seasons (72.9%) (p < 0.01). Initial severity and long-term prognoses were worse in patients admitted during the cold season. Our findings highlight the importance of optimal prevention and follow-up of AMI patients with cold season onset.

A lower eicosapentaenoic acid/arachidonic acid ratio is associated with in-hospital fatal arrhythmic events in patients with acute myocardial infarction: a J-MINUET substudy.

The ratio of serum eicosapentaenoic acid (EPA) to arachidonic acid (AA) is significantly associated with long-term clinical outcomes in patients with acute myocardial infarction (AMI). However, it has not been conclusively demonstrated that higher serum EPA/AA ratio fares better clinical outcomes in the early phase of AMI. The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry conducted in 28 Japanese medical institutions between July 2012 and March 2014. We enrolled 3,283 consecutive AMI patients who were admitted to participating institutions within 48 h of symptom onset. A serum EPA/AA ratio was available for 629 of these patients. The endpoints were in-hospital mortality and major adverse cardiac events (MACE), defined as a composite of all cause death, cardiac failure, ventricular tachycardia (VT) and/or ventricular fibrillation (VF) and bleeding during hospitalization. Although similar rates of in-hospital mortality, cardiac failure, bleeding, and MACE were found in the lower serum EPA/AA group and higher serum EPA/AA group, the incidence of VT/VF during hospitalization was significantly higher in the low ratio group (p = 0.008). Receiver operating characteristic curve analysis showed that an EPA/AA ratio < 0.35 could predict the incidence of VT/VF with 100% sensitivity and 64.0% specificity. A lower serum EPA/AA ratio was associated with a higher frequency of fatal arrhythmic events in the early phase of AMI.

Comparison of the Benefit Feeling Rate Based on the Sho of OTC Kakkonto, Cold Remedy and Cold Remedy with Kakkonto Combination Product.

Kakkonto (KK), a traditional Japanese Kampo formulation for cold and flu, is generally sold as an OTC pharmaceuticals used for self-medication. Kampo formulations should be used according to the Sho-symptoms of Kampo medicine. These symptoms refer to the subjective symptoms themselves. Although with OTC pharmaceuticals, this is often not the case. We surveyed the relationship of agreement of Sho with the benefit feeling rate (BFR) of patients who took KK (n=555), cold remedies with KK (CK, n=315), and general cold remedies (GC, n=539) using internet research. BFR of a faster recovery was greater in participants who took the medication early and who had confidence in their physical strength in all treatment groups. BFR was significantly higher in the GC group than in the KK group for patients with headache, runny nose, blocked nose, sneezing, and cough. BFR was also significantly higher in the GC group than in the CK group for headache (males) and cough (females). BFR was the highest in the KK group for stiff shoulders. All cold remedies were more effective when taken early, and the larger the number of Sho that a patient had, the greater the BFR increased. Therefore, a cold remedy is expected to be most effective when there are many cold symptoms and when it is taken at an early stage of the common cold.

Study on the Increased Probability of Detecting Adverse Drug Reactions Based on Bayes' Theorem: Evaluation of the Usefulness of Information on the Onset Timing of Adverse Drug Reactions.

In order to avoid adverse drug reactions (ADRs), pharmacists are reconstructing ADR-related information based on various types of data gathered from patients, and then providing this information to patients. Among the data provided to patients is the time-to-onset of ADRs after starting the medication (i.e., ADR onset timing information). However, a quantitative evaluation of the effect of onset timing information offered by pharmacists on the probability of ADRs occurring in patients receiving this information has not been reported to date. In this study, we extracted 40 ADR-drug combinations from the data in the Japanese Adverse Drug Event Report database. By applying Bayes' theorem to these combinations, we quantitatively evaluated the usefulness of onset timing information as an ADR detection predictor. As a result, when information on days after taking medication was added, 54 ADR-drug combinations showed a likelihood ratio (LR) in excess of 2. In particular, when considering the ADR-drug combination of anaphylactic shock with levofloxacin or loxoprofen, the number of days elapsed between start of medication and the onset of the ADR was 0, which corresponded to increased likelihood ratios (LRs) of 138.7301 or 58.4516, respectively. When information from 1-7 d after starting medication was added to the combination of liver disorder and acetaminophen, the LR was 11.1775. The results of this study indicate the clinical usefulness of offering information on ADR onset timing.

Identification and Characteristics of Time-Related Shifts in Suicide-Related Event Frequency During Smoking Cessation Treatment with Varenicline.

Objectives: To survey time-related shifts in number of suicide-related events (SRE) during smoking cessation treatment with varenicline (VAR) in cases from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), as well as the characteristics of these shifts. Methods: We isolated cases from the FAERS database involving VAR usage where SRE was reported as an adverse event (SRE+/VAR+ case) and established a histogram of SRE+/VAR+ case numbers per week. Furthermore, we focused on "cases reporting specific adverse events prior to drug usage start" using X-bar and R chart concepts. We also attempted to exclude the influence of smoking history from the created histogram. Moreover, we constructed a histogram on central nervous system adverse events, which were frequently seen during VAR usage. Results: By removing the effects of smoking history, SRE onset signals were detected over a long period from the start of VAR use. However, expression signals for nausea and abnormal dreams were detected only in the early VAR administration period. Discussion: These results suggest that VAR use-induced SRE is expressed over a long timeframe from the start of treatment. Additionally, the period of SRE expression signal detection was longer than that of the other central nervous system adverse events (nausea and abnormal dreams). Therefore, SRE onset must be carefully monitored during smoking cessation treatment with VAR over the entire treatment period.

Identification of the Discrepancies between Pharmacist and Patient Perception of the Pharmacist's Role as an Advisor on Drug Therapy Based on Social Science Theory.

Article 25-2 of the Japanese Pharmacists' Act was revised in June 2014, establishing the position of pharmacists as "advisors on the use of pharmaceuticals." Prior to the Act's revision, we investigated the perceptions of patients and pharmacists about pharmacists' roles using a social science methodology. We also examined current opinions and necessary factors for the future growth and development of pharmacists. This questionnaire survey was conducted using an internet method. Patients and pharmacists answered 12 questions. Responses from 529 patients and 338 pharmacists were analyzed. For all items, pharmacists' awareness of their roles exceeded patients' awareness of the roles. In this study, the difference between pharmacist and patient awareness was larger than in similar research conducted in the United States. The greatest difference was observed in three items: "Understanding the effects of the drugs the patients are taking" (rate of high ratings: pharmacists 80.2%, patients 37.8%), "Understanding the health changes caused by the drugs dispensed to the patients" (pharmacists 80.2%, patients 28.4%), and "Consciously protecting patients from the adverse effects of drugs" (pharmacists 82.8%, patients 42.2%), indicating role discrepancy. Partition analysis indicated the three factors for a pharmacist to be regarded as a drug therapy or medication specialist: "The patient regards the pharmacist as his/her family or regular pharmacist," "The pharmacist is making it easy for a patient to talk with him/her" and "The pharmacist is aware of a patient's use of products other than prescribed drugs, such as over the counter (OTC) medications or health foods and nutritional supplements." Future efforts are necessary to resolve role discrepancy and implement ongoing monitoring.

Postoperative hyperglycemia and atrial fibrillation after coronary artery bypass graft surgery.

BACKGROUND: Postoperative atrial fibrillation (AF) is a common complication following coronary artery bypass grafting (CABG). We investigated the risk factors for postoperative AF and analyzed the relationship between blood sugar concentration (BS) and AF after CABG. METHODS AND RESULTS: A total of 199 consecutive patients who underwent isolated CABG were retrospectively examined and classified according to the presence (n=95) or absence (n=104) of postoperative AF. On univariate analysis mean postoperative BS (P<0.001), postoperative drainage volume (P<0.001), age (P=0.034), presence of diabetes mellitus (DM; P=0.004), and postoperative estimated glomerular filtration rate (P=0.032) were significant risk factors for postoperative AF. On multivariate analysis mean postoperative BS (OR, 1.041; 95% CI: 1.008-1.079; P<0.001), postoperative drainage volume (OR, 1.003; 95% CI: 1.001-1.006; P=0.001), and age (OR, 1.040; 95% CI: 1.002-1.083; P=0.041) were significant risk factors for postoperative AF. Postoperative AF often occurred in patients with high postoperative BS, irrespective of DM. The BS cut-off that predicted postoperative AF occurrence was 180 mg/dl. A strong positive correlation existed between the time of the maximum postoperative BS and AF onset time (ρ=0.746). CONCLUSIONS: Mean postoperative BS and postoperative drainage volume are risk factors for AF after CABG. AF was strongly associated with maximum postoperative BS. Intensive glycemic control could reduce AF occurrence after CABG.

Absorption Kinetics of Subcutaneously Administered Ceftazidime in Hypoperfused Guinea Pigs.

BACKGROUND: Pneumonia is the most common cause of death in patients with severe motor and intellectual disabilities (SMID), and intravenous ceftazidime (CAZ) is a widely used treatment for such infections. However, intravenous administration in patients with SMID may be difficult because of insufficient vascular development. OBJECTIVES: The aim of our study was to determine the feasibility of subcutaneous drug administration by mentholated warm compresses (WMCs) as an alternative delivery method for ceftazidime in patients with SMID. METHODS: CAZ was subcutaneously administered to the abdominal region of naphazoline-treated hypoperfused guinea pigs, which were used as a hemodynamic model of patients with SMID. MWCs or warm compresses (WCs) were applied to the injection site to increase blood flow. We calculated the cumulative CAZ absorption over time by using the deconvolution method. RESULTS: Application of MWCs or WCs increased blood flow at the administration site and increased CAZ plasma levels. Application of MWCs or WCs after subcutaneous CAZ injection led to higher CAZ plasma levels than the mutant prevention concentration for a longer period than was observed for CAZ administration without the application of MWCs or WCs. CONCLUSIONS: The application of MWCs or WCs enhanced subcutaneous CAZ absorption by increasing blood flow. MWCs and WCs are considered to be safe and routine methods to induce defecation after surgery on the digestive system; thus, the combination of these methods and subcutaneous CAZ administration is a potential method for treating pneumonia in patients with SMID.

A novel rhabdovirus detected in Anisakis larvae distributed in the coastal areas of Japan: Viral genome analysis and possible coevolutionary relationship between virus and host nematodes.

In the last decade, it has become evident that various RNA viruses infect helminths including Order Ascaridida. However, there is still no information available for viruses infecting Anisakis. We herewith demonstrate the presence of a novel rhabdovirus from Anisakis larvae detected by next-generation sequencing analysis and following RT-PCR. We determined the nearly all nucleotide sequence (12,376 nucleotides) of the viral genome composed of seven open reading frames, and we designated the virus as Suzukana rhabdo-like virus (SkRV). BLASTx search indicated that SkRV is a novel virus belonging to the subfamily Betanemrhavirus, rhabdovirus infecting parasitic nematodes of the Order Ascaridida. SkRV sequence was detectable only in the total RNA but not in the genomic DNA of Anisakis, ruling out the possibility of SkRV being an endogenous viral element incorporated into the host genomic DNA. When we individually tested Anisakis larvae obtained from Scomber japonicus migrating in the coastal waters of Japan, not all but around 40% were SkRV-positive. In the phylogenetic trees of Betanemrhavirus and of the host Ascaridida nematodes, we observed that evolutional distances of viruses were, to some extent, parallel with that of host nematodes, suggesting that viral evolution could have been correlated with evolution of the host. Although biological significance of SkRV on Anisakis larvae is still remained unknown, it is interesting if SkRV were somehow related to the pathogenesis of anisakiasis, because it is important matter of public health in Japan and European countries consuming raw marine fishes.

Phagocytosis model of calcium oxalate monohydrate crystals generated using human induced pluripotent stem cell-derived macrophages.

Macrophages play a role in nephrolithiasis, offering the possibility of developing macrophage-mediated preventive therapies. To establish a system for screening drugs that could prevent the formation of kidney stones, we aimed to develop a model using human induced pluripotent stem cell (iPSC)-derived macrophages to study phagocytosis of calcium oxalate monohydrate (COM) crystals. Human iPSCs (201B7) were cultured. CD14+ monocytes were recovered using a stepwise process that involved the use of growth factors and cytokines. These cells were then allowed to differentiate into M1 and M2 macrophages. The macrophages were co-cultured with COM crystals and used in the phagocytosis experiments. Live cell imaging and polarized light observation via super-resolution microscopy were used to visualize phagocytosis. Localization of phagocytosed COM crystals was observed using transmission electron microscopy. Intracellular fluorescence intensity was measured using imaging cytometry to quantify phagocytosis. Human iPSCs successfully differentiated into M1 and M2 macrophages. M1 macrophages adhered to the culture plate and moved COM crystals from the periphery to cell center over time, whereas M2 macrophages did not adhere to the culture plate and actively phagocytosed the surrounding COM crystals. Fluorescence assessment over a 24-h period showed that M2 macrophages exhibited higher intracellular fluorescence intensity (5.65-times higher than that of M1 macrophages at 4.5 h) and maintained this advantage for 18 h. This study revealed that human iPSC-derived macrophages have the ability to phagocytose COM crystals, presenting a new approach for studying urinary stone formation and highlighting the potential of iPSC-derived macrophages as a tool to screen nephrolithiasis-related drugs.

Evaluation of licorice flavonoids as protein tyrosine phosphatase 1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator in insulin- and leptin-signaling cascades as well as a positive regulator in tumorigenesis, and much attention has been paid to PTP1B inhibitors as potential therapies for diabetes, obesity, and cancer. In the present study, the screening of a compound library of licorice flavonoids allowed for the discovery of several compounds, including licoagrone (3), licoagrodin (4), licoagroaurone (5), and isobavachalcone (6), as new PTP1B inhibitors. It was revealed that these compounds inhibit the activity of PTP1B in different modes and with different selectivities and that they exhibit different cellular activity in the insulin-signaling pathway. Glycybenzofuran (1), a competitive PTP1B inhibitor, showed both excellent inhibitory selectivity against PTP1B and cellular activity on the insulin-stimulated Akt phosphorylation level. The similarity of its action profiling in the insulin-signaling pathway suggested its potential as a new anti-insulin-resistant drug candidate.

Preprocedural therapeutic international normalized ratio influence on bleeding complications in atrial fibrillation ablation with continued anticoagulation with warfarin.

BACKGROUND: Safety of atrial fibrillation (AF) ablation in conditions of periprocedural therapeutic international normalized ratio (INR) in combination with heparin is still uncertain, and little is known about the pre-procedural therapeutic INR influence on bleeding complications (BC) in this method. METHODS AND RESULTS: The subjects were 150 consecutive patients who underwent catheter ablation for AF with therapeutic INR. The patients were classified into 2 groups, BC (Group BC) and no BC (Group No BC), by whether they did or did not have BC, respectively. Differences in various parameters, including pre- and post-procedural prothrombin time-INR and activated partial thromboplastin time (APTT), were compared between the 2 groups. None of the patients experienced stroke or transient ischemic attack. In the 22 patients (15%) who had BC (Group BC), 3 patients had major and 19 patients had minor BC. There were no significant differences between the 2 groups in pre-procedural INR, APTT, and amount of heparin administered during the procedure. However, post-procedural INR and APTT were significantly prolonged in Group BC (2.5 ± 0.5 vs. 2.2 ± 0.5, P=0.016, 65 ± 45 vs. 44 ± 11, P<0.0001 respectively). Multivariable analysis showed that post-procedural APTT was the only independent bleeding risk factor (P=0.022). CONCLUSIONS: AF ablation with peri-procedural therapeutic INR in combination with heparin seems to be safe. Presence or absence of BC are not related to the pre-procedural INR level, but to post-procedural APTT.

Differential kinetic activities of glycerol kinase among African trypanosome species: phylogenetic and therapeutic implications.

African trypanosome species are causative agents for sleeping sickness in humans and nagana disease in cattle. Trypanosoma brucei can generate ATP via a reverse reaction with glycerol kinase (GK) when alternative oxidase (AOX) is inhibited; thus, GK is considered to be a crucial target for chemotherapy combined with AOX. However, the energy metabolism systems of African trypanosome species other than T. brucei are poorly understood. Thus, GK genes were surveyed from genome databases and cloned by PCR from T. vivax and T. congolense. Then, recombinant GK proteins (rGK) of T. vivax, T. congolense and T. brucei were expressed and purified. Kinetic analysis of these rGK proteins revealed that the K(m) values of T. congolense rGK for ADP and G-3-P substrates were lower than those of T. vivax and T. brucei. The expression level of GK molecules was highest in T. congolense cells and lowest in T. vivax cells. Based on these results, effective combination dosages of ascofuranone, a specific inhibitor of AOX, and glycerol, an inhibitor of the GK reverse reaction, were determined by using in vitro-cultured trypanosome cells.

Categorisation of Pharmaceutical Adverse Events Using the Japanese Adverse Drug Event Report Database: Characteristic Adverse Drug Events of the Elderly Treated with Polypharmacy.

BACKGROUND: Pharmacokinetics and pharmacodynamics of drugs in elderly individuals differ from those in younger adults; thus, adverse drug events (ADEs) are common in older patients with polypharmacy because co-existing comorbidities elevate the risk of ADEs occurring. However, ADEs have not yet been characterised based on the elderly patients of Japanese origin and polypharmacy. OBJECTIVE: The 100 most commonly reported ADEs were grouped into four classes (Class 1-Class 4) based on elderly patients with polypharmacy. PATIENTS AND METHODS: In this study, logistic regression analysis was performed using cases recorded in the Japanese Adverse Drug Event Report (JADER) database. RESULTS: ADEs in elderly patients treated with polypharmacy-in whom the risk of electrolyte abnormalities, renal and respiratory disorders, and coagulopathy was high-were categorised as 'Class 1 [E(+), P(+)]', while ADEs in elderly patients not treated with polypharmacy-in whom the risk of delirium and fall was high-were categorised as 'Class 2 [E(+), P(-)]'. When there was no association with being elderly, ADEs associated with polypharmacy that carried a high risk of myelosuppression and infection were categorised as 'Class 3 [E(-), P(+)]', and allergic ADEs that were not affected by being elderly or polypharmacy, were categorised as 'Class 4 [E(-), P(-)]'. Class 1 events as well as Class 3 ADEs occurred more frequently in females than in males, whereas Class 3 ADEs (deep vein thrombosis and pulmonary embolism) occurred more frequently in males. CONCLUSIONS: Class 1 and Class 2 ADEs should be investigated in analyses that focus on individual drugs.

Efficacy of Add-on Therapy with Carvedilol and the Direct Renin Inhibitor Aliskiren for Improving Cardiac Sympathetic Nerve Activity, Cardiac Function, Symptoms, Exercise Capacity and Brain Natriuretic Peptide in Patients with Dilated Cardiomyopathy.

Purpose/Method: Aliskiren is a direct renin inhibitor that has been reported to be effective for CHF, but the usefulness of combined therapy with carvedilol and aliskiren has not been reported. Forty-four patients with dilated cardiomyopathy (DCM) were randomized into a group receiving add-on therapy with carvedilol plus aliskiren and another group receiving carvedilol alone for 6 months. Nuclear imagings with 123I-Metaiodobenzylguanidine (MIBG) and 99mTc-Sestamibi were performed. Exercise capacity using a specific activity scale (SAS) and the New York Heart Association (NYHA) class were evaluated. Cardiac sympathetic nerve activity was evaluated by 123I-MIBG imaging, with the delayed heart-to-mediastinum activity ratio (H/M), delayed total defect score (TDS), and washout rate (WR). Results: Combined add-on therapy with carvedilol and aliskiren improved several parameters much more than carvedilol alone (p<0.05) with respect to TDS, ejection fraction (EF), NYHA, SAS on 6 months and the changes in TDS, EF, end-diastolic volume and brain natriuretic peptide (BNP). Conclusion: Add-on therapy with carvedilol and aliskiren is more effective than carvedilol alone for improving cardiac sympathetic nerve activity, cardiac function, symptoms, exercise capacity, and brain natriuretic peptide in patients with DCM.

Antidiabetic Drugs for the Risk of Alzheimer Disease in Patients With Type 2 DM Using FAERS.

Alzheimer disease (AD) may develop after the onset of type 2 diabetes mellitus (T2DM), and the risk of AD may depend on the antidiabetic drug administered. We compared the risk of AD among 66 085 patients (≥ 65 years) with T2DM (1250 having concomitant AD) who had been administered antidiabetic drug monotherapy for T2DM who had voluntarily reported themselves in the Food and Drug Administration Adverse Event Reporting System. The risk of AD from the use of different antidiabetic drug monotherapies compared to that of metformin monotherapy was assessed by logistic regression. Rosiglitazone (adjusted reporting odds ratio [aROR] = 0.11; 95% confidence interval [CI]: 0.07-0.17; P < .001), exenatide (aROR = 0.22; 95% CI: 0.11-0.37; P < .001), liraglutide (aROR = 0.36; 95% CI: 0.19-0.62; P < .001), dulaglutide (aROR = 0.39; 95% CI: 0.17-0.77; P = .014), and sitagliptin (aROR = 0.75; 95% CI: 0.60-0.93; P = .011) were found to have a significantly lower associated risk of AD than that of metformin. Therefore, the administration of glucagon-like peptide 1 receptor agonists and rosiglitazone may reduce the risk of AD in patients with T2DM.

Prediction of Long-Term Outcomes in ST-Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction with and without Creatinine Kinase Elevation-Post-Hoc Analysis of the J-MINUET Study.

BACKGROUND: A Japanese prospective, nation-wide, multicenter registry (J-MINUET) showed that long-term outcomes were worse in non-ST elevation acute myocardial infarction (NSTEMI), diagnosed by increased cardiac troponin levels, compared to STEMI. This was observed in both non-STEMI with elevated creatine kinase (CK) (NSTEMI+CK) and non-STEMI without elevated CK (NSTEMI-CK). However, predictive factors for long-term outcomes in STEMI, NSTEMI+CK, and NSTEMI-CK have not been elucidated. METHODS: Using the Cox proportional hazards model, we determined significant independent predictors of long-term outcomes from a total of 111 parameters evaluated in the J-MINUET study in each of our groups, including STEMI, NSTEMI+CK, and NSTEMI-CK. Then, we calculated the risk score using the regression coefficients for the determined independent predictors for the strict prediction of long-term outcomes. RESULTS: Prognostic factors, as well as composite cardiovascular events and all-cause death, were different between STEMI, NSTEMI+CK, and NSTEMI-CK. Risk scores could effectively and powerfully predict both composite cardiovascular events and all-cause death in each group. CONCLUSIONS: The prediction of long-term outcomes using cored parameters of baseline demographics and clinical characteristics is feasible and could prove useful in establishing therapeutic strategies in patients with STEMI, NSTEMI+CK, and NSTEMI-CK.