Risk Assessment for Heart Failure in Patients with Type 2 Diabetes Mellitus Treated with Dipeptidyl Peptidase 4 Inhibitor Using a Large Claims Dataset.

Heart failure is a prevalent comorbidity in patients with diabetes mellitus (DM). However, it is unclear whether the risk factors for heart failure in DM patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are the same as those for the general population. In this study, we evaluated the factors of new-onset heart failure in working-age patients with diabetes who started DPP-4 inhibitor therapy. This study included 7938 working-age patients. The primary endpoint of the study was the proportion of patients developing heart failure within 12 months of starting DPP-4 inhibitor therapy, which was found to be 1.89% (n = 150). In these patients, risk factors of new-onset heart failure were aging, history of atrial fibrillation, and hypertension but not sex, smoking, high body mass index, weight gain of over 10 kg from 20 years of age, levels of low-density lipoprotein or glycated hemoglobin A1c (HbA1c), history of angina pectoris, myocardial infarction, and chronic kidney disease. We confirmed that cardiovascular comorbidities are risk factors for new-onset heart failure in patients with DM, while general risk factors are not. In conclusion, physicians and pharmacists need to carefully monitor working-age patients with cardiovascular history who start DPP-4 inhibitor therapy even if they do not exhibit general risk factors for heart failure.

An international comparative analysis and roadmap to sustainable biosimilar markets.

Background: Although biosimilar uptake has increased (at a variable pace) in many countries, there have been recent concerns about the long-term sustainability of biosimilar markets. The aim of this manuscript is to assess the sustainability of policies across the biosimilar life cycle in selected countries with a view to propose recommendations for supporting biosimilar sustainability. Methods: The study conducted a comparative analysis across 17 countries from North America, South America, Asia-Pacific, Europe and the Gulf Cooperation Council. Biosimilar policies were identified and their sustainability was assessed based on country-specific reviews of the scientific and grey literature, validation by industry experts and 23 international and local non-industry experts, and two advisory board meetings with these non-industry experts. Results: Given that European countries tend to have more experience with biosimilars and more developed policy frameworks, they generally have higher sustainability scores than the other selected countries. Existing approaches to biosimilar manufacturing and R&D, policies guaranteeing safe and high-quality biosimilars, exemption from the requirement to apply health technology assessment to biosimilars, and initiatives counteracting biosimilar misconceptions are considered sustainable. However, biosimilar contracting approaches, biosimilar education and understanding can be ameliorated in all selected countries. Also, similar policies are sometimes perceived to be sustainable in some markets, but not in others. More generally, the sustainability of the biosimilar landscape depends on the nature of the healthcare system and existing pharmaceutical market access policies, the experience with biosimilar use and policies. This suggests that a general biosimilar policy toolkit that ensures sustainability does not exist, but varies from country to country. Conclusion: This study proposes a set of elements that should underpin sustainable biosimilar policy development over time in a country. At first, biosimilar policies should guarantee the safety and quality of biosimilars, healthy levels of supply and a level of cost savings. As a country gains experience with biosimilars, policies need to optimise uptake and combat any misconceptions about biosimilars. Finally, a country should implement biosimilar policies that foster competition, expand treatment options and ensure a sustainable market environment.

Dilemma Facing Patients Aged 75 Years and Older on Fluid Restriction When Drug Package Inserts Advise Use of a Lot of Water: A Cross-Sectional, Descriptive, and Hypothesis-Generating Study Using a Large Claims Database.

BACKGROUND: Several oral drugs are recommended to be taken with large amounts of water for reasons such as peptic ulcer prophylaxis. On the other hand, there are many patients with diseases that restrict water intake, and the actual frequency of patients receiving prescriptions in these conflicting situations is not clear. OBJECTIVE: Using a large claims database in Japan, this study aimed to determine the proportion of patients aged ≥ 75 years on fluid restriction who received drugs whose drug package insert mentioned "a large amount of water intake is needed when taking the drug". METHODS: We performed a prescription survey of older patients over 75 years of age using the Japan Medical Data Centre (JMDC) claims database. Out of approximately 8800 oral drugs used in Japan, we defined 29 drugs for which package inserts noted that a large amount of water intake is recommended during drug administration. We defined diagnosis codes for some common diseases for which restricted water intake is likely recommended: heart failure (NYHA class III or IV), liver cirrhosis with ascites, and chronic kidney disease stage 5, including dialysis patients. RESULTS: Of 5968 patients aged ≥ 75 years (men 47.7%), 320 (5.4%) patients with heart failure (2.8%, n = 170), liver cirrhosis (0.7%, n = 40), or chronic kidney disease (1.9%, n = 113), diagnoses likely associated with the need for fluid restriction, were prescribed drugs for which abundant fluid at intake was recommended. Among 29 identified drugs, 15 drugs were administered to older patients over 75 years with fluid restriction due to said diseases. CONCLUSIONS: Of patients 75 years and older with disease likely requiring water restriction, 5.4% faced the dilemma of following advice to restrict fluid intake due to their diagnoses or to adhere to instructions in drug package inserts to have abundant fluid intake when taking the drug. Our study raises awareness regarding the dilemma of water restriction and intake in clinical settings, highlighting the importance of considering individual patient needs. These real-world findings emphasize the need for information and guidelines to assist healthcare professionals in navigating this dilemma and making informed decisions for the benefit of their patients.

[Exploring for Drug Development Seeds for Children Using a Large Claims Data-Survey for Powderization or Decapsulation of Oral Tablets or Capsule Formula in Children].

Medical big data is accumulated numerous medical related data day by day. These data may have tips for new approach for drug development. Authors tried to find drug-development-needs in children using medical big data analysis with prescription survey. Medical big data were provided from JMDC (Japan Medical Data Centre) Inc. about 3 million participants between January 2005 and June 2017. In these, we identified randomly identified 22787 participants from 466701 participants who are aged ≤11 years. In these participants, 9644 were administered "capsule," "tablet," "orally distegrating tablet," "controlled release tablet/capsule" or "enteric coated tablet" formula drugs. In these, 514 were administered these as powderization or decapsulation. Sixty components administered in 145 participants (28.2%) are not marketed for pediatric formula. On the other hands, 92 components administered in 369 participants (71.8%) are decapsulation or powderization, though pediatric formulas are marketed. These 152 components may have a development seeds for children. In conclusion, prescription survey using medical big data may partially resolve the drug-development-need in pediatrics because by using medical big data will leads low biased data depending each institution.

Prognostic Model of Baseline Medications plus Neutrophil-to-lymphocyte Ratio in Patients with Advanced Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitor plus Platinum Doublet: A Multicenter Retrospective Study.

Background: Association between baseline medications plus neutrophil-to-lymphocyte ratio (NLR) and the effectiveness of immune checkpoint inhibitor (ICI) plus platinum doublet remains unknown, despite several reported prognostic models. We used real-world data to investigate whether baseline medications plus NLR predict survival outcomes in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICI plus platinum doublet. Methods: This multicenter, retrospective, observational study conducted in Japan between December 2018 and March 2021 used real-world data of consecutive patients with advanced NSCLC who received ICI (pembrolizumab or atezolizumab) plus platinum doublet as first-line treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The prognostic score for baseline medications plus NLR was weighted by regression ß coefficients and used to categorize patients into good, intermediate, and poor prognoses groups. In addition, time-dependent receiver operating characteristic curve analyses and univariable and multivariable Cox proportional hazards models were constructed. Results: Overall, 241 patients were included. Poor prognosis was significantly associated with worse PFS (hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.08-2.94; P = 0.025) and OS (HR: 3.59; 95% CI: 2.05-6.28; P < 0.001) than good prognosis. Harrell's C-index for this prognostic model was 0.648. Conclusions: Baseline medication plus NLR could predict progressively worse survival outcomes in patients with advanced NSCLC receiving ICI plus platinum doublet and could be used as a prognostic index for poor outcomes.

Five cases of skin desquamation due to bevacizumab combined with docetaxel-carboplatin in ovarian cancer.

The standard of care for ovarian cancer chemotherapy is paclitaxel-carboplatin. In Stage III and Stage IV patients, the addition of bevacizumab has been reported to be effective, and bevacizumab combined with paclitaxel-carboplatin and bevacizumab combined with docetaxel-carboplatin are used. Patients who received bevacizumab combined with docetaxel-carboplatin experienced a high incidence of skin hardening followed by peeling. In patients treated with bevacizumab combined with docetaxel-carboplatin, we experienced a high incidence of post-sclerotic peeling of the skin, a symptom that is rarely seen with paclitaxel-carboplatin (TC), docetaxel-carboplatin (DC), or bevacizumab combined with paclitaxel-carboplatin, and has been reported in a few cases. Therefore, we investigated the actual situation of skin desquamation caused by bevacizumab combined with docetaxel-carboplatin. Thirty-one patients were included in the study, and their age (mean ± SD) was 62.9 ± 9.0. The breakdown of treatment was as follows: TC in nine patients, bevacizumab combined with paclitaxel-carboplatin in ten patients, DC in six patients, and bevacizumab combined with docetaxel-carboplatin in six patients. No number of patients with TC or bevacizumab combined with paclitaxel-carboplatin showed skin desquamation. One for DC, and five for bevacizumab combined with docetaxel-carboplatin. The five patients treated with bevacizumab combined with docetaxel-carboplatin improved with topical steroids and moisturizers, but symptoms repeatedly appeared after each course. Skin desquamation was more frequent in bevacizumab combined with docetaxel-carboplatin.

Negative effects of rivaroxaban observed in a patient with multiple common risks triggered by a bicycle accident.

The negative effects of anticoagulants are well-known in patients with renal impairment, drug-drug interaction, lower physical conditions, and multiple comorbidities. We highlight that even in patients with controllable multiple risks for rivaroxaban use, add-on inevitable risks will lead to negative effects greater than those expected.

Failure of liposomal amphotericin B therapy in patients with severe pancreatitis complicated by Candida lusitaniae infection.

Candida lusitaniae is an uncommon pathogen that accounts for approximately 1% of patients with candidiasis. In this report, we present the case of a 24-year-old woman with severe pancreatitis who was emergently admitted to Northern Yokohama Hospital. We started treating the pancreatitis and infections according to her culture results. However, her symptoms, accompanied by a necrotic pancreas, did not improve. Finally, C. lusitaniae was detected in the blood and catheter samples. We started antifungal treatment according to the culture results, but the patient died. Generally, the mortality rate for acute pancreatitis ranges from 3% for patients with interstitial edematous pancreatitis to 17% for those who develop pancreatic necrosis. Although we chose appropriate antibiotics and antifungal agents based on the culture results, the treatments failed. Early detection, sufficient doses of antimicrobials and frequent monitoring using sample culture are crucial because infection control may be inadequate, especially in tissues with low blood flow, such as necrotic tissues.

A Case of Hepatocellular Carcinoma Successfully Resumed Atezolizumab and Bevacizumab After Associated Grade 3 Diarrhea and Grade 2 Colitis: Case Report and Literature Review.

Systemic chemotherapy has shown a significant survival benefit in patients with hepatocellular carcinoma (HCC). However, it is associated with various immune-related adverse events (irAEs). We report a case with grade 3 diarrhea and grade 2 colitis following systemic chemotherapy, successfully treated with prednisolone. An 89-year-old man was incidentally detected with a 140-mm hypervascular intrahepatic nodule on contrast-enhanced computed tomography (CECT). Washout of the contrast medium was also detected, and protein induced by vitamin K deficiency or antagonists-II (PIVKA-II) was elevated. Since the Albumin-Bilirubin (ALBI) grade was 2a without any distant metastasis, transarterial chemoembolization (TACE) was performed to treat the HCC, but several intrahepatic nodules were seen in both lobes. Therefore, the patient was treated with lenvatinib for 1 year and 4 months. A complete response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was achieved in 2 months; however, multiple hypervascular nodules were detected again. Since the ALBI grade was 1, a second round of chemotherapy with atezolizumab and bevacizumab was initiated. Although a complete response was achieved, the therapy was discontinued due to grade 3 diarrhea and grade 2 colitis after the sixth course. Based on the stool analysis and culture, CECT, and colonoscopy, the diagnosis was atezolizumab-associated colitis. Diarrhea was controlled following the oral administration of 0.5 mg/kg/day of prednisolone, and atezolizumab-bevacizumab therapy was successfully reinitiated without recurrence of colitis. The management of irAEs is important for a significant survival benefit. Systemic chemotherapy with atezolizumab and bevacizumab can be resumed despite a grade 3 irAE due to atezolizumab.

Identification of the Components of Proton Pump Inhibitors and Potassium-Competitive Acid Blocker That Lead to Cardiovascular Events in Working-Age Individuals: A 12-Month Retrospective Cohort Study Using a Large Claims Database.

This study aimed to identify the components of proton pump inhibitors (PPIs) or potassium-competitive acid blocker (PCAB) that lead to cardiovascular events in individuals of working age. We analyzed large claims data of individuals who were administered PPIs or PCAB. We enrolled working-age individuals administered PPI or PCAB without cardiovascular history with a 12-month screening and 12-month observation period and determined the proportion of cardiovascular events and the predictive factors of cardiovascular events in this population. Among the eligible individuals, 0.5% (456/91098) had cardiovascular events during the 12-month observation period. Predictive factors for cardiovascular events were age for +1 year (p < 0.0001), male sex (p < 0.0001), hypertension (p = 0.0056), and diabetes mellitus (p < 0.0001). The cardiovascular disease risk was higher in working-age individuals administered lansoprazole than in those administered other drugs (vs. rabeprazole; p = 0.0002, vs. omeprazole; p = 0.0046, vs. vonoprazan; p < 0.0001, and vs. esomeprazole; p < 0.0001). We identified the risk for cardiovascular events in individuals being treated with lansoprazole. Lansoprazole is known for its higher CYP2C19 inhibition activity compared with other PPIs or PCAB. A possible mechanism by which lansoprazole may lead to cardiovascular events is inhibiting the generation of epoxyeicosatrienoic acids from arachidonic acids, an intrinsic cardioprotective activator via CYP2C19 inhibition. Thus, we recommend avoiding administering lansoprazole to working-age individuals require PPIs or PCAB.

Simple determination of urine cefazolin concentration in pediatric patients with urinary tract infections using high-performance liquid chromatography.

Recently, global health concerns regarding increasing multidrug resistance have arisen. This study aimed to develop a simple, inexpensive and rapid high-performance liquid chromatography-ultraviolet (HPLC-UV) method for determining urinary concentrations of a first-generation cephem antibiotic in pediatric patients with urinary tract infections (UTIs). HPLC-UV was used to analyze urinary cefazolin concentrations at a detection wavelength of 254 nm. The assay used contained 10-fold diluted urine with an internal standard (cephapirin). The standard calibration curve for cefazolin was linear in the concentration range of 31.25-500 µg/ml (r2  > 0.999). The retention times of cefazolin and the internal standard were 4.2 and 4.9 min, respectively. The within- and between-day coefficients of variation were in the concentration ranges 1.2-15.2 and 5.5-19.2%, respectively. The urinary cefazolin concentration of a pediatric patient with a UTI was 1,476.6 µg/ml, which was over 700-fold higher than the minimum inhibitory concentration of cefazolin (≤2 µg/ml). The developed method is applicable to the confirmation of appropriate use for UTI treatment as therapeutic drug monitoring of cefazolin. Therefore, the findings of this study may contribute to the appropriate use of antibiotics to prevent antimicrobial resistance in pediatric patients with UTIs.

Acute kidney injury in villous cancer patients treated with vancomycin and tazobactam/piperacillin.

In this report, we present a 37-year-old woman with villous cancer who developed AKI after co-administration of VCM and TAZ/PIPC. Trough concentration of VCM reach a toxic level. Finally, she recovered on day 17.

[Impact of the Antimicrobial Stewardship Team Intervention Focusing on Changes in Prescribing Trends and the Rate of Carbapenem-resistant P. aeruginosa].

Antimicrobial stewardship (AS) intervention strategy is a critical process in promoting appropriate antibiotic use, thus preventing unnecessarily prolonged therapy and reducing antimicrobial resistance (AMR). Although limiting unnecessary carbapenem use by AS intervention is speculated to reduce AMR, there is a lack of specific data on the efficacy of AS team (AST) intervention regarding carbapenem-resistant Pseudomonas aeruginosa (CRPA). Consequently, this study aimed to evaluate the impact of our AS strategy on carbapenem use and CRPA. The AS intervention strategy was launched in July 2017 and consisted of daily audits and feedback on carbapenem use. We evaluated the 4-year prescription trend, including the rate of switching to other antimicrobials, and the rate of CRPA and the days of therapy required prior to and after the beginning of the AST intervention. The rate of switching to narrow-spectrum antibiotics and the discontinuation of carbapenem treatment were significantly higher in the pre-intervention period compared with the post-intervention period. (7.0% vs. 14.5%; p<0.001; 54.1% vs. 50.9%; p=0.027). However, there were no significant differences in the rate of CRPA prior to and after the beginning of the AST intervention. Furthermore, there was no correlation found between consumption and resistance rate (Pearson's r=0.123). Our results suggest that it is extremely important for AST to promote de-escalation and reduce unnecessary use, while the combination of process and outcome indicators other than antimicrobial consumption and resistance rate are required for the evaluation of the AS programs.

Potential drug-drug interaction between tolvaptan and warfarin in a geriatric patient with heart failure.

Tolvaptan is a key drug for patients with heart failure. Here, we present a 92-year-old woman, whose PT-INR/dose increased from 1.74 to 3.30 after warfarin and tolvaptan co-administration, and resulted in a large cerebral infarction after warfarin dose down. Therefore, the interaction between these two drugs may be clinically significant.

Irinotecan-induced severe hypotension in a patient with lung cancer.

Most hypotension during chemotherapy is caused by an allergic mechanism. Conversely, non-allergic hypotension due to chemotherapy is rare. In this case report, we present a patient who suffered severe hypotension followed by the administration of irinotecan-based chemotherapy and some supportive care such as steroids for preventing emesis. A 71-year-old man with hypertension was diagnosed with stage IV small cell lung cancer (sT1cN3M0). Severe hypotension occurred in the patient after every administration of chemotherapy. Finally, he was able to receive all four courses of chemotherapy as planned along with the medical staff's support care. This case provides that a regimen that contained irinotecan and steroid could cause hypotension and the mechanism is partially explained by inhibiting choline esterase and adrenal insufficiency. We should be careful about non-allergic hypotension when we administer irinotecan-based chemotherapy.

Clinical course involving thrombocytosis and thrombocytopenia in a patient with bladder cancer treated with gemcitabine and cisplatin.

Gemcitabine induce thrombocytopenia and thrombocytosis as toxicity. In this report, we show detailed time-course for platelet fluctuation. Our case emphasis attention to monitor see-saw-like toxicity on platelet count.