Yasunari Mano

Background/Objectives: The non-neuronal cardiac cholinergic system (NNCCS) is known to synthesize ACh independently of the parasympathetic nervous system, thereby regulating cardiac homeostasis, which includes sustainability of energy metabolism, anti-inflammatory and anti-ischemic properties, electrical stability, and mitochondrial calcium handling. Given these beneficial functions of NNCCS, we were prompted to search for an inducer. One such inducer is SNPiP, a novel low-molecular-weight chemical compound developed by us. SNPiP accelerates ACh synthesis in the heart via cGMP elevation and, intriguingly, enhances diastolic function, increasing cardiac output and end-systolic pressure without elevating heart rate. However, the pharmacokinetics of SNPiP remain unknown, which led us to conduct the present study. Methods and Results: We found that the half-life of SNPiP in the blood was extremely short, similar to that of a nitric oxide (NO) donor, S-nitroso-N-acetyl-DL-penicillamine. This short half-life is caused by the rapid distribution of SNPiP into organs, including the heart, kidney, and liver. In addition, once transferred into blood cells, SNPiP itself became stable and remained intact for up to 1 h. Moreover, the short half-life was partly explained by the rapid degradation of SNPiP and concomitant loss of the nitroso group in the blood. Notably, when rats were treated with SNPiP, NO levels in the heart elevated bimodally: immediately after administration and again about 12 h later, coinciding with the previous report of NNCCS upregulation and accelerated ACh synthesis with NO production. Importantly, our previous transcriptome analysis of SNPiP-treated hearts supports these findings, as it revealed upregulation of diastolic function-related genes and proteins. Conclusions: Collectively, these results clarify the pharmacokinetics of SNPiP and demonstrate that, despite a shorter half-life, SNPiP is efficiently distributed to the heart, where it confers beneficial effects through induction of NNCCS.

Background: Although experimental studies suggest that low-dose aspirin has chemopreventive effects against colorectal cancer, clinical evidence remains inconsistent, and studies on Japanese populations are limited. This study aimed to evaluate the relationship between low-dose aspirin and colorectal cancer using a large-scale Japanese database. Methods: A nested case–control study was conducted using a health insurance claims database (2005–2021). Cases were defined as patients with a diagnosis of colorectal cancer during the study period, with the month of the first diagnosis as the index month, and were matched 1:4 risk-set sampling with population controls based on age and sex. Exposure was defined as the use of low-dose aspirin prior to the index month. We further analyzed recency and duration. Recency was categorized as recent use (<3 months before the index month) and past use (≥3 months before the index month). Duration was classified into two groups: <2 years and ≥2 years. Results: In total, 17,373 cases and 69,492 controls were included. Conditional logistic regression analysis, adjusted for patient background, showed that low-dose aspirin use may reduce the risk of colorectal cancer (adjusted odds ratio: 0.87; 95% confidence interval, 0.79–0.97). For recency and duration, the risk of colorectal cancer was significantly reduced by recent use and ≥2 years compared with never use. Conclusions: Low-dose aspirin use may be associated with a reduced risk of colorectal cancer. Impact: These findings contribute to the clinical evidence regarding colorectal cancer prevention in Asian populations.

Supplementary Figure from Association between Statins and Incidence of Cancer in Patients with Dyslipidemia Using Large-Scale Health Insurance Claims Data

BACKGROUND: While the efficacy of statins, which are cholesterol-lowering agents, in preventing subarachnoid hemorrhage (SAH) has been examined in experimental animal models and some clinical studies, findings remain inconclusive. This study aimed to investigate the association between statin use and the risk of SAH. METHODS: We conducted a large population-based case-control study using data from the Japanese Health Insurance Claims Database from January 2005 to August 2021. This nationwide database includes the data of individuals aged 0 to 74 years. Cases were defined as patients hospitalized with a first diagnosis of SAH ( International Classification of Diseases, Tenth Revision code I60) during this period. Four controls per case were randomly selected and matched by age, sex, and follow-up period using incidence density sampling. Statin exposure (use, recency, and duration) was evaluated before the incidence of SAH. Conditional logistic regression, adjusted for patient characteristics, was used to assess the association between statin use and SAH risk. We also investigated whether this association varies with a history of hypertension, diabetes, cerebrovascular disease, unruptured intracranial aneurysms, and the use of antihypertensive medications. RESULTS: The study identified 3498 cases and 13 992 matched controls. Statin use was reported in 12.2% of SAH cases and 12.7% of the controls. After adjusting for patient characteristics, statin use was associated with a significantly reduced risk of SAH (adjusted odds ratio, 0.81 [95% CI, 0.69–0.95]). The association was significantly influenced by a history of hypertension or cerebrovascular disease ( P _interaction =0.042 and 0.042, respectively). CONCLUSIONS: Statin use was significantly associated with a reduced risk of SAH. These findings suggest that statins may play a role in the prevention of SAH, particularly in patients with a history of hypertension or cerebrovascular disease.

Background/Aim: We previously reported a decrease in prostate-specific antigen (PSA) levels in patients with castration-resistant prostate cancer treated with angiotensin II receptor blockers (ARBs). However, no studies have reported the effect of ARBs on PSA variability in patients without a history of prostate cancer. Therefore, we conducted a population-based, retrospective study to determine whether ARBs have an inhibitory effect on elevated PSA levels in Japanese patients without a history of prostate cancer. Patients and Methods: This study was conducted using a large-scale Japanese claim database, including male patients aged ≥60 years who had two or more PSA measurements with an interval between measurements of 3 months to 2 years between April 2008 and June 2019. Patients who had been prescribed ARBs were grouped into the ARB group, and those who were prescribed antihypertensive drugs other than ARBs were grouped into the non-ARB group. We compared the proportions of patients with second PSA levels greater than the first. The numbers of eligible patients in the ARB and non-ARB groups were 777 and 527, respectively. Results: Multivariate logistic regression analysis revealed that the proportion of patients with elevated PSA levels was significantly lower in the ARB group than in the non-ARB group (adjusted odds ratio=0.80, 95% confidence interval=0.64-0.99, p=0.047). Conclusion: ARBs may suppress elevated PSA levels in patients without a history of prostate cancer. This contributes to the prevention of prostate cancer.

Background: Prostate cancer is one of the most common cancers among men worldwide and the fourth most common cause of death. The number of prostate cancer cases and deaths is increasing every year because of population aging. This study aimed to clarify the risk of developing prostate cancer due to fluctuations in Prostate Specific Antigen (PSA) levels in patients without a history of prostate cancer using large medical information data. Results: This retrospective cohort included 1707 male patients aged 60 years or older who had a PSA level measurement date (2-PSA) within 3 months or more and 2 years from the first PSA level measurement date (1-PSA) in the database between 2008 and 2019. We subtracted 1-PSA from 2-PSA and designated patients with a higher 2-PSA than 1-PSA to the “up” group (n = 967) and patients with a lower 2-PSA than 1-PSA to the “down” group (n = 740). By using Cox proportional hazards model, a significant increase in prostate cancer risk was observed in the up group compared with the down group (adjusted hazard ratio [HR] = 1.82, 95% confidence interval [CI] = 1.21–2.72; adjusted for patient background factors). Subgroup analysis showed that patients with PSA levels < 4 ng/mL had a significantly increased risk of developing prostate cancer if the next PSA level increases by approximately 20% (adjusted HR = 2.94, 95% CI = 1.14–7.58), and patients with PSA levels of 4 ng/mL or higher if the next PSA level is decreased by approximately 20% had a significantly reduced risk of developing prostate cancer (adjusted HR = 0.36, 95% CI = 0.18–0.74), compared to that with no change. Conclusions: This is the first study to clarify the association between PSA variability and risk of developing prostate cancer in patients without a history of prostate cancer. These results suggest that the suppression of elevated PSA levels may lead to the prevention of prostate cancer and that it would be better to perform a biopsy because the risk of developing prostate cancer may increase in the future if the PSA value increases above a certain level.

Recent experimental studies have examined the efficacy of statins in preventing cancer, but the findings of clinical studies are inconsistent, and studies on Japanese patients are limited. This study aimed to clarify the association between statins and cancer risk among Japanese patients. We conducted a large population-based retrospective cohort study using the Japanese health insurance claims database, including patients newly diagnosed with dyslipidemia between 2005 and 2015. Patients who were on newly prescribed statins during the study period were designated as statin users. They were matched 1:1 with randomly selected drug nonusers who were not prescribed drugs for dyslipidemia according to age, sex, and year of first diagnosis of dyslipidemia. There were 23,746 patients in each group. The mean duration of follow-up for statin users and drug nonusers was approximately 2 years. Using a Cox proportional hazards model, significant reduction in cancer risk was observed in statin users compared with that in drug nonusers [adjusted HR = 0.84; 95% confidence interval (CI), 0.72–0.97; adjusted for patient background factors]. The results of subgroup analyses suggested that prescribed statins reduced the incidence of cancer of the digestive organs (adjusted HR = 0.79; 95% CI, 0.63–0.99) as well as reduced cancer risk in patients with nonsmokers (adjusted HR = 0.78, 95% CI = 0.65–0.92). Our results suggest that statin use may reduce cancer risk in patients with dyslipidemia.Prevention Relevance:This study clarified the relationship between statin use and cancer risk in patients with dyslipidemia. Our study will contribute to medicine selection in patients with hypercholesterolemia level.See related Spotlight, p. 1

Recent experimental studies have examined the efficacy of statins in preventing cancer, but the findings of clinical studies are inconsistent, and studies on Japanese patients are limited. This study aimed to clarify the association between statins and cancer risk among Japanese patients. We conducted a large population-based retrospective cohort study using the Japanese health insurance claims database, including patients newly diagnosed with dyslipidemia between 2005 and 2015. Patients who were on newly prescribed statins during the study period were designated as statin users. They were matched 1:1 with randomly selected drug nonusers who were not prescribed drugs for dyslipidemia according to age, sex, and year of first diagnosis of dyslipidemia. There were 23,746 patients in each group. The mean duration of follow-up for statin users and drug nonusers was approximately 2 years. Using a Cox proportional hazards model, significant reduction in cancer risk was observed in statin users compared with that in drug nonusers [adjusted HR = 0.84; 95% confidence interval (CI), 0.72–0.97; adjusted for patient background factors]. The results of subgroup analyses suggested that prescribed statins reduced the incidence of cancer of the digestive organs (adjusted HR = 0.79; 95% CI, 0.63–0.99) as well as reduced cancer risk in patients with nonsmokers (adjusted HR = 0.78, 95% CI = 0.65–0.92). Our results suggest that statin use may reduce cancer risk in patients with dyslipidemia.Prevention Relevance:This study clarified the relationship between statin use and cancer risk in patients with dyslipidemia. Our study will contribute to medicine selection in patients with hypercholesterolemia level.See related Spotlight, p. 1

Supplementary Figure from Association between Statins and Incidence of Cancer in Patients with Dyslipidemia Using Large-Scale Health Insurance Claims Data