Objective: Clinical trials are designed to clarify the dose-dependency of drugs.  However, the dose-dependency of adverse drug reactions (ADR), especially in the subtherapeutic range, often remains unclear.  Whether decreasing a drug’s dose would reduce the risk of ADR is of interest to both clinicians and regulators.  This study aimed to clarify the dose-dependency of ADR during subtherapeutic exposure to non-steroidal anti-inflammatory drugs, immunosuppressants, β-adrenoceptor antagonists, or corticosteroids.
Methods: Data about the ADR risk profiles and the area under the concentration curve (AUC) values of the examined drugs during their subtherapeutic administration, e.g., after their topical or low-dose oral administration, were collected from the literature and compared with data obtained during the therapeutic administration of the drugs; i.e., at the standard oral dosage.
Results: The drugs that exhibited AUC of ≥20% during their therapeutic administration continued to cause significant systemic ADR during their subtherapeutic administration.  Whilst the drugs that demonstrated AUC of 3-20% during their therapeutic administration continued to cause systemic ADR during their subtherapeutic administration, the ADR tended to be less frequent.
Conclusion: The dose-dependency of ADR can be estimated by comparing the AUC and ADR risk profile data for a drug obtained during its topical, parenteral, or low-dose oral administration with that obtained during its oral administration at the standard dose.  However, some studies have detected high ADR frequencies even during reduced systemic exposure, suggesting that factors affecting the risk of ADR, e.g., patients’ background data, should be carefully matched between the datasets being compared.

Shichimotsukokato is composed of shimotsuto with chotoko, ogi, obaku, and this formula has been frequently used for the treatment of hypertension, eye-fundal hemorrhage and headaches. Here we describe three cases of chronic dermatitis with hypertension and dry skin of legs, which were successfully treated with shichimotsukokato. Case 1 was a 67-year-old man whose chief complaint was pruritus and skin eruption on his chest. He also had dry skin accompanied with pruritus on his legs, and hypertension. Case 2 was a 59-year-old man who had skin eruption accompanied with pruritus on his trunk and extremities. He also showed diastolic hypertension and renal insufficiency due to the side effect of an immunosuppressant. Case 3 was a 64-year-old man who had dry skin with eruption on the upper trunk. Furthermore, his blood pressure fluctuated within the high normal range. After medication with shichimotsukokato, both the hypertension and dermatitis improved in all three cases.
According to these observations, shichimotsukokato may alleviate dermatitis along with dry skin of legs and hypertension, and it may be worth noting that shichimotsukokato is an option for the treatment of skin lesion.

Objectives: To investigate effects of romosozumab treatment on disease activity and bone mineral density (BMD) in patients with rheumatoid arthritis (RA) and severe osteoporosis in comparison with effects of denosumab treatment. Methods: A total of 50 women were enrolled in this study. The subjects were randomized equally into 2 groups: the romosozumab group or the denosumab group. Disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) and BMD at lumbar spine were evaluated. Results: The percent changes (Δ) in the BMD values at 3 and 6 months for the lumbar spine were as follows: romosozumab; 4.9% and 5.2%, denosumab: 2.3% and 3.2%. The ΔBMD for the lumbar spine at 3 months was significantly higher in the romosozumab group than in the denosumab group (P = 0.044). The DAS28-ESR at baseline, 3 and 6 months in the romosozumab group were 2.88, 2.60 (P = 0.427) and 2.58 (P = 0.588), respectively. The change from baseline in DAS28-ESR did not differ significantly between these 2 groups at any time point. Conclusions The present study revealed that romosozumab treatment is more effective than denosumab treatment in increasing BMD of the lumbar spine at 3 months. Furthermore, the present study suggested that romosozumab treatment has no effects on the disease activity of RA in patients with RA and severe osteoporosis for 6 months.

Objectives: This study aims to examine the 2-year outcomes of zoledronic acid (ZOL) with or without eldecalcitol (ELD) on bone mineral density (BMD) and fracture in Japanese patients with osteoporosis. Methods: The subjects were 98 patients who were randomly (1:1) assigned to treatment with ZOL combined with ELD (ZOL + ELD group; n = 51) and ZOL alone (ZOL group; n = 47). Treatment efficacy was examined based on a comparison of changes in BMD from baseline (DBMD) in the lumbar spine, total hip, and femoral neck in the 2 groups. Results: The percent change from baseline in BMD values for the lumbar spine, total hip, and femoral neck at 24 months were 10.8% ± 6.1%, 6.0% ± 6.6%, and 5.1% ± 5.1%, respectively, in the ZOL + ELD group, and 7.7% ± 6.2%, 5.1% ± 5.6%, and 2.9% ± 8.3%, respectively, in the ZOL group. The percent change from baseline BMD for the lumbar spine at 24 months differed significantly between the 2 groups. Conclusions The effect of a combination of ZOL + ELD on BMD for 24 months was more favorable than that of ZOL alone. This drug combination is promising for the treatment of drug-naïve Japanese patients with primary osteoporosis.

Objectives: To investigate effects of romosozumab treatment on disease activity and bone mineral density (BMD) in patients with rheumatoid arthritis (RA) and severe osteoporosis in comparison with effects of denosumab treatment. Methods: A total of 50 women were enrolled in this study. The subjects were randomized equally into 2 groups: the romosozumab group or the denosumab group. Disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) and BMD at lumbar spine were evaluated. Results: The percent changes (Δ) in the BMD values at 3 and 6 months for the lumbar spine were as follows: romosozumab; 4.9% and 5.2%, denosumab: 2.3% and 3.2%. The ΔBMD for the lumbar spine at 3 months was significantly higher in the romosozumab group than in the denosumab group (P = 0.044). The DAS28-ESR at baseline, 3 and 6 months in the romosozumab group were 2.88, 2.60 (P = 0.427) and 2.58 (P = 0.588), respectively. The change from baseline in DAS28-ESR did not differ significantly between these 2 groups at any time point. Conclusions The present study revealed that romosozumab treatment is more effective than denosumab treatment in increasing BMD of the lumbar spine at 3 months. Furthermore, the present study suggested that romosozumab treatment has no effects on the disease activity of RA in patients with RA and severe osteoporosis for 6 months.

Background: The long-term effects of daily teriparatide (D-TPTD) and twice-weekly TPTD (W-TPTD) injections are compared among postmenopausal women with severe osteoporosis. Methods: A total of 102 patients were enrolled and randomly allocated into two groups for the administration of either D-TPTD or W-TPTD. Treatment efficacy was measured as the percentage change in bone mineral density (ΔBMD) from baseline in the lumbar spine, total hip, and femoral neck. The findings were compared between the two groups. Results: At 24 months after treatment, the persistence rates and medication possession ratios in the D-TPTD and W-TPTD groups were 68.6% and 56.9%, and 87.8% and 92.0%, respectively. The ΔBMD in the lumbar spine, total hip, and femoral neck were 15.6%±10.2%, 5.3%± 6.3%, and 5.5%±6.2%, respectively, in the D-TPTD group; and 9.5%±7.9%, 2.3%±6.2%, and 3.1%±7.4%, respectively, in the W-TPTD group following 24 months of treatment. The ΔBMD of the lumbar spine (p=0.008) at 24 months and total hip (p=0.024) at 18 months differed significantly between the two groups. Conclusions D-TPTD administration resulted in a significantly higher BMD in the lumbar spine and total hip, supporting this therapeutic regimen for postmenopausal women with severe osteoporosis.

Purpose: In Japan, the data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody titers after the booster dose of the coronavirus disease 2019 (COVID-19) vaccine are insufficient. The aim of this study is to evaluate changes in SARS-CoV-2 antibody titers before, 1, 3, and 6 months after the booster dose of the BNT162b2 COVID-19 vaccine among health care workers. Materials and Methods: A total of 268 participants who received the booster dose of the BNT162b2 vaccine were analyzed. SARS-CoV-2 antibody titers were measured before (baseline) and at 1, 3, and 6 months after the booster dose. Factors associated with changes in SARS-CoV-2 antibody titers at 1, 3, and 6 months were analyzed. Cutoff values at baseline were calculated to prevent infection of the omicron variant of COVID-19. Results: The SARS-CoV-2 antibody titers at baseline, and 1, 3, and 6 months were 1,018.3 AU/mL, 21,396.5 AU/mL, 13,704.6 AU/mL, and 8,155.6 AU/mL, respectively. Factors associated with changes in SARS-CoV-2 antibody titers at 1 month were age and SARS-CoV-2 antibody titers at baseline, whereas changes in SARS-CoV-2 antibody titers at 3 and 6 months were associated with the SARS-CoV-2 antibody titers at 1 month. The cutoff values of the SARS-CoV-2 antibody titers at baseline were 515.4 AU/mL and 13,602.7 AU/mL at baseline and 1 month after the booster dose, respectively. Conclusion This study showed that SARS-CoV-2 antibody titers increase rapidly at 1 month after the booster dose of the BNT162b2 vaccine and begin to decrease from 1 to 6 months. Hence, another booster may be needed as soon as possible to prevent infection.

A Task Force team consisting of members from pharmaceutical companies --a central player to develop and implement RMP (Risk Management Plan)-- as well as health care professionals and members from academia was established in JSPE. The Task Force developed guidance for scientific approach to practical and ICH-E2E-compliant Pharmacovigilance Plan (PVP) stated in Japanese Risk Management Plan issued in April 2012 by the Ministry of Health, Labour and Welfare. The guidance contains the following topics.
1．Introduction: JSPE's activities and this task force's objectives for pharmacovigilance activities
2．How to select Safety Specification (SS) and describe its characteristics
・Selection of SS
・Characterization of SS
・Association with Research Questions (RQ)
3．How to define and describe RQ
・What is RQ ?
・RQ interpretation in other relevant guidelines
・Methodology to develop RQ for PVP with examples
・Best approach to integrating PVP for whole aspects of safety concern
4．How to optimize PVP for specific RQ
・Routine PVP or additional PVP ?
・Additional PVP design (RQ and study design, RQ structured with PICO or GPP's research objectives, specific aims, and rationale)
・Checklist to help develop PVP
5．Epilogue:
・What can/should be “Drug use investigation” in the context of ICH-E2E-compliant PVP.
・Significance of background incidence rate and needs for comparator group
・Infrastructure for the future PVP activities
6．Appendix: Checklist to help develop PVP activities in RMP
The task force team is hoping that this guidance help develop and conduct SS and PVP in accordance with ICH E2E, as stated in Japanese Risk Management Plan Guideline.

Background: Although transferring drugs to a third party, even in a personal capacity, is illegal in Japan, many drug transactions are carried out via internet auction sites. Pharmacy consumers might not be aware of the illegality of transferring drugs to others due to various factors. To clarify pharmacy consumers’ awareness of this issue and its covariates, we carried out a questionnaire survey.Methods: A self-completed questionnaire, consisting of yes/no and multiple-choice questions, was used. The adult patients who visited Keio University Pharmacy were asked to fill out the questionnaire.Results and Discussion: One hundred and fifty-one response sheets were effectively collected from 173 responders. The subjects’awareness of the illegality of transferring drugs was significantly affected by the formulation (oral vs. patches) and pharmacological category of the drug, as well as the source of the drug (prescribed vs. over the counter). Patient education about the illegality of personally transferring drugs, especially patches, might be required to avoid illegal drug transfers, including via the internet.

Objective: To clarify challenges and strategies to execute pharmaceutical care by community pharmacists and obtain pragmatic implications for further improvement. Design: Cross-sectional study.. Methods: We conducted a nationwide internet-based questionnaire survey about pharmaceutical care by the Japanese community pharmacists in June and July 2016. Using text data of 161 respondents, we investigated their challenges and strategies in implementing pharmaceutical care. The text data were reviewed and determined for categorization through stepwise process and reconciliation between reviewers. Results: Fourteen categories were retrieved and integrated into 4 domains (pharmacists, patients, other medical professionals, and environment) from 2 dimensions (challenges and strategies). In the challenge dimension (total n＝142), communication capability (n＝26), participation in medical team (n＝17), patients’ understanding of pharmacists’ work (n＝14), lack of timeand staff (n＝14),patient- and people-centered viewpoint (n＝13). Whilein thestrategy dimension (total n＝72), communication capability (n＝21),lack of patients’ medical information (n＝18), patient- and people-centered viewpoint (n＝11), lack of timeand staff (n＝9), and self development (n＝5). As strategies for the communication capability, attitude of acceptance and collaboration, brief explanation,utilization of visual aids, adoption of objective evaluation, various acquisition of patients’ information, active listening, and sharing patients’ information were retrieved as subcategories. The highest level of attention to communication capability implies that community pharmacists certainly recognize their expected responsibility described in the government document titled “Vision for patient-centered pharmacies”. Conclusion: Community pharmacists face many challenges but have some practical strategies. Although part of such challenges is not for pharmacists themselves but for patients, other medical professionals, or entire health system, improving essential skills of pharmacists may havepositiveinfluenceto theother challenges.