Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan最新文献

Approximately 7000 rare diseases have been identified globally; however, effective treatments are available for only 5% of them, highlighting substantial unmet medical needs worldwide. In Japan, drug loss-the lack of domestic approval or development of drugs already approved overseas-has become a pressing public health issue. We analyzed orphan drugs (ODs) approved in the United States (U.S.) between 2005 and 2021 to examine trends in OD development in the U.S., drug loss and associated research and development (R&D) models, with the aim of identifying factors that could facilitate more seamless OD development in Japan. Despite a marked increase in OD approvals in the U.S. since 2018, the number of ODs not approved in Japan have increased rapidly, reaching 120 drugs (49%), of which approximately 70% had not entered development, indicating greater OD loss in Japan. U.S./Europe-based startups have become key players in rare disease drug R&D, significantly contributing to this drug loss trend. They successfully develop drugs in the U.S. by combining in-licensing with in-house drug discovery. Out-licensing to Japanese companies or large pharma is critical for expansion into Japan, with successes attributed to drug innovation, target indications, and transactional capabilities. Underlying this trend were Japan's perceived low market potential, its complex clinical trial environment and regulatory requirements, and the financial limitations of startups. These findings highlight the need to foster partnerships with startups and cultivate an ecosystem in Japan that nurtures local startups, to address drug loss and ensure access to promising drugs.

Piperacillin/tazobactam (PIPC/TAZ) and vancomycin (VCM) are frequently used in combination (PTV) to manage severe healthcare-associated infections, but are also associated with an increased risk of acute kidney injury (AKI). In 2019, Ogaki Municipal Hospital implemented pharmacist-led interventions aimed at reducing PTV use and mitigating AKI. This study evaluated the impact of these interventions on antibiotic safety and patient outcomes. This retrospective study included hospitalized patients treated with PTV between January 2010 and December 2023. Details of these pharmacist interventions were reviewed retrospectively. Patients were categorized into pre- and post-intervention periods. The primary outcomes reported were the duration of PTV therapy and the incidence of AKI. Multivariable regression analyses were performed to evaluate the association between the intervention, therapy duration, and AKI incidence. Mediation analysis was conducted to assess whether the reduction in PTV duration mediated the effect of the intervention on AKI incidence. As a result, AKI incidence decreased from 19.8% in the pre-intervention period to 7.7% in the post-intervention period (p=0.038). In the PTV cohort, multivariable models showed lower AKI risk in the post period [adjusted odds ratio (OR) 0.283; 95% confidence interval (CI) 0.086 to 0.803; p=0.024] and a shorter PTV duration (β=-2.011 d; 95% CI -3.459 to -0.563; p=0.007). In mediation analysis, the shortening of PTV duration partially mediated the AKI reduction (ACME p=0.016). In conclusion, pharmacist-led interventions effectively reduced PTV duration leading to a decrease in AKI incidence, highlighting the critical role of pharmacists in promoting antimicrobial stewardship and improving patient outcomes.

Cutaneous adverse events associated with tirabrutinib have been reported in clinical trials; however, their overall incidence and severity vary, and real-world data remain limited. This study aimed to assess the incidence and management of tirabrutinib-associated cutaneous adverse events in patients with primary central nervous system lymphoma (PCNSL). This single-center case series included patients with PCNSL who received tirabrutinib treatment between March 1, 2020, and February 29, 2024. Cutaneous adverse events were evaluated using the Common Terminology Criteria for Adverse Events, version 5.0. Patient characteristics, tirabrutinib dosage, concomitant medications, disease severity, time to onset, treatment, and outcomes were analyzed. Seven patients (mean age: 71.1 years, range, 52-88 years) were included herein. Skin disorders were observed in 5 patients (71.4%), including maculopapular rash (grade 2) in 3 patients, erythema multiforme (grade 3) in 1 patient, and eczema-like lesions (grade 2) in 1 patient. The median onset was 22.4 d (range: 1-56 d), with 4 cases occurring within 1 month. Treatments included oral antihistamines (4 cases) and topical corticosteroids (4 cases). One patient discontinued tirabrutinib treatment because of severe cutaneous adverse events. Tirabrutinib-associated cutaneous adverse events were common but manageable, except in 1 case. As most cutaneous adverse events develop within a month, early monitoring is crucial. Large-scale studies are needed to assess the risk factors and preventive strategies for tirabrutinib-associated cutaneous adverse events.

Patients with rare diseases worldwide face substantial unmet therapeutic needs. In Japan, drug lag-delays in drug approval compared to other countries-has resurfaced as a pressing public health issue. This study analyzes orphan drugs (ODs) approved in the United States (U.S.) from 2005 to 2021, examining OD lag trends, and research and development (R&D) models to streamline OD development in Japan. Despite increased OD approval in the U.S. since 2018, the number of unapproved ODs in Japan has substantially increased. Although OD lag had once decreased, it has shown a tendency to resurge since 2017. This is largely due to changes in the R&D strategies of pharmaceutical companies, which are driven by the growing presence of U.S.- and Europe-based small- to mid-sized enterprises (SMEs) and the evolving industry landscape. Large foreign pharmaceutical companies have shifted toward a global development strategy for Japan, aiming for more efficient development and competitive advantage. This has been propelled by a move toward in-licensing earlier-stage drug candidates with global exclusivity from SMEs. Japanese pharmaceutical companies have focused on in-licensing late-stage drug candidates for the Japanese market from SMEs without a business presence in Japan, which have not been developed locally, thereby employing a bridging strategy for Japan. With the increase in ODs developed in the U.S. by these SMEs, this practice has substantially exacerbated the OD lag. As these SMEs are unlikely to enter the Japanese market, it is crucial for Japanese pharmaceutical companies to proactively pursue earlier, more proactive global partnerships with SMEs.

Although zinc oxide ointment is commonly used to treat diaper dermatitis in infants, there exists limited evidence of pharmacists suspecting hyperzincemia due to zinc oxide ointment and early intervention for mitigation of severity. This case study is female infant who was born at 27 weeks and 1 d of gestation and weighing 542 g. On postnatal 49 d, the serum zinc concentration was 65 µg/dL. Thereafter, treatment with oral zinc acetate hydrate (2 mg/kg/d) began on 56 d for ameliorating hypozincemia. Zinc oxide ointment was administered on 86 d as a treatment for diaper dermatitis. Despite of attaining hyperzincemia (427 µg/dL), treatment with zinc acetate hydrate and zinc oxide ointment continued because diarrhea and nausea had not developed. On 105 d, the serum zinc concentration was 199 µg/dL and the dermatitis conditions showed a marked improvement. Consequently, the pharmacist considered that zinc oxide ointment might have contributed to the hyperzincemia and consulted with the physician. Subsequently, both the zinc acetate hydrate and zinc oxide ointment were discontinued. Although zinc acetate hydrate was restarted on 114 d, serum zinc concentration was 101 µg/dL on 128 d. The Naranjo Adverse Drug Reaction Probability Scale score was 9 points, which is categorized as "definitive." Administration of zinc oxide ointment to diaper dermatitis with decrease skin barrier may have increased percutaneous absorption of zinc, resulting hyperzincemia. The pharmacist may be able to conduct early intervention for hyperzincemia by monitoring not only serum zinc concentration but also changes in the dermatitis conditions in infant patients.

Our early study showed the vasoactive effects of soybean lecithin-derived lysophosphatidic acid (LPA). The finding indicates that the oral administration of LPA-rich supplements is beneficial to human health. Our studies have showed five beneficial effects of LPA in the upper digestive systems. First, we detected LPA at high levels in various herbs used in Chinese traditional medicine for the treatment of gastric ulcers, as well as other foods, including various vegetables. Second, we found human mixed saliva to be an LPA-rich biological fluid, suggesting its protective effect on human oral mucosa. Third, LPA levels in gingival crevicular fluid from patients with periodontitis was lower than that in healthy subjects, reinforcing the protective quality of LPA. Fourth, daily topical injections of LPA in rat buccal gingiva reduced the degree of alveolar bone absorption induced by oral bacteria in rats with experimental periodontitis. Fifth, repeated intragastric administration of LPA-rich herb reduced the degrees of gastric ulcer induced by stress (rats) or medication (mouse). Previous findings on the beneficial effects of LPA acting on the lumen side of the lower digestive tracts in mammals are well documented, although results on the harmful effects of LPA on mouse and rats with genetically easy to progress colon cancer are noted. Our studies also showed a novel pathway of LPA generation by lysophospholipase D activity of glycerophosphodiesterase 7 on the lumen side of digestive tracts. These findings suggest that additional research into creative food supplements focusing on LPA as a food factor could be beneficial.

While drugs affecting stroke rehabilitation outcomes have been studied in the context of convalescent hospitals, data on acute stroke patients remain insufficient. This retrospective single-center study aimed to evaluate the impact of medications on functional outcomes during rehabilitation in acute stroke patients. The study included stroke patients who received rehabilitation between April 2017 and March 2018. A total of 144 patients (mean age: 70.6±12.3 years; male/female: 86/58) were analyzed, including 101 with cerebral infarction (mean age: 72.3±12.1 years; male/female: 65/36) and 43 with cerebral haemorrhage (mean age: 66.7±12.1 years; male/female: 21/22). Multiple regression analysis was used to identify associations between drug use and recovery of activities of daily living (ADL). Multiple regression analysis of the overall data identified the use of non-steroidal anti-inflammatory drugs (NSAIDs) as a promoting factor for ADL recovery [partial regression coefficient (PRC): 34.52, p<0.01] and the use of angiotensin-converting enzyme inhibitors (ACE-Is) as an inhibiting factor (PRC: -36.33, p<0.01). In the cerebral infarction group, only ACE-I use was identified as an inhibiting factor (PRC: -28.85, p<0.01). In the cerebral haemorrhage group, NSAID use was identified as a promoting factor (PRC: 51.27, p=0.01), while the use of diabetes drugs was identified as an inhibiting factor (PRC: -39.82, p=0.046). Our results suggest that certain drugs influence functional recovery after stroke. However, further research is needed to understand the underlying mechanisms.

Acyl glucuronides (AG), reactive metabolites formed via the glucuronidation of carboxylic acid-containing drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), are closely associated with drug-induced liver injury (DILI), particularly idiosyncratic types. AG can covalently bind to proteins, potentially disrupting their function and triggering immune responses. Their toxicity is influenced by chemical instability, stereoselectivity, and interactions with specific uridine 5'-diphospho-glucuronosyltransferase (UGT) isoforms. Transporters such as multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP) mediate AG disposition, while enzymes like β-glucuronidase and esterases regulate AG degradation. Studies have shown that AG derived from NSAIDs differ in their ability to form protein adducts, with propionic acid derivatives exhibiting higher reactivity. Glutathione (GSH), a key detoxifying molecule, plays a critical role in mitigating AG toxicity. GSH depletion in rats has been shown to increase AG accumulation and protein binding, even for drugs generally considered safe. Quantitative analysis of AG formation, degradation, and protein binding using liver microsomes and LC-MS/MS has revealed that AG degradation rates can distinguish between safe drugs, those requiring a warning, and those withdrawn. Furthermore, AG exhibit stereoselective binding to UGTs, with R-enantiomers often showing higher reactivity. These findings underscore the importance of evaluating AG kinetics and protein interactions in predicting DILI risk. Future research should focus on the qualitative assessment of AG-protein adducts and the development of personalized risk models. Integrating AG behavior into drug safety evaluations may enhance the prediction and prevention of DILI, contributing to safer drug development and regulatory strategies.