Drug Discoveries and Therapeutics最新文献

Several sodium-glucose cotransporter 2 (SGLT2) inhibitors are known to have beneficial effects on renal function in patients with type 2 diabetes. However, the long-term effects of luseogliflozin, an SGLT2 inhibitor, remain uncertain in real-world settings. This multicenter, open-label, prospective observational study evaluated the long-term effects of luseogliflozin on renal function in Japanese patients with type 2 diabetes. Fifty-four outpatients initiated on luseogliflozin at Fukuoka University Chikushi Hospital or associated clinics were enrolled from April 2018 to December 2019, with 46 patients included in the final analysis set. The primary outcome was the change in estimated glomerular filtration rate (eGFR) from baseline to 104 weeks, and secondary outcomes included the change in eGFR at week 52 and changes in body weight and blood and urinary parameters at 52 and 104 weeks. The mean duration of diabetes was 8.1 years. Baseline eGFR was 75.8 ± 17.4 mL/min/1.73m², and no decline in eGFR was observed from baseline to 104 weeks. Decline in eGFR was suppressed in the two groups stratified by baseline eGFR (< 60 and ≥ 60 mL/min/1.73m²). No changes were noted in urinary albumin excretion rate. Blood glucose, body weight, blood pressure, liver function, and uric acid levels showed significant improvements. There were four adverse events, but no serious adverse events closely related to luseogliflozin treatment. In type 2 diabetes patients, 2-year treatment with luseogliflozin provided beneficial metabolic effects and improved the rate of decline in eGFR, suggesting a renal protective effect.

Previously, we developed a dynamic magnetic field (DMF) device using neodymium magnets that induced c-fos expression in cortical neurons, while activity-regulated cytoskeleton-associated protein (Arc), and brain-derived neurotrophic factor (BDNF) remained unaffected. The precise signal transduction pathway for c-fos induction under DMF was unclear. This study aimed to investigate the mechanism of immediate early gene (IEG) induction using calcium channel blockers (CCBs). Six experiments were conducted with cortical neurons, employing an NMDA receptor antagonist and an L-type voltage-dependent calcium channel blocker as CCBs. Neuronal cultures were exposed to DMF, CCBs, or both, and IEG expression (Arc, c-fos, BDNF) was measured through polymerase chain reaction. Results showed a tendency for increased c-fos expression with DMF exposure, which was unaffected by CCBs. In contrast, Arc and BDNF were not induced under DMF exposure but were significantly inhibited by CCBs. These findings suggest that c-fos induction under DMF involves a distinct pathway, potentially relevant to stress resistance and drug discovery.

This paper presents a summary of seven cases of combined pulmonary and central cryptococcal infection and analyses of their clinical features, treatment and prognosis. No clear correlation was identified between the intracranial cryptococcal capsular antigen titre and either the intracranial pressure or the amount of protein in the cerebrospinal fluid. Pulmonary lesions may develop in any of the lung lobes and manifest in multiple forms. Infection at the central level is predominantly meningitis. As the central cerebrospinal fluid (CSF) capsular antigen titre can be considerably elevated even when serum capsular antigen titres are markedly low, lumbar puncture and subsequent analysis are essential for every case of pulmonary cryptococcal infection. Patients with renal insufficiency or who refused intravenous treatment opted for oral fluconazole therapy, and their prognoses were favourable.

Gestational diabetes mellitus (GDM) is linked to a greater risk of various maternal and fetal complications, including the possibility of long-term metabolic issues in offspring. Our initial research suggests that the Traditional Chinese Medicine formula, Shenling Guchang prescription (SLGP), may have an impact on the gut microbiota. However, the specific mechanisms through which it affects intestinal barrier inflammation in GDM are still not fully understood. This study explored SLGP's mechanisms in GDM. Firstly, network pharmacology predicted key bioactive constituents targeting toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB), guiding experimental design. Subsequently, the pregnant female rats were induced with GDM through intraperitoneal streptozotocin injection and then divided into control, model, metformin, and SLGP treatment groups. Blood samples were collected for ELISA analysis to measure levels of inflammatory markers, intestinal tissues were examined histologically using hematoxylin-eosin (HE) staining, and western blot analysis was conducted to evaluate TLR4 and NF-κB expression. Relative to control rats, model group animals exhibited significant increases in the levels of inflammatory markers (IL-1β, IL-6, TNF-α, TGF-β, CRP), as well as enhanced TLR4 and p-NF-κB p65 expression, along with intestinal histopathological changes. Treatment with SLGP notably reduced inflammatory markers and protein expression in the colonic tissue of GDM rats, leading to a decrease in histopathological damage. Overall, SLGP was found to modulate the TLR4/NF-κB pathway, resulting in enhancements in insulin resistance and a reduction in inflammatory responses in GDM rats, thereby providing protection for the intestines. This study demonstrates the potential therapeutic effectiveness of SLGP in addressing intestinal inflammation linked to GDM.

Kampo medicine, comprising various conventional crude drug products, poses challenges in identifying adverse event causality. We present a case of severe liver injury following the administration of Saibokuto and attempted to identify the likely causative crude drug inducing liver injury through a systematic literature review. A 29-year-old woman developed severe liver injury approximately two months after Saibokuto administration, necessitating steroid pulse therapy for recovery. The literature search was conducted on February 15, 2023 in Japan. Using PubMed and the "Igaku Chuo Zasshi (ICHUSHI) database," two individuals independently selected studies published between January 1997 and February 15, 2023. The search focused on studies involving human subjects, published in either English or Japanese, and specifically investigated Kampo medicines categorized as over-the-counter or prescription drugs suspected as causative agents of drug-induced liver injury (DILI). Studies on health supplements, discontinued Kampo medicines, and autoimmune hepatitis, were excluded. As it is ethically impossible to rechallenge drugs that cause liver injury, this review primarily relied on case report literature. Through the review, 37 cases (men/women: 12/25, including present case) were analyzed, including 32 reports (36 cases) from 3,055 studies that met the inclusion criteria. Notably, 65.9% of cases were associated with Scutellariae radix, with onset occurring within 45 (1-730) days and recovery within 35 (7-184) days. Our case study and literature review underscore a prevalent association between liver injury and Kampo medicines containing Scutellariae radix. Vigilant liver function monitoring, particularly within the first 2 months of administration, is recommended, especially for formulations containing Scutellariae radix.

The effect of increasing corticosteroid doses on clinical outcomes and chest findings in patients with coronavirus disease (COVID-19) pneumonia and lung disease remains unknown. We aimed to investigate the effects of increasing steroid dosage on chest lesion area and clinical outcomes in patients with moderate or severe COVID-19 and progressive lung involvement on chest computed tomography (CT). A total of 105 patients with radiological progression during methylprednisolone (MP) therapy either received an increased MP dose (n = 79) or were maintained on the same MP dose (n = 26). These patients were divided into dose-increment and no-change groups according to the MP dose adjustment strategy. Clinical features, changes in CT severity scores within 7 days after steroid adjustment, and outcomes were compared between the groups. Six (7.6%) and one (3.8%) patients in the dose-increment and no-change groups, respectively, had increasing World Health Organization outcome scores 96 h after MP adjustment (P = 0.678). Length of stay [15 days (IQR: 10-24) vs. 14 days (IQR: 10-25); P = 0.994] and in-hospital death rate (7.6% vs. 3.8%; P = 0.678) showed no significant differences between the groups. Logistic regression analyses revealed that an increased MP dose was significantly associated with improvement in CT lesion area compared with no change in MP dose, but the CT lesions deteriorated subsequently (79.7% vs. 53.8%, P = 0.044). In conclusion, increasing the MP dose in patients with worsening CT findings ameliorates CT lesions but fails to prevent serious adverse outcomes.

Acupuncture and traditional Chinese medicine (TCM) have shown certain benefits in assisted in vitro fertilization and embryo transfer (IVF-ET). In this study, we evaluated the efficacy and safety of the combination of acupuncture combined with the Bushen Quyu decoction in patients with failures of IVF-ET. This study was conducted at Shanghai Yangpu District Hospital of TCM from May to November of 2021. Patients with failed IVF-ET received either combined therapy or the routine procedure (control group). The main outcomes were implantation rate and clinical pregnancy rate. Radioimmunoassay was used to detect serum levels of estradiol (E2) and progesterone on the day of injection of human chorionic gonadotropin (hCG). The endometrial thickness, resistance index (RI), and pulsatility index (PI) of bilateral uterine arteries were measured by color Doppler ultrasound. Safety was assessed in all participants. After 3 months of treatment, the implantation rate (61.9% vs. 47.7%, P = 0.187) and clinical pregnancy rate (52.4% vs. 36.4%, P = 0.135) of patients with IVF-ET failure receiving acupuncture therapy combined with Bushen Quyu decoction appeared to be higher than those of the routine procedure group, although the increase was not statistically significant. However, the serum E2 level and endometrial thickness of patients in the combined therapy group increased significantly than those of the control group after hCG injection. The RI and PI values of bilateral uterine arteries in the combined therapy group were significantly lower than those in the control group after hCG injection. No difference of adverse events was observed between combined therapy group and control group (11.9% vs. 11.36%, P = 0.962). Acupuncture therapy combined with TCM treatment may improve endometrial receptivity and hormone secretion, and increase uterine artery blood flow.

This study evaluated the impact of initiating antiretroviral therapy (ART) within 14 days compared to starting after 14 days in newly diagnosed, late-presenting people living with human immunodeficiency virus (PLWH). A total of 1,538 PLWH with a baseline CD4⁺ T-cell count < 350 cells/μL who attended our outpatient clinic from January 2017 to June 2022 were included. Participants were divided into two groups based on ART initiation timing: rapid initiation (ART within 14 days) and delayed initiation (ART after 14 days). Rapid initiation led to significantly higher virologic suppression rates at 6 months (62.5% vs. 52.7%, P < 0.05) and 1 year (81.6% vs. 72.1%, P < 0.01) compared to delayed initiation. While overall treatment retention rates were comparable, rapid initiation improved retention at 6 months for those with baseline CD4⁺ < 200 cells/μL and at 1 year for those with baseline CD4⁺ between 200 and 350 cells/μL. No significant differences in CD4⁺ T-cell counts or CD4/CD8 ratio were observed. A positive correlation was found between baseline viral load and time to virologic suppression, with rapid initiation of ART leading to faster suppression, especially in those with higher baseline viral loads. Multivariate analysis confirmed that ART initiation timing and baseline viral load were key determinants of virologic suppression. In conclusion, rapid ART initiation within 14 days was associated with higher virologic suppression at 6 months and 1 year. Rapid initiation of ART and lower baseline viral load were critical for virologic suppression, with improved retention for specific subgroups.

Herpes Zoster (HZ), caused by the reactivation of the varicella-zoster virus (VZV), is a common infectious disease. Recent studies suggest a potential association between HZ and the development of dementia, particularly Alzheimer's disease and other neurodegenerative disorders. Epidemiological evidence indicates that HZ infection, especially in individuals with central nervous system involvement, may increase the risk of dementia. Pathologically, VZV may contribute to neuronal dysfunction and degeneration by inducing chronic neuroinflammation, infection-related cerebrovascular lesions, and direct central nervous system toxicity. HZ vaccines, particularly novel recombinant subunit vaccines (e.g., Shingrix), not only effectively prevent HZ but may also confer cognitive protection through mechanisms such as "trained immunity" activation and anti-inflammatory response modulation. Multiple natural experiments and retrospective cohort studies have found that HZ vaccination is significantly associated with a reduced risk of dementia, with particularly pronounced protective effects in women and older adults. Although most evidence currently stems from observational studies and is subject to potential confounding factors, the biological plausibility and consistent findings support the potential of HZ vaccination as an adjunctive strategy for dementia prevention. Future prospective randomized controlled trials are needed to further clarify the causal relationship and underlying neuroimmune mechanisms, providing a stronger evidence base for establishing scientific vaccination strategies for older adults and dementia prevention systems.

Hematologic abnormalities are the most common symptoms of Shwachman-Diamond syndrome (SDS). The causative gene for SDS is the Shwachman-Bodian-Diamond syndrome (SBDS) gene; however, the function of SBDS and pathogenesis of each condition in SDS are largely unknown. SBDS is known to be localized at mitotic spindles and stabilizes microtubules. Previously, we demonstrated that SBDS is ubiquitinated and subsequently degraded in the mitotic phase, thereby accelerating mitotic progression. In this study, we examined mitosis in a myeloid cell model of SDS (SDS cells). 4',6-Diamidino-2-phenylindole (DAPI)-stained chromosome observation and cell cycle analysis of nocodazole-synchronized cells revealed that the SDS cells have abnormally rapid mitosis. In addition, many lagging chromosomes and micronuclei were detected. Moreover, the phosphorylation of threonine tyrosine kinase, the crucial kinase of the spindle assembly checkpoint (SAC), was suppressed. Chromosomal instability caused by SAC dysfunction may cause a variety of clinical conditions, including hematologic tumors in patients with SDS.