International journal of clinical pharmacology and therapeutics最新文献

In recent years, immune checkpoint inhibitors, such as programmed death-1 (PD-1) inhibitors, have become key therapeutic options for specific cancers, used as first-, second-, or third-line treatments for various metastatic conditions. Nivolumab, a programmed death-1 (PD-1) inhibitor, is FDA-approved for metastatic renal cell carcinoma among other cancers. As the use of nivolumab becomes more widespread, understanding both its common and rare side effects is essential. Although nivolumab has been associated with autoimmune hemolytic anemia (AIHA), there are rare cases where this adverse effect may be compounded by other underlying conditions. Here, we report the first case of AIHA in a patient with glucose-6-phosphate dehydrogenase deficiency, triggered as a complication of nivolumab treatment.

Toripalimab, a humanized anti-PD-1 monoclonal antibody, is widely employed in the treatment of non-small cell lung cancer (NSCLC) and various other malignancies. However, there have been no reported cases linking prolonged administration of toripalimab to immune-mediated hepatitis (IMH). Typically, immune checkpoint inhibitor (ICI)-related IMH manifests within the first few weeks or months following the initiation of therapy. In this report, we presented a case of IMH in a patient with NSCLC following ~ 17 months of toripalimab treatment. IMH induced by toripalimab may occur at any time during treatment, underscoring the need for clinicians to remain vigilant in monitoring for adverse reactions. Throughout toripalimab treatment, careful attention must be paid to the symptoms, diagnosis, and pathological features of IMH. Glucocorticoids, such as methylprednisolone, can effectively reduce liver enzyme markers like aspartate aminotransferase and alanine aminotransferase in patients experiencing toripalimab-induced IMH.

Objective: Predicting the occurrence of hyperkalemia in patients undergoing co-trimoxazole treatment for Pneumocystis pneumonia is critical. However, other factors besides drug exposure affect serum potassium levels, and various interventions are often used to treat hyperkalemia in clinical practice. Therefore, we aimed to develop a Markov model to predict the risk of hyperkalemia under various intervention conditions.

Materials and methods: This was a retrospective, observational study. Information on daily dose of co-trimoxazole and hyperkalemia events was obtained from adult patients administered oral co-trimoxazole between 2015 and 2020 at Mie University Hospital (Mie, Japan). A Markov model with an intermediate layer was applied using NONMEM. The drug-effect model was assumed to have a maximum effective model. Bootstrapping and visual predictive checks were used to assess model validity.

Results: A total of 271 patients with 4039 observations of potassium levels were included. Baseline serum potassium level was a significant covariate of drug response. The successful bootstrap completion rate was 99.5%, and each parameter estimate was consistent with the bootstrap median; therefore, the model was sufficiently robust.

Conclusion: The Markov model, including an intermediate layer, provides a robust framework for predicting the risk of hyperkalemia, even in datasets where post-onset interventions vary from patient to patient. Thus, it is postulated that higher baseline potassium levels increase hyperkalemia.

The high incidence of malignant tumors continues to pose a significant threat to public health. In recent years, there have been notable advancements in tumor treatment methods, leading to substantial changes in the concepts and clinical approaches to treatment. The primary clinical methods for treating malignant tumors currently include surgical resection, radiation therapy, and chemotherapy. Among these, chemotherapy is one of the most crucial and comprehensive treatment strategies. The rapid progress in nanoscience has fostered the development of nanocarrier compounds and their clinical applications in disease treatment. Notably, nanomedicines, including goserelin sustained-release implants, doxorubicin liposomes, albumin-bound paclitaxel, and paclitaxel liposomes, have been effectively utilized in tumor treatment in China [1]. The article presents a comprehensive overview of recent advancements in utilizing various nanocarriers for combination therapy in tumors. It also examines the clinical application and efficacy of drug delivery carriers. The development of efficient and safe co-delivery systems that facilitate the effective transport and precise release of drugs within the cancerous tissues while also elucidating the internalization of nanoparticles into tumor cells and their functional mechanisms represents critical areas for future research. Concurrently, advancements in nanocarriers and tumor treatment are anticipated to yield superior therapeutic outcomes and improved quality of life for cancer patients.

Background: Bone-related disorders pose significant challenges in clinical practice. Bone marrow mesenchymal stem cells (BMSCs), as multipotent stem cells, play a pivotal role in bone regeneration. The TGF-β1-Smad2/3 signaling pathway is a well-recognized regulator of BMSC osteogenic differentiation. Traditional Chinese medicine (TCM), such as Bushen Tian Sui decoction (BSTSD), has shown potential in enhancing bone health; however, its molecular mechanisms remain poorly understood.

Objective: Investigating the effects and underlying mechanisms of BSTSD on the osteogenic differentiation of BMSCs.

Materials and methods: The impact of BSTSD on BMSCs was comprehensively analyzed using Cell Counting Kit-8 (CCK8), quantitative polymerase chain reaction (qPCR), western blot (WB), and immunofluorescence assays.

Results: CCK8 results revealed the highest optical density (OD) values in the BSTSD + activator group at 24, 48, and 72 hours, indicating enhanced cell proliferation. qPCR analysis showed significantly increased expression levels of TGF-β1, Smad2, Smad3, SOX9, and RUNX2 in the BSTSD + activator group, suggesting a synergistic effect in promoting osteogenic and chondrogenic differentiation. WB results demonstrated elevated phosphorylation levels of Smad2 and Smad3 (p-Smad2, p-Smad3) in the BSTSD + activator group, while total Smad2 and Smad3 protein levels remained consistent among groups. Immunofluorescence assays confirmed the highest fluorescence intensity, positive area ratio, and cell count containing Smad2 and Smad3 proteins in the BSTSD + activator group, validating the synergistic effect of BSTSD and TGF-β1.

Conclusion: BSTSD exhibits promising effects on BMSC differentiation and bone regeneration, mediated through the TGF-β1-Smad2/3 signaling pathway.

Background: Colorectal cancer (CRC) is a malignant tumor with the third highest incidence worldwide. The comprehensive economic evaluation of programmed cell death protein-1 inhibitors in China, however, has not yet been carried out. The aim of this study is to assess the cost-utility of pembrolizumab and nivolumab in the treatment of metastatic colorectal cancer (mCRC).

Materials and methods: A Markov model microsimulation of efficacy and cost-utility analysis (CUA) was carried out, and efficacy and safety data were compared using network meta-analysis. Literature screening and data extraction were performed according to established criteria where the main outcome indicators, complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were compared between two treatments. The lifetime cost and outcomes of mCRC treatment were estimated, and quality-adjusted life years (-QALYs) and incremental cost-effectiveness ratio (ICER) were used to evaluate the economy of each program.

Results: A total of 442 studies were evaluated of which 15, with a total of 798 patients, were included in the analysis. Of these, 13 evaluated PD, and total patients for CR, PR, SD, and PD were 82, 283, 160, and 180 respectively. The corresponding heterogeneity values were (p = 0.13, heterogeneity index as percentage (I²) = 29.53%), (p < 0.01, I² = 72.55%), (p = 0.03, I² = 46.54%), (p < 0.01, I² = 80.31%), and (p = 0.13 > 0.05). The proportion of patients classified as CR in the pembrolizumab group was greater than in the nivolumab group (0.105 vs. 0.085). However, the number of patients classified as PR and SD in the nivolumab group exceeded those in the pembrolizumab group. The number of patients classified as PD were similar in the two groups. Combination therapy nivolumab + ipilimumab yielded an incremental gain of 0.04 QALYs at an additional cost of 356,723 ¥. The ICER reached 8,918,075 ¥/QALYs, surpassing three times the per capita gross domestic product (GDP).

Conclusion: Both pembrolizumab and nivolumab showed beneficial effects in patients with mCRC. Nivolumab in combination with ipilimumab led to improved progression-free survival, but the values for ICER reached 8,918,075 ¥/QALYs. Treatment of non-resectable or metastatic microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) advanced solid tumors CRC with pembrolizumab alone, in the Chinese population examined, was the most cost-effective, where the willingness-to-pay threshold was 242,928 ¥/QALY (100 ¥ = 13.75 US$ and 12.63 €).