Naunyn-Schmiedeberg's archives of pharmacology最新文献

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of cancer and immune disorders. However, their cardiotoxicity, particularly the risk of atrial fibrillation (AF), raises growing concerns. We aimed to comprehensively examine the associations between TKIs and AF using real-world pharmacovigilance data. We conducted a case-control study by analyzing adverse event (AE) reports from the FDA Adverse Event Reporting System between 2004 and 2023 for 56 FDA-approved TKIs. AF cases were identified using the preferred term "atrial fibrillation". Patient characteristics were compared between fatal and non-fatal cases. Disproportionality analysis, quantified using the reporting odds ratio (ROR), was employed to assess the associations between TKIs and AF. Among 561,551 TKI-related AE reports, 3794 (0.7%) involved AF. The majority of AF events (89.7%) were classified as serious, with 11.3% associated with fatal outcomes. Significant differences in gender, age, drug categories, and systems involved in the indication were observed between fatal and non-fatal outcome groups (all P < 0.05). Disproportionality analysis identified 12 TKIs significantly associated with AF. Notably, Bruton's tyrosine kinase inhibitors showed the strongest signals, with ibrutinib (ROR: 9.83; 95% CI: 9.34-10.34) leading, followed by zanubrutinib (ROR: 6.29; 95% CI: 3.70-10.69) and acalabrutinib (ROR: 5.58; 95% CI: 4.38-7.11). Additionally, nine other TKIs, including nilotinib, ponatinib, and nintedanib, among others, were associated with increased reporting frequencies. These findings suggest that certain TKIs are associated with an elevated risk of AF, underscoring the importance of vigilant cardiovascular monitoring during TKI therapy.

The increasing incidence of breast cancer is leading researchers to investigate new treatment approaches. Targeted therapy approaches are particularly attractive because they minimize the detrimental effects of therapeutic agents on healthy tissues and cells by focusing on tumor sites. This study focuses on synthesizing mPEG-modified triblock copolymers as carrier materials for drug delivery applications, enabling the efficient encapsulation of DOX, and evaluating the cytotoxic effects of the resulting nanocarriers on breast cancer cell lines. In this study, mPEG-poly(butylene adipate)-mPEG and mPEG-poly(ethylene adipate)-mPEG triblock copolymers were synthesized by a step-growth polycondensation polymerization method. Firstly, poly(butylene adipate) (pBAd) and poly(ethylene adipate) (pEAd) were synthesized to form the body of the triblock copolymer, and their chemical structures were characterized using Fourier transform infrared (FT-IR) and ¹H NMR spectroscopy. The end-group analysis method was applied to determine the average molecular weights of the pBAd and pEAd polymers before their modification with mPEG-500. The nanocarriers produced by the double emulsion method were analyzed using the dynamic light scattering (DLS) method, while encapsulation efficiency and the DOX release profile were measured using a spectrofluorometer. The antiproliferative effects and cellular uptake capacities of the resulting nanocarriers were subsequently examined in MCF-7 and MDA-MB-231 cells. The cytotoxicity of DBANP and DEANP nanocarriers was lower than that of free DOX, demonstrating that encapsulation reduces drug-associated toxicity and may enhance safety. These findings suggest that the nanocarrier systems developed in this study show strong potential as promising candidates for breast cancer therapy.

Paraquat (PQ) is a highly toxic herbicide that causes rapid and severe lung injury via oxidative stress and inflammatory activation. The present study aimed to investigate the protective effects of curcumin on PQ inhalation-induced lung injury in a mice model. Therefore, the intranasal route of PQ administration was selected, where mice were euthanized after 48 h of PQ exposure. Enhanced oxidative damage and the formation of neutrophil extracellular traps were released by activated neutrophils, along with elevated inflammatory mediators. Oxidative stress-induced lung injury was accompanied with increased DNA damage and reduced antioxidant defenses. Lung injury severity was higher with intranasal PQ in terms of inflammatory cell infiltration and early fibrotic changes, with collagen deposition around the bronchioles. Reduced E-cadherin, a marker of epithelial cells, and enhanced α-SMA were noted, showing enhanced epithelial to mesenchymal transition (EMT) in PQ-induced groups, which was reduced in intranasal curcumin treatment groups. Substantially reduced oxidative stress, NF-kB expression, and enhanced Nrf2 levels were noted, indicative of restored antioxidant enzymes and limited inflammatory responses, signifying a protective effect against PQ-induced lung injury. Immunofluorescence and protein expression analysis revealed fibrotic changes in the lungs, where enhanced alpha smooth muscle actin (α-SMA) and MMP9 expressions were reduced with intranasal curcumin treatment.

Sacubitril/valsartan is a combined neprilysin inhibitor/angiotensin II receptor blocker which simultaneously potentiates the beneficial effects of natriuretic peptides while blocking angiotensin II accumulation. Numerous studies suggest that sacubitril/valsartan has better renal protective effects compared to valsartan but the evidence remains inconsistent. This study compared renal and blood pressure (BP)-lowering effects of sacubitril/valsartan versus valsartan in rats with adenine-induced chronic kidney disease (CKD). This model replicates slow progression and structural and functional characteristics of human CKD. Male Wistar rats (n = 24) were divided into four groups and treated for 35 days as follows: group 1 served as control; group 2 received 0.25% adenine; group 3 received adenine plus sacubitril/valsartan; group 4 received adenine plus valsartan. Adenine significantly increased systolic BP. It also significantly increased the urinary albumin/creatinine ratio, N-acetyl-β-D-glucosaminidase (NAG), plasma urea, creatinine, uric acid, and neutrophil gelatinase-associated lipocalin (NGAL) while reducing creatinine clearance. Additionally, adenine significantly increased inflammatory markers, decreased antioxidant activity, and induced tubular necrosis, dilatation, and interstitial inflammation. Sacubitril/valsartan significantly reduced systolic BP, with greater effects than valsartan. Both treatments reversed adenine-induced alterations in urinary albumin/creatinine ratio, NAG, plasma urea, creatinine, NGAL, and creatinine clearance, with more pronounced improvements in urea, NAG, and creatinine clearance observed with valsartan. Furthermore, both treatments ameliorated inflammatory and antioxidant changes to a comparable extent. Both treatments showed histopathological improvements, but these were more marked with valsartan. To conclude, both sacubitril/valsartan and valsartan effectively mitigated adenine-induced CKD changes, with sacubitril/valsartan producing greater systolic BP reduction and valsartan showing more pronounced renoprotective effects.

Nowadays, the media make a major contribution to the medical education of the population. However, people who are not experts are hardly able to assess the accuracy of the situations depicted. To test the reliability of the statements made, this paper deals with the analysis of the accuracy of the pharmacological content in the television series Dr. House. The database is currently around 20 years old. The series was first broadcasted in the United States in 2004. The aim of this study was to check the quality of the pharmacological content. In addition, it analyzed the education by the TV series Dr. House in the field of pharmacological knowledge. Ten episodes containing 105 pharmacological items were analyzed. The analysis was illustrated with eleven comparable parameters of the items. This includes, for example, naming the drugs, evaluating the indication, assessing the therapy, and presenting the drug within the scene. In addition, the course of the series was analyzed for the first and eleventh episodes of each season. This resulted in 131 additional pharmacological contents. The study shows a high usage rate of international non-proprietary names (INN). The indications are often correctly stated, and an appropriate therapy is initiated. A particular and quite unusual feature of the series is that drugs are used as diagnostic tools to come to the correct diagnosis. Antibacterial drugs and psychotropic drugs are strongly presented. The analysis also highlights differences in the use of drugs between various genres in which drugs play an important role. Due to the cynical character traits of Dr. House, there were issues of concerns such as lack of patient information and use of dangerous/experimental therapies. There were also several medication errors. The way of drug administration often remained unclear and the mechanism of action was not explained. A comparison of the seasons throughout the series reveals a decline in the quality of naming, explanation, and accuracy of indications and presentation of pharmacological content. The lowest quality is evident in season 6, with a marked improvement in seasons 7 and 8. Despite some concerns regarding ethical issues, the TV series Dr. House makes a valuable contribution to introducing to the public a broad diversity of pharmacological topics.

Despite the rising burden of hypertension (HTN) across Africa, the rate of blood pressure (BP) control among hypertensive patients remains unacceptably low. One of the key contributors to this treatment gap is therapeutic inertia (TI) the failure to initiate or intensify therapy when clinically indicated. However, evidence on the magnitude and determinants of TI in Ethiopia remains scarce. Objective: To assess the prevalence of therapeutic inertia and identify associated factors among hypertensive patients attending the outpatient department of Wolaita Sodo University Comprehensive Specialized Hospital. A hospital-based cross-sectional study was conducted among 189 hypertensive patients from August to November 2023. Participants were selected through consecutive sampling. Data were collected via interviews with patients and physicians, along with a review of medical charts. Descriptive statistics (frequencies, percentages, means ± SD, and medians with interquartile ranges) were used to summarize patient characteristics. Bivariate and multivariable logistic regression analyses were performed to identify factors associated with TI. Adjusted odds ratios (AORs) with 95% confidence intervals (CIs) were reported. Of the 189 patients, 50.8% were male, with a mean age of 53.8 years. The prevalence of therapeutic inertia was 58.7% (95% CI: 52.3%-65.4%). Factors significantly associated with lower odds of TI included treatment with amlodipine (AOR = 0.137; 95% CI: 0.019-0.975), use of NPH insulin (AOR = 0.174; 95% CI: 0.036-0.833), and higher diastolic BP readings (AOR = 0.910; 95% CI: 0.839-0.986). In contrast, physician-reported reasons for not intensifying treatment such as "BP being close to the target value" (AOR = 6.074; 95% CI: 1.315-28.060) and "concerns about patient adherence" (AOR = 5.487; 95% CI: 1.061-28.362) were positively associated with TI. Therapeutic inertia was observed in nearly 6 out of 10 cases of uncontrolled hypertension in this setting, highlighting a significant gap in clinical decision-making. Addressing therapeutic inertia through improved adherence to hypertension treatment guidelines and strengthened physician education may help improve blood pressure control in similar settings. Stakeholders should implement systems that support timely treatment intensification and encourage adherence to evidence-based management strategies.

Angiogenesis, the production of new blood capillaries from pre-existing vasculature, is an important mechanism necessary for cancer progression and metastasis. This process may be regulated by the balance of pro-angiogenic and anti-angiogenic factors. The disruption of this balance leads to the induction of angiogenesis. Thus, there is a high necessity to identify these angiogenesis-related genes. In this study, we have used GeneCards database to obtain a list of angiogenesis-related genes followed by construction of protein-protein interaction (PPI) network using STRING database. Out of 37 angiogenesis-related genes, a single-gene cluster containing 27 genes was identified using MCODE analysis. The top ten hub genes were identified as FGF2, HIF1A, VEGFC, VEGFA, MMP9, THBS1, MMP2, KDR, IL6, and NOS, which were further analyzed. FunRich application was used to perform gene enrichment analysis and identify top interactors by constructing an interaction map. PPI map of each individual hub gene was constructed using search tool for the retrieval of interacting genes/proteins (STRING) database. The expression levels of each individual hub gene in HCC (liver hepatocellular carcinoma-LIHC dataset) and normal tissue were analyzed using the gene expression profiling interactive analysis 2 (GEPIA2) portal. The prognostic value of the hub genes was analyzed using Kaplan-Meier survival plot. The translational-level expression was analyzed using the IHC section images from the Human Protein Atlas (HPA) database. Thus, targeting these factors for therapy, diagnosis, or prognosis could be a key strategies in the field of oncology.