Correlation of ischemic ophthalmopathy with lacunar infarction

AIM: To investigate the effects of nintedanib thermo-sensitive hydrogel (NTH) on neovascularization and related markers in corneal alkali burns of Wistar rats. METHODS: NTH was prepared by grinding, and its phase-transition temperature was determined. Thirty specific-pathogen-free Wistar rats served as a model of corneal alkali burn in the right eye were randomly divided into 3 groups (n=10, each): model group treated with 0.9% saline once a day, NTH group with 0.2% nintedanib b.i.d, and dexamethasone (DEX) group with DEX ointment once a day. The left eye of rats served as the controls. The corneal transparency was observed under a slit-lamp microscope, and the area of neovascularization was calculated. On day 7, the rats were sacrificed, and the cornea was removed and embedded with paraffin, then stained with hematoxylin-eosin, and the expression of VEGFR-2 and CD31 in the corneal tissues of each group was detected by immunofluorescence. RESULTS: The phase-transition temperature of nintedanib obtained by grinding was 37°C after adding artificial tears. The results of the alkali burn model indicated that the growth rate of neovascularization in the NTH group was slower than that in the model group, and the neovascularization area was significantly smaller than that in the model group (P<0.05). Moreover. CD31 and VEGFR-2 expression levels in the NTH group were significantly lower than those in the model group. CONCLUSION: NTH becomes colloidal at body temperature, which is beneficial for releasing the drug slowly and can significantly inhibit the neovascularization of corneal induced by alkali burn in rats.     

Disease staging and sub setting of interstitial lung disease associated with systemic sclerosis: impact on therapy

Introduction: Interstitial lung disease (ILD) is the most serious complication of systemic sclerosis (SSc). There is no accepted guidance as to which clinical, radiological or physiological thresholds should prompt initiation or changes in treatment. Furthermore, some patients with extensive disease remain stable without the need for intervention whilst others with limited disease at the outset, experience a precipitous decline.

Areas covered: In this article, evidence for the integration of a number of disease-specific and patient-related domains are discussed and proposed. Introduction and maintenance of therapy requires a nuanced understanding of these factors and is crucial when weighing up the risks and benefits of immunomodulation. The evidence for the existing treatment modalities is discussed and the future directions for management of patients with SSc-ILD, which may include antifibrotic or biologic therapy, are explored.

Expert commentary: In the management of SSc-ILD, a multidisciplinary team approach which integrates physiology and radiology with the patient at the centre of the process is crucial for effective management and provision of the best outcomes.     

Inhibition of corneal neovascularization by topical application of nintedanib in rabbit models

AIM: To evaluate the potential efficacy and mechanisms of nintedanib in corneal neovascularization (NV) in rabbit models. METHODS: Corneal NV was induced using 1 mol/L NaOH. Rabbits (n=21) were randomized to 3 groups: Group 1 were treated with 0.9% NaCl, Group 2 with Avastin (5 mg/mL), and Group 3 with nintedanib (1 mg/mL). All treatments started 1d after alkaline burns and were topically performed 3 times a day for 2wk. Photographs were taken on a slit lamp microscope on day 7 and 14. The NV area, the length of the vascularization and angiogenesis index (AI) were used to evaluate the corneal NV. On day 14, the immunohistochemical (IHC) studies of the cornea were examined. Western blot was performed to test the expression levels of vascular endothelial growth factor (VEGF), Akt, p-Akt, P38, p-P38, MMP-2 and MMP-9. RESULTS: The corneal NV area, vessel length and AI in Group 3 were significantly lower than Group 2, with both being lower than Group 1. IHC staining showed that VEGF was significantly overexpressed in the epithelium and stroma of cornea following alkaline burns. In contrast, the level of VEGF was significantly suppressed in both Group 2 and Group 3. Western blot results further confirmed that, compared with Group 1, Group 3 had significantly reduced expressions of VEGF, Akt, p-Akt, p-P38, MMP-2, and MMP-9 in corneal tissues. Trends of lower levels of MMP-2, AKT, and p-AKT in Group 3 than Group 2 were identified. CONCLUSION: Nintedanib and Avastin can effectively inhibit corneal NV, with P38 MAPK and AKT signaling pathways being possibly involved. Nintedanib seems more effective than Avastin and has the potential to be a novel therapy for preventing corneal NV.     

尼达尼布治疗特发性肺纤维化的长期疗效及安全性: 单中心参与INPULSIS及INPULSIS ON的系列病例分析

 目的 探讨尼达尼布治疗特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)的长期临床疗效及安全性。方法 本中心于2012年7月起参加全球尼达尼布治疗IPF的为期52周的随机双盲Ⅲ期临床试验(INPULSIS,INPULSIS ON),共入组10例IPF患者。1年研究结束后,继续追踪随访至今,共约9年。经揭盲分析后发现,试验组(尼达尼布组)6例,对照组(安慰剂组)4例。记录治疗前后两组患者用力肺活量(FVC绝对值及FVC%pre)、一氧化碳弥散量(DLCO%pre)、SGRQ评分的变化及急性发作次数,持续记录患者的生存状况,并观察不良反应发生情况。结果 治疗前两组FVC和DLCO无显著差异,治疗后试验组FVC下降趋势相对较缓,FVC%pre年下降率为2%,对照组为4.9%。DLCO的年下降率及SGRQ评分变化两组无明显差异。随访期间8例患者病死,其中试验组4例(4/6),对照组4例(4/4)。Kaplan-Meier生存曲线发现试验组有生存优势,但由于病例数少,未达到统计学差异。试验组不良反应发生率为50%(3/6),多为腹泻、腹部不适。程度多为轻至中度。2例生存至今的受试者,1例服用尼达尼布至今,1例服用尼达尼布1.5年后因腹泻退出研究。这2例肺功能追踪发现,长期服用尼达尼布者FVC%pre更稳定,急性加重次数较少。而中途停药者8年时复查FVC%pre已下降24.8%,急性加重3次。结论 尼达尼布可能延缓IPF患者FVC的下降趋势及延长生存时间,减少急性加重,长期服用具有较好的耐受性。     

尼达尼布乙磺酸盐固体分散体的制备和性能研究

目的 制备尼达尼布乙磺酸盐固体分散体，并考察其性能。方法 采用溶剂蒸发法制备尼达尼布乙磺酸盐固体分散体，并采用差示扫描量热法、粉末X射线衍射和傅里叶变换红外光谱进行物理表征和高温高湿稳定性考察。结果 尼达尼布乙磺酸盐与Soluplus按质量比1∶9制备固体分散体。尼达尼布乙磺酸盐以无定形存在于分散体中。温度对固体分散体基本无影响，湿度的影响较大。结论 将尼达尼布乙磺酸盐制备固体分散体提高了药物的溶解度和溶出度。     

Anti-SARS-CoV-2 activity of targeted kinase inhibitors: Repurposing clinically available drugs for COVID-19 therapy

Coronavirus disease 2019 (COVID-19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID-19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis. We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS-CoV-2 infection. Using multiple cell-based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS-CoV-2 variants. Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein-mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS-CoV-2 variant infectivity, supporting a role for AXL in SARS-CoV-2 infection and supporting further investigation of drug-mediated AXL inhibition as a COVID-19 treatment. This study supports further evaluation of AXL-targeting kinase inhibitors as potential antiviral agents and treatments for COVID-19. Additional mechanistic studies are needed to determine underlying differences in virus response.     

Nintedanib induces apoptosis in human pterygium cells through the FGFR2-ERK signalling pathway

AIM: To investigate whether nintedanib can inhibit pterygium cells through the fibroblast growth factor receptor 2 (FGFR2)/extracellular-signal-regulated kinase (ERK) pathway. METHODS: Human primary pterygium cells were cultured in vitro. After treatment with nintedanib, the cell morphology was observed under microscopy, the morphological changes of the nucleus were observed after DAPI staining, apoptosis was analyzed by Annexin-V FITC/PI double staining, and the changes of apoptosis-associated proteins were detected by Western blot. The binding ability of nintedanib to FGFR2 was predicted by molecular docking. Finally, by silencing FGFR2, we explored whether nintedanib inhibited FGFR2/ERK pathway. RESULTS: The results showed that nintedanib inhibited the growth of pterygium cells and caused nuclear pyknosis. The results of Annexin-VFITC/PI double staining showed that nintedanib was able to induce early and late apoptosis of pterygium cells, significantly increasing the expression of apoptosis-associated proteins Bax and cleaved-Caspase3 (P<0.05), and reducing the expression of Bcl-2 (P<0.05). In addition, nintedanib significantly inhibited ERK1/2 phosphorylation through FGFR2 (P<0.05). After silencing the expression of FGFR2, there was no significant difference in the inhibition of ERK1/2 phosphorylation by nintedanib (P>0.05). CONCLUSION: Nintedanib induces apoptosis of pterygium cells by inhibiting FGFR2/ERK pathway.     

State of the art and up-and-coming angiogenesis inhibitors for ovarian cancer

ABSTRACT

Angiogenesis inhibitors have clearly shown activity in ovarian cancer in various settings; however, preliminary data did not reflect significant survival benefit. Bevacizumab has been extensively studied and is approved for use in ovarian malignancy. However, the efficacy of bevacizumab is modest and most treated patients eventually develop acquired resistance, which highlights the need for new targeted therapies and/or combination strategies. Newer therapies are being evaluated and their role of these newer therapies is upcoming and promising. Recent research focuses on the role of this drug group in frontline, maintenance and recurrent settings. Combination of PARP inhibitors with angiogenesis inhibitors has recently shown to improved survival rates. Potential strategies need to be devised for selecting patients most likely to benefit from such therapy.