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Frontiers in Pharmacology 2024Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We...
BACKGROUND
Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects.
METHODS
Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, ) on days 1-6 and once in the morning on day 7.
RESULTS
Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg-600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in T by approximately 1 h and a slight reduction of approximately 20% in C compared to that in fasting conditions, but it did not significantly affect systemic exposure.
CONCLUSION
Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone.
CLINICAL TRIAL REGISTRATION
clinicaltrials.gov, identifier CXHL1900206.
PubMed: 38933669
DOI: 10.3389/fphar.2024.1414066 -
Pharmaceuticals (Basel, Switzerland) Jun 2024This study aimed to evaluate the feasibility of using [Ga]-fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET) imaging for diagnosing...
PURPOSE
This study aimed to evaluate the feasibility of using [Ga]-fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET) imaging for diagnosing pulmonary fibrosis in a mouse model. We also examined its value in monitoring treatment response and compared it with traditional [F]-fluorodeoxyglucose (FDG) PET and computed tomography (CT) imaging.
METHODS
A model of idiopathic pulmonary fibrosis was established using intratracheal injection of bleomycin (BLM, 2 mg/kg) into C57BL/6 male mice. For the treatment of IPF, a daily oral dose of 400 mg/kg/day of pirfenidone was administered from 9 to 28 days after the establishment of the model. Disease progression and treatment efficacy were assessed at different stages of the disease every week for four weeks using CT, [F]FDG PET, and [Ga]FAPI PET (baseline imaging performed at week 0). Mice were sacrificed and lung tissues were harvested for hematoxylin-eosin staining, picrosirius red staining, and immunohistochemical staining for glucose transporter 1 (GLUT1) and FAP. Expression levels of GLUT1 and FAP in pathological sections were quantified. Correlations between imaging parameters and pathological quantitative values were analyzed.
RESULTS
CT, [F]FDG PET and [Ga]FAPI PET revealed anatomical and functional changes in the lung that reflected progression of pulmonary fibrosis. In untreated mice with pulmonary fibrosis, lung uptake of [F]FDG peaked on day 14, while [Ga]FAPI uptake and mean lung density peaked on day 21. In mice treated with pirfenidone, mean lung density and lung uptake of both PET tracers decreased. Mean lung density, [F]FDG uptake, and [Ga]FAPI uptake correlated well with quantitative values of picrosirius red staining, GLUT1 expression, and FAP expression, respectively. Although traditional CT and [F]FDG PET reflect anatomical and metabolic status in fibrotic lung, [Ga]FAPI PET provides a means of evaluating fibrosis progression and monitoring treatment response.
PubMed: 38931393
DOI: 10.3390/ph17060726 -
Pharmaceuticals (Basel, Switzerland) May 2024Pirfenidone and Nintedanib are specific drugs used against idiopathic pulmonary fibrosis (IPF) that showed efficacy in non-IPF fibrosing interstitial lung diseases... (Review)
Review
Pirfenidone and Nintedanib are specific drugs used against idiopathic pulmonary fibrosis (IPF) that showed efficacy in non-IPF fibrosing interstitial lung diseases (ILD). Both drugs have side effects that affect patients in different ways and have different levels of severity, making treatment even more challenging for patients and clinicians. The present review aims to assess the effectiveness and potential complications of Pirfenidone and Nintedanib treatment regimens across various ILD diseases. A detailed search was performed in relevant articles published between 2018 and 2023 listed in PubMed, UpToDate, Google Scholar, and ResearchGate, supplemented with manual research. The following keywords were searched in the databases in all possible combinations: Nintedanib; Pirfenidone, interstitial lung disease, and idiopathic pulmonary fibrosis. The most widely accepted method for evaluating the progression of ILD is through the decline in forced vital capacity (FVC), as determined by respiratory function tests. Specifically, a decrease in FVC over a 6-12-month period correlates directly with increased mortality rates. Antifibrotic drugs Pirfenidone and Nintedanib have been extensively validated; however, some patients reported several side effects, predominantly gastrointestinal symptoms (such as diarrhea, dyspepsia, and vomiting), as well as photosensitivity and skin rashes, particularly associated with Pirfenidone. In cases where the side effects are extremely severe and are more threatening than the disease itself, the treatment has to be discontinued. However, further research is needed to optimize the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. Finally, other studies are requested to establish the treatments that can stop ILD progression.
PubMed: 38931376
DOI: 10.3390/ph17060709 -
Cells Jun 2024Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates...
Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in the carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-Acetylaminofluorene (2-AAF). The HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, β-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.
Topics: Animals; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Pyridones; Rats; Carcinoma, Hepatocellular; Humans; Hep G2 Cells; Proliferating Cell Nuclear Antigen; Male; Rats, Inbred F344; Liver Neoplasms; Gene Expression Regulation, Neoplastic; Diethylnitrosamine; Liver Neoplasms, Experimental
PubMed: 38920644
DOI: 10.3390/cells13121013 -
Signal Transduction and Targeted Therapy Jun 2024Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it. The tumor microenvironment...
Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it. The tumor microenvironment (TME) in pancreatic cancer, distinguished by fibrosis and the existence of cancer-associated fibroblasts (CAFs), exerts a pivotal influence on both tumor advancement and resistance to therapy. Recent advancements in the field of engineered extracellular vesicles (EVs) offer novel avenues for targeted therapy in pancreatic cancer. This study aimed to develop engineered EVs for the targeted reprogramming of CAFs and modulating the TME in pancreatic cancer. EVs obtained from bone marrow mesenchymal stem cells (BMSCs) were loaded with miR-138-5p and the anti-fibrotic agent pirfenidone (PFD) and subjected to surface modification with integrin α5-targeting peptides (named IEVs-PFD/138) to reprogram CAFs and suppress their pro-tumorigenic effects. Integrin α5-targeting peptide modification enhanced the CAF-targeting ability of EVs. miR-138-5p directly inhibited the formation of the FERMT2-TGFBR1 complex, inhibiting TGF-β signaling pathway activation. In addition, miR-138-5p inhibited proline-mediated collagen synthesis by directly targeting the FERMT2-PYCR1 complex. The combination of miR-138-5p and PFD in EVs synergistically promoted CAF reprogramming and suppressed the pro-cancer effects of CAFs. Preclinical experiments using the orthotopic stroma-rich and patient-derived xenograft mouse models yielded promising results. In particular, IEVs-PFD/138 effectively reprogrammed CAFs and remodeled TME, which resulted in decreased tumor pressure, enhanced gemcitabine perfusion, tumor hypoxia amelioration, and greater sensitivity of cancer cells to chemotherapy. Thus, the strategy developed in this study can improve chemotherapy outcomes. Utilizing IEVs-PFD/138 as a targeted therapeutic agent to modulate CAFs and the TME represents a promising therapeutic approach for pancreatic cancer.
Topics: Pancreatic Neoplasms; Extracellular Vesicles; Humans; Cancer-Associated Fibroblasts; Mice; MicroRNAs; Animals; Tumor Microenvironment; Cellular Reprogramming; Cell Line, Tumor; Mesenchymal Stem Cells; Neoplasm Proteins; Gemcitabine
PubMed: 38910148
DOI: 10.1038/s41392-024-01872-7 -
Molecular Metabolism Jun 2024Obesity increases deposition of extracellular matrix (ECM) components of cardiac tissue. Since obesity aggregates with insulin resistance and heart disease, it is...
AIMS/HYPOTHESIS
Obesity increases deposition of extracellular matrix (ECM) components of cardiac tissue. Since obesity aggregates with insulin resistance and heart disease, it is imperative to determine whether the increased ECM deposition contributes to this disease cluster. The hypotheses tested in this study were that in cardiac tissue of obese mice i) increased deposition of ECM components (collagens and hyaluronan) contributes to cardiac insulin resistance and that a reduction in these components improves cardiac insulin action and ii) reducing excess collagens and hyaluronan mitigates obesity-associated cardiac dysfunction.
METHODS
Genetic and pharmacological approaches that manipulated collagen and hyaluronan contents were employed in obese C57BL/6 mice fed a high fat (HF) diet. Cardiac insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and cardiac function was measured by pressure-volume loop analysis in vivo RESULTS: We demonstrated a tight association between increased ECM deposition with cardiac insulin resistance. Increased collagen deposition by genetic deletion of matrix metalloproteinase 9 (MMP9) exacerbated cardiac insulin resistance and pirfenidone, a clinically available anti-fibrotic medication which inhibits collagen expression, improved cardiac insulin resistance in obese mice. Furthermore, decreased hyaluronan deposition by treatment with PEGylated human recombinant hyaluronidase PH20 (PEGPH20) improved cardiac insulin resistance in obese mice. These relationships corresponded to functional changes in the heart. Both PEGPH20 and pirfenidone treatment in obese mice ameliorated HF diet-induced abnormal myocardial remodelling.
CONCLUSION
Our results provide important new insights into the role of ECM deposition in the pathogenesis of cardiac insulin resistance and associated dysfunction in obesity of distinct mouse models. These findings support the novel therapeutic potential of targeting early cardiac ECM abnormalities in the prevention and treatment of obesity-related cardiovascular complications.
PubMed: 38908792
DOI: 10.1016/j.molmet.2024.101970 -
Toxicon : Official Journal of the... Jun 2024To date there are only pirfenidone (PFD) and nintedanib to be given conditional recommendation in idiopathic pulmonary fibrosis (IPF) therapies with slowing disease...
To date there are only pirfenidone (PFD) and nintedanib to be given conditional recommendation in idiopathic pulmonary fibrosis (IPF) therapies with slowing disease progression, but neither has prospectively shown a reduced mortality. It is one of the urgent topics to find effective drugs for pulmonary fibrosis in medicine. Previous studies have demonstrated that microcystin-RR (MC-RR) effectively alleviates bleomycin-induced pulmonary fibrosis, but the mechanism has not been fully elucidated yet. We further conducted a comparison of therapeutic effect on the model animals of pulmonary fibrosis between MC-RR and PFD with histopathology and the expression of the molecular markers involved in differentiation, proliferation and metabolism of myofibroblasts, a major effector cell of tissue fibrosis. The levels of the enzyme molecules for maintaining the stability of interstitial structure were also evaluated. Our results showed that MC-RR and PFD effectively alleviated pulmonary fibrosis in model mice with a decreased signaling and marker molecules associated with myofibroblast differentiation and lung fibrotic lesion. In the meantime, both MC-RR and PFD treatment are beneficial to restore molecular dynamics of interstitial tissue and maintain the stability of interstitial architecture. Unexpectedly, MC-RR, rather than PFD, showed a significant effect on inhibiting PKM2-HIF-1α signaling and reducing the level of p-STAT3. Additionally, MC-RR showed a better inhibition effect on FGFR1 expression. Given that PKM2-HIF-1α and activated STAT3 molecular present a critical role in promoting the proliferation of myofibroblasts, MC-RR as a new strategy for IPF treatment has potential advantage over PFD.
PubMed: 38908528
DOI: 10.1016/j.toxicon.2024.107822 -
Respiratory Research Jun 2024Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with a high mortality rate. The antifibrotic medications pirfenidone and nintedanib...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with a high mortality rate. The antifibrotic medications pirfenidone and nintedanib have been in use since 2014 for this disorder and are associated with improved rate of lung function decline. Less is known about their long-term outcomes outside of the clinical trial context.
METHODS
The Pulmonary Fibrosis Foundation Patient Registry was used for this study. Patients with an IPF diagnosis made within a year of enrollment were included. The treated group was defined as patients receiving either pirfenidone or nintedanib for at least 180 days. The untreated group did not have any record of antifibrotic use. Demographic data, comorbidities, serial lung function, hospitalization, and vital status data were collected from the registry database. The primary outcomes were transplant-free survival, time to first respiratory hospitalization, and time to 10% absolute FVC decline. Time-to-event analyses were performed utilizing Cox proportional hazards models and the log-rank test. Model covariates included age, gender, smoking history, baseline lung function, comorbidities, and oxygen use.
RESULTS
The registry contained 1212 patients with IPF; ultimately 288 patients met inclusion criteria for the treated group, and 101 patients were designated as untreated. Patients treated with antifibrotics were significantly younger (69.8 vs. 72.6 years, p = 0.008) and less likely to have smoked (61.1% ever smokers vs. 72.3% never smokers, p = 0.04). No significant differences were seen in race, gender, comorbidities, or baseline pulmonary function between groups. The primary outcome of transplant-free survival was not significantly different between the two groups (adjusted HR 0.799, 95% CI 0.534-1.197, p = 0.28). Time to respiratory hospitalization was significantly shorter in the treated group (adjusted HR 2.12, 95% CI 1.05-4.30, p = 0.04). No significant difference in time to pulmonary function decline was seen between groups.
CONCLUSIONS
This multicenter study demonstrated 63% of newly diagnosed IPF patients had continuous antifibrotic usage. Antifibrotics were not associated with improved transplant-free survival or pulmonary function change but was associated with an increased hazard of respiratory hospitalization. Future studies should further investigate the role of antifibrotic therapy in clinically important outcomes in real-world patients with IPF and other progressive ILDs.
Topics: Humans; Male; Registries; Female; Idiopathic Pulmonary Fibrosis; Aged; Middle Aged; Antifibrotic Agents; Treatment Outcome; Pyridones; Indoles; Time Factors
PubMed: 38907239
DOI: 10.1186/s12931-024-02883-2 -
Cells May 2024Pulmonary fibrosis is a chronic, progressive, irreversible lung disease characterized by fibrotic scarring in the lung parenchyma. This condition involves the excessive... (Review)
Review
Pulmonary fibrosis is a chronic, progressive, irreversible lung disease characterized by fibrotic scarring in the lung parenchyma. This condition involves the excessive accumulation of extracellular matrix (ECM) due to the aberrant activation of myofibroblasts in the alveolar environment. Transforming growth factor beta (TGF-β) signaling is a crucial driver of fibrogenesis because it promotes excessive ECM deposition, thereby leading to scar formation and lung damage. A primary target of TGF-β signaling in fibrosis is Collagen Triple Helix Repeat Containing 1 (CTHRC1), a secreted glycoprotein that plays a pivotal role in ECM deposition and wound repair. TGF-β transcriptionally regulates CTHRC1 in response to tissue injury and controls the wound healing response through functional activity. CTHRC1 may also play an essential role in re-establishing and maintaining tissue homeostasis after wound closure by modulating both the TGF-β and canonical Wnt signaling pathways. This dual function suggests that CTHRC1 regulates tissue remodeling and homeostasis. However, deregulated CTHRC1 expression in pathogenic fibroblasts has recently emerged as a hallmark of fibrosis in multiple organs and tissues. This review highlights recent studies suggesting that CTHRC1 can serve as a diagnostic and prognostic biomarker for fibrosis in idiopathic pulmonary fibrosis, systemic sclerosis, and post-COVID-19 lung fibrosis. Notably, CTHRC1 expression is responsive to antifibrotic drugs that target the TGF-β pathway, such as pirfenidone and bexotegrast, indicating its potential as a biomarker of treatment success. These findings suggest that CTHRC1 may present new opportunities for diagnosing and treating patients with lung fibrosis.
Topics: Humans; Fibroblasts; Extracellular Matrix Proteins; Pulmonary Fibrosis; Animals; Transforming Growth Factor beta; Extracellular Matrix; Idiopathic Pulmonary Fibrosis
PubMed: 38891078
DOI: 10.3390/cells13110946 -
Advanced Science (Weinheim,... Jun 2024The unique physical tumor microenvironment (TME) and aberrant immune metabolic status are two obstacles that must be overcome in cancer immunotherapy to improve clinical...
The unique physical tumor microenvironment (TME) and aberrant immune metabolic status are two obstacles that must be overcome in cancer immunotherapy to improve clinical outcomes. Here, an in situ mechano-immunometabolic therapy involving the injection of a biomimetic hydrogel is presented with sequential release of the anti-fibrotic agent pirfenidone, which softens the stiff extracellular matrix, and small interfering RNA IDO1, which disrupts kynurenine-mediated immunosuppressive metabolic pathways, together with the multi-kinase inhibitor sorafenib, which induces immunogenic cell death. This combination synergistically augmented tumor immunogenicity and induced anti-tumor immunity. In mouse models of clear cell renal cell carcinoma, a single-dose peritumoral injection of a biomimetic hydrogel facilitated the perioperative TME toward a more immunostimulatory landscape, which prevented tumor relapse post-surgery and prolonged mouse survival. Additionally, the systemic anti-tumor surveillance effect induced by local treatment decreased lung metastasis by inhibiting epithelial-mesenchymal transition conversion. The versatile localized mechano-immunometabolic therapy can serve as a universal strategy for conferring efficient tumoricidal immunity in "cold" tumor postoperative interventions.
PubMed: 38884220
DOI: 10.1002/advs.202308734