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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA‐approved mast cell stabilizer. This study aims to investigate the anti‐fibrotic and antioxidant effects of the masitinib‐cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple‐immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl‐2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2‐induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti‐fibrotic, cell‐protective, and antioxidant effects of the masitinib‐cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously. [ABSTRACT FROM AUTHOR]

Objectives: This meta-analysis aimed to examine the safety of masitinib in patients with neurodegenerative diseases. Methods: We considered randomized controlled trials (RCTs) comparing different doses of masitinib versus placebo. We performed our analysis using the R (v.4.3.0) programming language and the incidence of adverse events was pooled using risk ratio (RR) and 95% confidence interval (CI). Results: We included five RCTs, focusing on multiple sclerosis (MS), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The meta-analysis revealed a significantly higher incidence of adverse events in the masitinib group compared to the control group, regardless of adverse event grade and masitinib dose (RR = 1.12, 95% CI [1.07 to 1.17], P < 0.01). Adverse events categorized as severe, non-fatal serious, leading to dose reduction, and leading to permanent discontinuation also showed a higher incidence in the masitinib group (P ≤ 0.01). Subgroup analysis for AD and MS supported these findings. The pooled incidence of adverse events, regardless of their grade, was higher in the masitinib group for both the 3 mg/kg/d dose (RR = 1.13, P = 0.01) and the 4.5 mg/kg/d dose (RR = 1.11, P < 0.01). However, there was no significant difference between masitinib 3 mg/kg/d dose and placebo regarding severe and non-fatal serious adverse events for the. Conclusion: Masitinib use in neurodegenerative diseases presents safety concerns that may impact patients' quality of life and require management. Further research is recommended to determine the optimal dose with minimal safety concerns in this patient population. [ABSTRACT FROM AUTHOR]

Objectives: Masitinib, originally developed as a tyrosine kinase inhibitor for cancer treatment, has shown potential neuroprotective effects in various neurological disorders by modulating key pathways implicated in neurodegeneration. This scoping review aimed to summarize the current evidence of masitinib's neuroprotective activities from preclinical to clinical studies. Methods: This scoping review was conducted following the guidelines described by Arksey and O'Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria covered all original studies reporting on the neuroprotective effects of masitinib, including clinical studies, animal studies, and in vitro studies. Results: A total of 16 studies met the inclusion criteria and were included in the review. These comprised five randomized controlled trials (RCTs), one post-hoc analysis study, one case report, and nine animal studies. The RCTs focused on Alzheimer's disease (two studies), multiple sclerosis (two studies), and amyotrophic lateral sclerosis (one study). Across all included studies, masitinib consistently demonstrated neuroprotective properties. However, the majority of RCTs reported concerns regarding the safety profile of masitinib. Preclinical studies revealed the neuroprotective mechanisms of masitinib, which include inhibition of certain kinases interfering with cell proliferation and survival, reduction of neuroinflammation, and exhibition of antioxidant activity. Conclusion: The current evidence suggests a promising therapeutic benefit of masitinib in neurodegenerative diseases. However, further research is necessary to validate and expand upon these findings, particularly regarding the precise mechanisms through which masitinib exerts its therapeutic effects. Future studies should also focus on addressing the safety concerns associated with masitinib use. [ABSTRACT FROM AUTHOR]

The social burden of dementia is remarkable since it affects some 57.4 million people all over the world. Impairment of autophagy in age-related diseases, such as dementia, deserves deep investigation for the detection of novel disease-modifying approaches. Several drugs belonging to different classes were suggested to be effective in managing Alzheimer's disease (AD) by means of autophagy induction. Useful autophagy inducers in AD should be endowed with a direct, measurable effect on autophagy, have a safe tolerability profile, and have the capability to cross the blood–brain barrier, at least with poor penetration. According to the PRISMA 2020 recommendations, we propose here a systematic review to appraise the measurable effectiveness of autophagy inducers in the improvement of cognitive decline and neuropsychiatric symptoms in clinical trials and retrospective studies. The systematic search retrieved 3067 records, 10 of which met the eligibility criteria. The outcomes most influenced by the treatment were cognition and executive functioning, pointing at a role for metformin, resveratrol, masitinib and TPI-287, with an overall tolerable safety profile. Differences in sample power, intervention, patients enrolled, assessment, and measure of outcomes prevents generalization of results. Moreover, the domain of behavioral symptoms was found to be less investigated, thus prompting new prospective studies with homogeneous design. PROSPERO registration: CRD42023393456. [ABSTRACT FROM AUTHOR]

In recent years, more than 200 countries of the world have faced a health crisis due to the epidemiological disease of COVID-19 caused by the SARS-CoV-2 virus. It had a huge impact on the world economy and the global health sector. Researchers are studying the design and discovery of drugs that can inhibit SARS‐CoV‐2. The main protease of SARS‐CoV‐2 is an attractive target for the study of antiviral drugs against coronavirus diseases. According to the docking results, binding energy for boceprevir, masitinib and rupintrivir with CMP are −10.80, −9.39, and −9.51 kcal/mol respectively. Also, for all investigated systems, van der Waals and electrostatic interactions are quite favorable for binding the drugs to SARS-CoV-2 coronavirus main protease, indicating confirmation of the complex stability.

The hepatitis A virus (HAV) infection causes acute hepatitis. HAV also induces acute liver failure or acute-on-chronic liver failure; however, no potent anti-HAV drugs are currently available in clinical situations. For anti-HAV drug screening, more convenient and useful models that mimic HAV replication are needed. In the present study, we established HuhT7-HAV/Luc cells, which are HuhT7 cells stably expressing the HAV HM175-18f genotype IB subgenomic replicon RNA harboring the firefly luciferase gene. This system was made by using a PiggyBac-based gene transfer system that introduces nonviral transposon DNA into mammalian cells. Then, we investigated whether 1134 US Food and Drug Administration (FDA)-approved drugs exhibited in vitro anti-HAV activity. We further demonstrated that treatment with tyrosine kinase inhibitor masitinib significantly reduced both HAV HM175-18f genotype IB replication and HAV HA11-1299 genotype IIIA replication. Masitinib also significantly inhibited HAV HM175 internal ribosomal entry-site (IRES) activity. In conclusion, HuhT7-HAV/Luc cells are adequate for anti-HAV drug screening, and masitinib may be useful for the treatment of severe HAV infection. [ABSTRACT FROM AUTHOR]

The social burden of dementia is remarkable since it affects some 57.4 million people all over the world. Impairment of autophagy in age-related diseases, such as dementia, deserves deep investigation for the detection of novel disease-modifying approaches. Several drugs belonging to different classes were suggested to be effective in managing Alzheimer’s disease (AD) by means of autophagy induction. Useful autophagy inducers in AD should be endowed with a direct, measurable effect on autophagy, have a safe tolerability profile, and have the capability to cross the blood–brain barrier, at least with poor penetration. According to the PRISMA 2020 recommendations, we propose here a systematic review to appraise the measurable effectiveness of autophagy inducers in the improvement of cognitive decline and neuropsychiatric symptoms in clinical trials and retrospective studies. The systematic search retrieved 3067 records, 10 of which met the eligibility criteria. The outcomes most influenced by the treatment were cognition and executive functioning, pointing at a role for metformin, resveratrol, masitinib and TPI-287, with an overall tolerable safety profile. Differences in sample power, intervention, patients enrolled, assessment, and measure of outcomes prevents generalization of results. Moreover, the domain of behavioral symptoms was found to be less investigated, thus prompting new prospective studies with homogeneous design. PROSPERO registration: CRD42023393456.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies, glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly reduces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib’s mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed.

Masitinib is an orally acceptable tyrosine kinase inhibitor that is currently investigated under clinical trials against cancer, asthma, Alzheimer’s disease, multiple sclerosis and amyotrophic lateral sclerosis. A recent study confirmed the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity of masitinib through inhibition of the main protease (Mpro) enzyme, an important pharmacological drug target to block the replication of the coronavirus. However, due to the adverse effects and lower potency of the drug, there are opportunities to design better analogues of masitinib. Herein, we substituted the N-methylpiperazine group of Masitinib with different chemical moieties and evaluated their drug-likeness and toxicities. The filtered analogues were subjected to molecular docking studies which revealed that the analogues with substituents methylamine in M10 (CID10409602), morpholine in M23 (CID59789397) and 4-methylmorpholine in M32 (CID143003625) have a stronger affinity to the drug receptor compared to masitinib. The molecular dynamics (MD) simulation analysis reveals that the identified analogues alter the mobility, structural compactness, accessibility to solvent molecules, and the number of hydrogen bonds in the native target enzyme. These structural alterations can help explain the inhibitory mechanisms of these analogues against the target enzyme. Thus, our studies provide avenues for the design of new masitinib analogues as the SARS-CoV-2 Mpro inhibitors.

Tyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the action of specific transport proteins, as they are hydrophilic and not able to cross cell membranes freely. Accordingly, the efficacy of TKI in target cells is closely dependent on the expression of their transporters. Specifically, Masitinib is an organic cation and is expected to interact with organic cation transporters (OCT and Multidrug and Toxin Extrusion proteins—MATE-). The aim of this work was to characterize the interaction of Masitinib with different OCTs. Human embryonic kidney 293 cells stably transfected with murine or human OCT were used for the experiments. The interaction of Masitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of this drug was quantified using high performance liquid chromatography. Our results identified interactions of Masitinib with almost all investigated mouse (m) and human (h) OCTs and hMATE1 and indicated OCT1 and hOCT2 to be especially potent Masitinib translocators across cell membranes. Interestingly, some important differences were observed for the interaction with murine and human OCTs. In the future, investigations concerning further in vitro and in vivo properties of Masitinib and its efficacy related to transporter-related uptake mechanisms under pathophysiological conditions should be performed. Clinical trials in humans and other animals with Masitinib have already shown promising results. However, further research is necessary to understand the disease specific transport mechanisms of Masitinib to contribute to a successful and responsible therapy employment. [ABSTRACT FROM AUTHOR]

Canine prostate cancer is classified into adenocarcinoma, transitional cell carcinoma with prostatic involvement, and mixed forms. Early metastatic spread leads to poor prognosis and limited treatment options. Masitinib is approved for the treatment of canine mast cell tumours and inhibits tyrosine kinase c‐Kit, tyrosine‐protein kinase Lyn (Lyn), and platelet‐derived growth factor receptors alpha and beta (PDGFR‐α, PDGFR‐β), which are known to be expressed in canine prostate cancer. The aim of this study was to evaluate masitinib in an in vitro model consisting of cell lines from primary prostate adenocarcinoma, the associated lymph node metastasis of the same patient, and transitional cell carcinoma. To assess the suitability of the model system, the targets of masitinib were investigated by immunocytochemistry in the cell lines and by immunohistochemistry in the respective formalin‐fixed, paraffin‐embedded (FFPE) original neoplastic tissue. After exposure to masitinib, cell viability, cell count, apoptosis induction, and protein expression of c‐Kit, Lyn, PDGFR‐α, and PDGFR‐β were assessed. To hedge the efficacy, two application protocols of masitinib (single application or 12‐h double‐dose regimen) were compared. Immunocytochemical and immunohistochemical analysis revealed increased Lyn, PDGFR‐α, and PDGFR‐β expression in cell lines and FFPE original neoplastic tissue compared to healthy prostate tissue. Masitinib exposure increased apoptosis, while the cell counts and cell viability decreased in a dose‐ and application interval‐dependent manner, with increased impact in the 12‐h double‐dose regimen. These in vitro effects of masitinib in canine prostate cancer and associated metastasis support further in vivo research and modifications of the clinical treatment protocol in future studies. [ABSTRACT FROM AUTHOR]

The hepatitis A virus (HAV) infection causes acute hepatitis. HAV also induces acute liver failure or acute-on-chronic liver failure; however, no potent anti-HAV drugs are currently available in clinical situations. For anti-HAV drug screening, more convenient and useful models that mimic HAV replication are needed. In the present study, we established HuhT7-HAV/Luc cells, which are HuhT7 cells stably expressing the HAV HM175-18f genotype IB subgenomic replicon RNA harboring the firefly luciferase gene. This system was made by using a PiggyBac-based gene transfer system that introduces nonviral transposon DNA into mammalian cells. Then, we investigated whether 1134 US Food and Drug Administration (FDA)-approved drugs exhibited in vitro anti-HAV activity. We further demonstrated that treatment with tyrosine kinase inhibitor masitinib significantly reduced both HAV HM175-18f genotype IB replication and HAV HA11-1299 genotype IIIA replication. Masitinib also significantly inhibited HAV HM175 internal ribosomal entry-site (IRES) activity. In conclusion, HuhT7-HAV/Luc cells are adequate for anti-HAV drug screening, and masitinib may be useful for the treatment of severe HAV infection.

Abstract Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically.

Masitinib mesylate, a selective tyrosine kinase inhibitor of the c-KIT receptor, is used for the treatment of mast cell tumours in dogs. Masitinib has previously been investigated in various cancers; however, its potential anticancer effect in canine mammary tumours (CMTs) is unknown. In the present paper, we investigated the antiproliferative effect of masitinib in CMT cells and its possible mechanisms of action.

The persistency of COVID-19 in the world and the continuous rise of its variants demand new treatments to complement vaccines. Computational chemistry can assist in the identification of moieties able to lead to new drugs to fight the disease. Fullerenes and carbon nanomaterials can interact with proteins and are considered promising antiviral agents. Here, we propose the possibility to repurpose fullerenes to clog the active site of the SARS-CoV-2 protease, Mpro. Through the use of docking, molecular dynamics, and energy decomposition techniques, it is shown that C60 has a substantial binding energy to the main protease of the SARS-CoV-2 virus, Mpro, higher than masitinib, a known inhibitor of the protein. Furthermore, we suggest the use of C70 as an innovative scaffold for the inhibition of SARS-CoV-2 Mpro. At odds with masitinib, both C60 and C70 interact more strongly with SARS-CoV-2 Mpro when different protonation states of the catalytic dyad are considered. The binding of fullerenes to Mpro is due to shape complementarity, i.e., vdW interactions, and is aspecific. As such, it is not sensitive to mutations that can eliminate or invert the charges of the amino acids composing the binding pocket. Fullerenic cages should therefore be more effective against the SARS-CoV-2 virus than the available inhibitors such as masinitib, where the electrostatic term plays a crucial role in the binding. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the action of specific transport proteins, as they are hydrophilic and not able to cross cell membranes freely. Accordingly, the efficacy of TKI in target cells is closely dependent on the expression of their transporters. Specifically, Masitinib is an organic cation and is expected to interact with organic cation transporters (OCT and Multidrug and Toxin Extrusion proteins—MATE-). The aim of this work was to characterize the interaction of Masitinib with different OCTs. Human embryonic kidney 293 cells stably transfected with murine or human OCT were used for the experiments. The interaction of Masitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of this drug was quantified using high performance liquid chromatography. Our results identified interactions of Masitinib with almost all investigated mouse (m) and human (h) OCTs and hMATE1 and indicated OCT1 and hOCT2 to be especially potent Masitinib translocators across cell membranes. Interestingly, some important differences were observed for the interaction with murine and human OCTs. In the future, investigations concerning further in vitro and in vivo properties of Masitinib and its efficacy related to transporter-related uptake mechanisms under pathophysiological conditions should be performed. Clinical trials in humans and other animals with Masitinib have already shown promising results. However, further research is necessary to understand the disease specific transport mechanisms of Masitinib to contribute to a successful and responsible therapy employment.

Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically. [ABSTRACT FROM AUTHOR]

Background: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001. Methods: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity. Results: A significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31–0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001. Conclusions: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality. This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015). [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis is a neurodegenerative disease, resulting in the loss of self-service and death of the middle-aged and elderly people. In the last 2 decades, significant progress has been made in the study of the pathogenesis of this disease. Two known drugs (riluzole and edaravone) have been approved by the Food and Drug Administration for treatment of amyotrophic lateral sclerosis. The efficacy of these drugs is extremely low, so clinical trials of new drugs are ongoing all over the world. This review discusses the current achievements and future directions of therapy of this disease.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes the progressive loss of motoneurons and, unfortunately, there is no effective treatment for this disease. Interconnecting multiple pathological mechanisms are involved in the neuropathology of this disease, including abnormal aggregation of proteins, neuroinflammation and dysregulation of the ubiquitin proteasome system. Such complex mechanisms, together with the lack of reliable animal models of the disease have hampered the development of drugs for this disease. Protein kinases, a key pharmacological target in several diseases, have been linked to ALS as they play a central role in the pathology of many diseases. Therefore several inhibitors are being currently trailed for clinical proof of concept in ALS patients. In this review, we examine the recent literature on protein kinase inhibitors currently in pharmaceutical development for this diseaseas future therapy for AS together with their involvement in the pathobiology of ALS. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc [ABSTRACT FROM AUTHOR]

The persistency of COVID-19 in the world and the continuous rise of its variants demand new treatments to complement vaccines. Computational chemistry can assist in the identification of moieties able to lead to new drugs to fight the disease. Fullerenes and carbon nanomaterials can interact with proteins and are considered promising antiviral agents. Here, we propose the possibility to repurpose fullerenes to clog the active site of the SARS-CoV-2 protease, Mpro. Through the use of docking, molecular dynamics, and energy decomposition techniques, it is shown that C60 has a substantial binding energy to the main protease of the SARS-CoV-2 virus, Mpro, higher than masitinib, a known inhibitor of the protein. Furthermore, we suggest the use of C70 as an innovative scaffold for the inhibition of SARS-CoV-2 Mpro. At odds with masitinib, both C60 and C70 interact more strongly with SARS-CoV-2 Mpro when different protonation states of the catalytic dyad are considered. The binding of fullerenes to Mpro is due to shape complementarity, i.e., vdW interactions, and is aspecific. As such, it is not sensitive to mutations that can eliminate or invert the charges of the amino acids composing the binding pocket. Fullerenic cages should therefore be more effective against the SARS-CoV-2 virus than the available inhibitors such as masinitib, where the electrostatic term plays a crucial role in the binding.

Jennifer Bourn,1,2 Maria Cekanova1,2 1Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA; 2UT-ORNL Graduate School of Genome Science and Technology, The University of Tennessee, Knoxville, TN, USA Purpose: Receptor tyrosine kinase inhibitors (RTKIs) are used as targeted therapies for patients diagnosed with cancer with highly expressed receptor tyrosine kinases (RTKs), including the platelet-derived growth factor receptor (PDGFR) and c-Kit receptor. Resistance to targeted therapies is partially due to the activation of alternative pro-survival signaling pathways, including cyclooxygenase (COX)-2. In this study, we validated the effects of two RTKIs, axitinib and AB1010, in combination with COX inhibitors on the V-akt murine thymoma oncogene homolog 1 (Akt) and COX-2 signaling pathways in bladder cancer cells.Methods: The expression of several RTKs and their downstream signaling targets was analyzed by Western blot (WB) analysis in human and canine bladder transitional cell carcinoma (TCC) cell lines. The effects of RTKIs and COX inhibitors in bladder TCC cells were assessed by MTS for cell viability, by Caspase-3/7 and Annexin V assay for apoptosis, by WB analysis for detection of COX-2 and Akt signaling pathways, and by enzyme-linked immunosorbent assay for detection of prostaglandin E2 (PGE2) levels.Results: All tested TCC cells expressed the c-Kit and PDGFRα receptors, except human 5637 cells that had low RTKs expression. In addition, all tested cells expressed COX-1, COX-2, Akt, extracellular signal regulated kinases 1/2, and nuclear factor kappa-light-chain-enhance of activated B cells proteins, except human UM-UC-3 cells, where no COX-2 expression was detected by WB analysis. Both RTKIs inhibited cell viability and increased apoptosis in a dose-dependent manner in tested bladder TCC cells, which positively correlated with their expression levels of the PDGFRα and c-Kit receptors. RTKIs increased the expression of COX-2 in h-5637 and K9TCC#1Lillie cells. Co-treatment of indomethacin inhibited AB1010-induced COX-2 expression leading to an additive effect in inhibition of cell viability and PGE2 production in tested TCC cells.Conclusion: Co-treatment of RTKIs with indomethacin inhibited cell viability and AB1010-induced COX-2 expression resulting in decreased PGE2 production in tested TCC cells. Thus, COX inhibition may further potentiate RTKIs therapies in bladder cancer. Keywords: transitional cell carcinoma, axitinib, masitinib, cyclooxygenase-2, prostaglandin E2, indomethacin

Abstract Masitinib (MST) is an orally administered drug that targets mast cells and macrophages, important cells for immunity, by inhibiting a limited number of tyrosine kinases. It is currently registered in Europe and USA for the treatment of mast cell tumors in dogs. AB Science announced that the European Medicines Agency has accepted a conditional marketing authorization application for MST to treat amyotrophic lateral sclerosis. In our work, we focused on studying in vivo metabolism of MST in Sprague–Dawley rats. Single oral dose of MST (33 mg kg−1) was given to Sprague–Dawley rats (kept in metabolic cages) using oral gavage. Urine was collected and filtered at 0, 6, 12, 18, 24, 48, 72 and 96 h from MST dosing. An equal amount of ACN was added to urine samples. Both organic and aqueous layers were injected into liquid chromatography-tandem mass spectrometry (LC–MS/MS) to detect in vivo phase I and phase II MST metabolites. The current work reports the identification and characterization of twenty in vivo phase I and four in vivo phase II metabolites of MST by LC–MS/MS. Phase I metabolic pathways were reduction, demethylation, hydroxylation, oxidative deamination, oxidation and N-oxide formation. Phase II metabolic pathways were the direct conjugation of MST, N-demethyl metabolites and oxidative metabolites with glucuronic acid. Part of MST dose was excreted unchanged in urine. The literature review showed no previous articles have been made on in vivo metabolism of MST or detailed structural identification of the formed in vivo phase I and phase II metabolites.

Background: Masitinib is a selective tyrosine kinase inhibitor that modulates mast cells activity. A previous phase II study reported a cognitive effect of masitinib in patients with Alzheimer's disease.Objective: We aimed to shed light on the mode of action of masitinib in Alzheimer's disease.Methods/results: We demonstrated here that chronic oral treatment of APPswe/PSEN1dE9 transgenic mice modeling Alzheimer's disease restored normal spatial learning performance while having no impacts on amyloid-β loads nor on neuroinflammation. However, masitinib promoted a recovery of synaptic markers. Complete genetic depletion of mast cells in APPswe/PSEN1dE9 mice similarly rescued synaptic impairments.Conclusion: These results underline that masitinib therapeutic efficacy might primarily be associated with a synapto-protective action in relation with mast cells inhibition. [ABSTRACT FROM AUTHOR]

Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65–6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53–6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data. [ABSTRACT FROM AUTHOR]

Abstract Masitinib (MST) is a selective tyrosine kinase inhibitor. Validated liquid chromatography tandem mass spectrometric method (LC–MS/MS) was developed for the quantification of MST in rat liver microsomes (RLMs) matrix. The developed method was applied to metabolic stability and excretion rate studies. Reversed phase liquid chromatography was used for resolution of MST and bosutinib (IS) using C18 (50 mm × 2.1 mm, 1.8 μm). Binary solvent system consisted of 35% solvent A (0.1% formic acid in H2O, pH: 3.2) and 65% solvent B (acetonitrile) used as mobile phase at flow rate of 0.25 mL with a total run time of 5 min. Injection volume was 5 µL. Generation of ions was done in positive ESI source and quantification of MST and IS were done using MRM mode. The developed method showed a linearity in the range of 5–200 ng/mL (r2 ≥ 0.9992) with LOQ and LOD of 0.25 and 0.76 ng/mL in RLMs. The intra- and inter-day precision and accuracy ranged from 0.95 to 1.49 and − 5.22 to 1.13%, respectively in RLMs. Rate of disappearance of MST during incubation with RLMs was almost linear allover incubation time. In vitro t1/2 was 50.38 min and CLin was 3.11 ± 0.2. The developed method was applied also to measure the rate of masitinib excretion in rat urine. The method can used for further pharmacokinetic studies of MST.

In recent years, more than 200 countries of the world have faced a health crisis due to the epidemiological disease of COVID-19 caused by the SARS-CoV-2 virus. It had a huge impact on the world economy and the global health sector. Researchers are studying the design and discovery of drugs that can inhibit SARS‐CoV‐2. The main protease of SARS‐CoV‐2 is an attractive target for the study of antiviral drugs against coronavirus diseases. According to the docking results, binding energy for boceprevir, masitinib and rupintrivir with CMP are −10.80, −9.39, and −9.51 kcal/mol respectively. Also, for all investigated systems, van der Waals and electrostatic interactions are quite favorable for binding the drugs to SARS-CoV-2 coronavirus main protease, indicating confirmation of the complex stability. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a deadly CNS neurodegenerative disease. The way ALS is now managed, from diagnosis to prognosis, is still not ideal despite many studies. Early diagnosis can help ALS patients live longer since prompt treatment can halt the disease's development. Two medications, riluzole and edaravone, have recently been licensed for use in therapy, and they very slightly increase life expectancy. Still, a lot of cutting-edge experimental medications are being developed. In the following article, we give a synopsis of the innovative medications and genetic remodeling that have emerged recently and help to halt the course of the illness. Studies have also been conducted on a few symptomatic and rehabilitative therapies that enhance the quality of life for ALS patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Gupta et al.)

The aim of the present prospective-retrospective study was to evaluate the response of high-risk canine mast cell tumours (MCTs) to tyrosine kinase inhibitors (TKIs) and to correlate this with prognostic factors. A total of 24 dogs presented with macroscopic cutaneous MCTs at disease stage II or III, and therefore, at high-risk of associated mortality, were included in the study and treated with masitinib (n=20) or toceranib (n=4). A total of 12/24 dogs achieved an objective response and the overall survival (OS) for all subjects was 113 days. Dogs responding to treatment had a significant increase in OS compared to non-responders (146.5 days vs. 47 days, P=0.02). Internal tandem duplications in exon 11 of the c-kit gene were identified in 6/24 cases. Ki67, KIT immunolabelling and c-kit mutation did not provide information regarding prognosis or prediction of response to TKIs in this population. Initial response to TKIs appears to be the most reliable prognostic factor for survival duration. [ABSTRACT FROM AUTHOR]

Masitinib (MST) is a selective tyrosine kinase inhibitor. Validated liquid chromatography tandem mass spectrometric method (LC-MS/MS) was developed for the quantification of MST in rat liver microsomes (RLMs) matrix. The developed method was applied to metabolic stability and excretion rate studies. Reversed phase liquid chromatography was used for resolution of MST and bosutinib (IS) using C (50 mm × 2.1 mm, 1.8 μm). Binary solvent system consisted of 35% solvent A (0.1% formic acid in HO, pH: 3.2) and 65% solvent B (acetonitrile) used as mobile phase at flow rate of 0.25 mL with a total run time of 5 min. Injection volume was 5 µL. Generation of ions was done in positive ESI source and quantification of MST and IS were done using MRM mode. The developed method showed a linearity in the range of 5-200 ng/mL (r ≥ 0.9992) with LOQ and LOD of 0.25 and 0.76 ng/mL in RLMs. The intra- and inter-day precision and accuracy ranged from 0.95 to 1.49 and − 5.22 to 1.13%, respectively in RLMs. Rate of disappearance of MST during incubation with RLMs was almost linear allover incubation time. In vitro t was 50.38 min and CL was 3.11 ± 0.2. The developed method was applied also to measure the rate of masitinib excretion in rat urine. The method can used for further pharmacokinetic studies of MST. [ABSTRACT FROM AUTHOR]

CD30 is a novel therapeutic target in human mast cell (MC) neoplasms. In this 'comparative oncology' study, we examined CD30 expression and regulation in neoplastic canine MC using a panel of immunomodulatory cytokines [interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-13 and stem cell factor (SCF)] and the canine mastocytoma cell lines NI-1 and C2. Of all cytokines tested IL-4 was found to downregulate expression of CD30 in NI-1 and C2 cells. We also found that the CD30-targeting antibody-conjugate brentuximab vedotin induces growth inhibition and apoptosis in both MC lines. Next, we asked whether IL-4-induced downregulation of CD30 interferes with brentuximab vedotin-effects. Indeed, pre-incubation of NI-1 cells with IL-4 decreased responsiveness towards brentuximab vedotin. To overcome IL-4-mediated resistance, we applied drug combinations and found that brentuximab vedotin synergizes with the Kit-targeting drugs masitinib and PKC412 in inhibiting growth of NI-1 and C2 cells. In summary, CD30 is a new marker and IL-4-regulated target in neoplastic canine MC. [ABSTRACT FROM AUTHOR]

Background: Malignant melanoma in the gastrointestinal tract may be primary or metastatic. Mucosal melanoma is a quite rare and aggressive disease, growing hidden and diagnosed with a certain delay which makes treatment difficult. Case Report: The authors present the first patient with c-kit exon 11 mutated primary esophageal melanoma treated with oral tyrosine kinase inhibitor masitinib. A 55-year-old-man presented with esophageal melanoma metastising into visceral organs and to the brain. The patient showed objective and clinical significant therapeutic response to masitinib. After initiation of masitinib, dysphagia and odynophagia disappeared within 1 week. Following 1 month of treatment, computed tomography showed a regression in the number and size of brain metastatic lesions and regression in visceral lesions. This therapeutic response, despite the aggressive disease on treatment initiation, effectively enabled the patient to have 6 months of quality life. Conclusion: This report corroborates the plausibility of treating advanced melanoma carrying a mutation of KIT with masitinib. It also raises the question of masitinib treatment beyond progression. Additionally, the observed masitinib treatment effect on the brain suggests accumulation of therapeutically relevant concentration of masitinib in the central nervous system. This observation has possible ramifications for treatment of intracranial neoplasms.

Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment. Riluzole received marketing authorization in 1995 in the USA and in 1996 in Europe. In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS. Despite significant research efforts, the overwhelming majority of human clinical trials (CTs) have failed to demonstrate clinical efficacy. In the past year, oral masitinib and intravenous edaravone have emerged as promising new therapeutics with claimed efficacy in CTs in ALS patients. Given their advanced phase of clinical development one may consider these drugs as the most likely near-term additions to the therapeutic arsenal available for patients with ALS. In terms of patient inclusion, CT with masitinib recruited a wider, more representative, less restrictive patient population in comparison to the only successful edaravone CT (edaravone eligibility criteria represents only 18% of masitinib study patients). The present manuscript reviews >50 CTs conducted in the last 20 years since riluzole was first approved. A special emphasis is put on the analysis of existing evidence in support of the clinical efficacy of edaravone and masitinib and the possible implications of an eventual marketing authorisation in the treatment of ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies, glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly reduces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib's mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed. [Display omitted] • Among recent ALS clinical trials, Masitinib emerged as a hopeful novel therapy. • Masitinib reduces inflammation by targeting macrophages, mast cells, and microglia. • Masitinib induces neuroprotection by decreasing the proinflammatory cytokines. • Masitinib can increase overall survival and slow ALSFRS-R deterioration. [ABSTRACT FROM AUTHOR]

This retrospective case series evaluates survival outcome of 94 dogs with high metastatic risk mast cell tumours (MCT). Patients were treated with a cytotoxic chemotherapy protocol or the tyrosine kinase inhibitor masitinib, in the presence of gross disease or as an adjunct to surgical resection of the primary tumour. In patients presenting with metastatic disease, surgical resection of the primary tumour with adjunctive therapy with any chemotherapy incurred a significant survival advantage [median survival time (MST): 278 days] compared to patients receiving chemotherapy without surgical excision of the primary tumour (MST: 91 days, P < 0.0001). Patients with a surgically excised Patnaik grade II tumour and high Ki-67 in the absence of metastatic disease treated with vinblastine and prednisolone showed a significantly longer survival (MST: 1946 days) than those treated with masitinib (MST: 369 days, P = 0.0037). Further prospective case-controlled clinical trials of high-risk MCTs are required to make precise evidence-based treatment decisions for individual patients. [ABSTRACT FROM AUTHOR]

Masitinib is an orally acceptable tyrosine kinase inhibitor that is currently investigated under clinical trials against cancer, asthma, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. A recent study confirmed the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity of masitinib through inhibition of the main protease (Mpro) enzyme, an important pharmacological drug target to block the replication of the coronavirus. However, due to the adverse effects and lower potency of the drug, there are opportunities to design better analogues of masitinib. Herein, we substituted the N -methylpiperazine group of Masitinib with different chemical moieties and evaluated their drug-likeness and toxicities. The filtered analogues were subjected to molecular docking studies which revealed that the analogues with substituents methylamine in M10 (CID10409602), morpholine in M23 (CID59789397) and 4-methylmorpholine in M32 (CID143003625) have a stronger affinity to the drug receptor compared to masitinib. The molecular dynamics (MD) simulation analysis reveals that the identified analogues alter the mobility, structural compactness, accessibility to solvent molecules, and the number of hydrogen bonds in the native target enzyme. These structural alterations can help explain the inhibitory mechanisms of these analogues against the target enzyme. Thus, our studies provide avenues for the design of new masitinib analogues as the SARS-CoV-2 Mpro inhibitors. [ABSTRACT FROM AUTHOR]

• We provide an outline of current MS medications in the pipeline including emerging DMTs and stem cell therapy. • these new therapies could potentially provide an increasing diversity of treatment options for patients in the future. • Many of the therapies discussed such as Evobrutinib, vidofludimus, fenebrutinib, and orelabrutinib offer higher selectivity or potency compared to current available treatments, which could improve overall MS patient satisfaction and quality of life due to theoretically fewer adverse side effects and possible improved efficacy. Multiple Sclerosis (MS) is a chronic neurodegenerative autoimmune disorder of the central nervous system (CNS) and the most common cause of serious physical disability in working-age adults. Drug development and research in this field have rapidly evolved over the past two decades, leading to the broad array of treatment options available today. These disease-modifying therapies (DMTs) work through distinct mechanisms of action and exhibit varying safety and efficacy profiles to help manage symptoms and reduce exacerbations in MS patients. Our extensive understanding of this condition has also led to novel approaches, such as the discovery of specific biomarkers that allow us to monitor the therapeutic response towards DMTs. The development of new DMTs continues to progress quickly today, and it can be difficult for clinicians to remain up to date on the most recent advancements and new treatment options for their patients. In this comprehensive review, we provide an outline of current MS medications in the pipeline including emerging DMTs and stem cell therapy, as well as the unique characteristics of these medications, including their indications, pharmacokinetic effects, and the relevant advancements. [ABSTRACT FROM AUTHOR]

Background: In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.Methods: The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset.Results: We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %.Conclusions: These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS. [ABSTRACT FROM AUTHOR]

Background: Canine oral fibrosarcoma (COF) is one of the most common oral tumors in dogs and carries a guarded prognosis due to a lack of effective systemic therapeutic options. Mastinib and imatinib are two commonly used tyrosine kinase inhibitors (TKIs) in veterinary oncology but their potential efficacy against COF is uncharacterized. To begin investigating the rationale for use of these TKIs against COF, the present study tested for the presence TKI targets PDGFR-α, PDGFR-β, Kit, and VEGFR-2 and examined the in vitro effects on cell viability after TKI treatment alone or with doxorubicin. Immunohistochemistry for PDGFR-α, PDGFR-β, Kit, and VEGFR-2 was performed in 6 COF tumor biopsies. Presence of these same receptors within 2 COF cell lines was probed by reverse transcription-polymerase chain reaction and, for those with mRNA detected, confirmed via western blot. Effects on cell viability were assessed using an MTS assay after masitinib or imatinib treatment alone (0-100 μM), or in combination with doxorubicin (0-3000 nM doxorubicin). Anti-PDGFRB siRNA knockdown was performed and the effect on cell viability quantified. Results: Expression of the TKI targets evaluated was similar between the 2 COF cell lines and the 6 COF tumor biopsies: PDGFR-α and PDGFR-β were detected in neoplastic cells from most COF tumor biopsies (5/6 and 6/6, respectively) and were present in both COF cell lines; KIT and KDR were not detected in any sample. Masitinib and imatinib IC50 values ranged from 7.9–33.4 μM, depending on the specific TKI and cell line tested. The addition of doxorubicin resulted in synergistic cytotoxicity with both TKIs. Anti-PDGFRB siRNA transfection reduced PDGFR-β protein expression by 77 % and 67 % and reduced cell viability by 24 % (p < 0.0001) and 28 % (0 = 0.0003) in the two cell lines, respectively. Conclusions: These results provide rationale for further investigation into the use of TKIs, possibly in combination with doxorubicin, as treatment options for COF. [ABSTRACT FROM AUTHOR]