Publications by authors named "Tritto E"

Article Synopsis
  • - This study assessed the safety, tolerability, and pharmacokinetics of DFV890, an oral NLRP3 inhibitor, in 122 healthy participants through a three-part trial involving single and multiple doses.
  • - DFV890 was well-tolerated with no serious adverse events, showing a dose-proportional increase in exposure in the adjusted formulation, while food intake significantly affected its pharmacokinetic profile.
  • - The drug effectively inhibited IL-1β release, maintaining about 90% inhibition over 24 hours with specific dosing regimens, suggesting its potential for treating conditions involving NLRP3 overactivation.
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Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington's disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity.

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Genetic disruption or short-term pharmacological inhibition of MALT1 protease is effective in several preclinical models of autoimmunity and B cell malignancies. Despite these protective effects, the severe reduction in regulatory T cells (Tregs) and the associated IPEX-like pathology occurring upon congenital disruption of the MALT1 protease in mice has raised concerns about the long-term safety of MALT1 inhibition. Here we describe the results of a series of toxicology studies in rat and dog species using MLT-943, a novel potent and selective MALT1 protease inhibitor.

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Originally conceptualized as an integrated approach combining conventional toxicology methods with genome-wide expression profiling, toxicogenomics has promised to provide unequivocal relationships between the molecular changes elicited by a compound or a target pathway and the lesions that appear subsequently in the tissues. However, the discipline has only partially delivered on this promise, and the number of publications and submissions related to toxicogenomics is stagnating. The purpose of this article is to outline key factors contributing to a successful implementation of toxicogenomics in the drug discovery and development process.

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Antibodies targeting IL-17A or its receptor IL-17RA show unprecedented efficacy in the treatment of autoimmune diseases such as psoriasis. These therapies, by neutralizing critical mediators of immunity, may increase susceptibility to infections. Here, we compared the effect of antibodies neutralizing IL-17A, IL-17F or TNFα on murine host responses to Mycobacterium tuberculosis infection by evaluating lung transcriptomic, microbiological and histological analyses.

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The aim of this study was to determine the relative safety of 4 antiviral drugs (telbivudine, tenofovir, adefovir, and entecavir) against hepatitis B virus with respect to kidney function and toxicity in male Sprague Dawley rats. The antiviral drugs were administered once daily for 4 weeks by oral gavage at ∼10 and 25-40 times the human equivalent dose. Main assessments included markers of renal toxicity in urine, magnetic resonance imaging (MRI) of kidney function, histopathology, and electron microscopic examination.

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Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins, thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with HDAC inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization is unknown.

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Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions. Conversely, IL-17 signaling is critical for immunity to opportunistic mucosal infections caused by the commensal fungus Candida albicans, as mice and humans lacking the IL-17R experience chronic mucosal candidiasis. IL-17A, IL-17F, and IL-17AF bind the IL-17RA-IL-17RC heterodimeric complex and deliver qualitatively similar signals through the adaptor Act1.

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Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically.

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A new triphenylene-imine (ImH) and its ortho-palladated complexes (μ-X)2[Pd2Im2] (X = CH3COO(-), Cl(-), Br(-)), (μ-Cl)(μ-SCnH2n+1)[Pd2Im2] (n = 6, 12), [PdIm(acac)] [PdIm Cl(CNC6H4OC12H25)], [PdImCl(CNC6H3(OC12H25)2)], and [PdImCl(CNC6H2(OC12H25)3)] have been prepared. The free imine ligand is not a liquid crystal, but most ortho-metalated dinuclear palladium complexes and the mononuclear trialkoxyphenyl isocyanide derivative display columnar mesophases at temperatures close to ambient. For the dimeric complexes the mesophase obtained is always columnar rectangular (Colr), with an uncommon structure: the dimeric triphenylene-Pd complex-triphenylene molecules give rise to a triple-column stacking consisting of two columns of stacked triphenylene groups connected to a central column formed by stacking of two ortho-palladated dimeric moieties.

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MF59 is a safe and effective vaccine adjuvant that has been used in a licensed seasonal influenza vaccine for 15 years. The purpose of the present studies was to directly address a question that has been asked of us on many occasions: "which is the adjuvant active component of MF59?". Since we have recently gained a number of insights on how MF59 works as an adjuvant, we were able to use these approaches to evaluate if the individual components of MF59 (squalene oil, the surfactants Span 85 and Tween 80 or the citrate buffer) showed any direct immunostimulatory activity.

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The innate immune pathways induced by adjuvants required to increase adaptive responses to influenza subunit vaccines are not well characterized. We profiled different TLR-independent (MF59 and alum) and TLR-dependent (CpG, resiquimod, and Pam3CSK4) adjuvants for the ability to increase the immunogenicity to a trivalent influenza seasonal subunit vaccine and to tetanus toxoid (TT) in mouse. Although all adjuvants boosted the Ab responses to TT, only MF59 and Pam3CSK4 were able to enhance hemagglutinin Ab responses.

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CpG-containing oligodeoxynucleotides are potent mucosal adjuvants and effective as stand-alone treatment of respiratory infections in mice. Although CpG is also used as a type 1 helper immunomodulator in the treatment of asthma and allergic disease, immune modulation following intranasal application has not been fully characterized yet. Using a B-type CpG, we monitored RNA expression profiles, cytokine production and cellular activation in lung tissue and bronchoalveolar lavages ex vivo and cytokine production of purified cell populations in vitro.

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Despite the fact that alum and oil-in-water emulsions have been used for decades as human vaccine adjuvants in a large number of individuals, their mechanism of action is not completely understood. It has been reported that these particulate adjuvants act by increasing antigen availability and uptake by immune cells. However, recent work on alum and on the squalene-based emulsion MF59, has demonstrated that besides antigen delivery functions, these classes of adjuvants can also activate innate immunity pathways in vivo, generating an immunocompetent environment at injection site.

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The development of vaccine adjuvants for human use has been one of the slowest processes in the history of medicine. For almost one century, aluminium hydroxide (alum) has been the only vaccine adjuvant approved worldwide. Only in the past decade have two oil-in-water emulsions and one TLR agonist been approved by the European authorities as new vaccine adjuvants.

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Oil-in-water emulsions are potent human adjuvants used for effective pandemic influenza vaccines; however, their mechanism of action is still unknown. By combining microarray and immunofluorescence analysis, we monitored the effects of the adjuvants MF59 oil-in-water emulsion, CpG, and alum in the mouse muscle. MF59 induced a time-dependent change in the expression of 891 genes, whereas CpG and alum regulated 387 and 312 genes, respectively.

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LTK63, a nontoxic mutant of Escherichia coli heat labile enterotoxin (LT), is a potent and safe mucosal adjuvant that has also been shown to confer generic protection to several respiratory pathogens. To understand the mechanisms of action underlying the LTK63 protective effect, we analyzed the molecular and cellular events triggered by its administration in vivo. We show here that LTK63 intrapulmonary administration induced in the mouse lung a specific gene expression signature characterized by the up-regulation of cell cycle genes, several host defense genes, chemokines, chemokine receptors, and immune cell-associated genes.

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