successful antiviral treatment of chronic hepatitis c in patients with rare comorbidities two case reports

Abstract Antiviral therapy in patients suffering from chronic hepatitis C virus (HCV) infection and rare comorbidities cannot be easily started, as it can reduce the likelihood of a good therapeutic response with an increased frequency of side effects. We report two patients presenting unusual comorbidities associated with chronic C hepatitis: one with the Ehlers-Danlos Syndrome (EDS), a rare genetic disease caused by a defect in collagen synthesis, the other one with the Charcot Marie Tooth (CMT) disease, an uncommon but severe form of demyelinating peripheral neuropathy. Both patients were successfully treated with pegylated Interfe-ron (Peg-IFN) and ribavirin (RBV) combined therapy, with the achievement of a sustained viral response (SVR) and a low occurrence of adverse effects. Up to now there are no reports of patients suffering from chronic C hepatitis associated with these uncommon but severe comorbidities treated with antiviral therapy. In conclusion, in such clinical situations, anti-HCV therapy may be started and tailored, especially if the patient is highly motivated and if optimal predictors of response (i.e. young age, favourable genotype and low baseline viraemia) do exist

Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

Proteolysis targeting chimera (PROTAC)-mediated protein degradation has prompted a radical rethink and is at a crucial stage in driving a drug discovery transition. To fully harness the potential of this technology, a growing paradigm toward enriching PROTACs with other therapeutic modalities has been proposed. Could researchers successfully combine two modalities to yield multifunctional PROTACs with an expanded profile? In this Perspective, we try to answer this question. We discuss how this possibility encompasses different approaches, leading to multitarget PROTACs, light-controllable PROTACs, PROTAC conjugates, and macrocycle-and oligonucleotide-based PROTACs. This possibility promises to further enhance PROTAC efficacy and selectivity, minimize side effects, and hit undruggable targets. While PROTACs have reached the clinical investigation stage, additional steps must be taken toward the translational development of multifunctional PROTACs. A deeper and detailed understanding of the most critical challenges is required to fully exploit these opportunities and decisively enrich the PROTAC toolbox

Severe pneumonia after intravesical BCG instillation in a patient with invasive bladder cancer: case report and literature review

We present here the case of a 66 year old man with a severe bilateral community acquired pneumonia secondary to dissemination after an intravesical instillation of bacilllus Calmette-Guérin (BCG). Diagnosis was based on positive polymerase chain reaction (PCR) for mycobacterium tuberculosis complex in bronchoalveolar lavage and on the finding on transbronchial biopsy of non necrotising granulomas histopathologically similar to the granulomas found in bladder biopsies. These findings were confirmed using a validated real time PCR assay demonstrating the presence of the BCG genome in transbronchial and bladder biopsies

Severe pneumonia after intravesical BCG instillation in a patient with invasive bladder cancer: case report and literature review

We present here the case of a 66 year old man with a severe bilateral community acquired pneumonia secondary to dissemination after an intravesical instillation of bacilllus Calmette-Guérin (BCG). Diagnosis was based on positive polymerase chain reaction (PCR) for mycobacterium tuberculosis complex in bronchoalveolar lavage and on the finding on transbronchial biopsy of non necrotising granulomas histopathologically similar to the granulomas found in bladder biopsies. These findings were confirmed using a validated real time PCR assay demonstrating the presence of the BCG genome in transbronchial and bladder biopsies

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

textabstractThe classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research

Design and synthesis of novel Cystic Fibrosis (CF) modulators - Development of novel inhibitors of the anti-infective target DXS using Dynamic Combinatorial Chemistry (DCC)

Cystic Fibrosis (CF) is a lethal, autosomal recessive genetic disease characterized by an accumulation of viscous mucus at epithelia surface of multiple organs, including lungs, pancreas, gut and testis, which results in obstruction, infection, inflammation and ultimately organ failure. The primary cause of CF is the mutation of a gene, the Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which leads to a decrease in CFTR chloride channel function and ultimately to a reduced ionic and water homeostasis at epithelial surfaces. Historically conventional CF treatments focused on symptomatic therapy, until recently when the growing understanding of the molecular basis of CF pathologies stimulated the development of small-molecule drugs, called CFTR modulators, which address the primary cause of CF with the hope to repair the defects in mutated CFTR. Aiming to expand the portfolio of novel modulators available to CF patients, also considering the relevant but limited pharmacological efficacy elicited by some of the current treatments, there is still the need to develop more CFTR small molecule modulators, primarily correctors, which may address the primary cause of CF by rescuing the activity of defective CFTR (Chapter 1). The present PhD thesis describes the design, synthesis and biological characterization of novel CFTR correctors. Starting from primary hits ARN9364 and ARN5562, selected for their promising initial biological activity after a High-Throughput Screening (HTS) campaign, new analogs were designed and synthesized to elucidate the Structure-Activity Relationship (SAR) patterns around these chemo-types (Chapter 2). The biological test of these novel compounds in a phenotypic cell-based assay (HS-YFP assay) using CFBE41o- cells, allowed to get clear information about the most suited structural modifications needed to improve rescuing activity of defective F508del-CFTR. An iterative process of design, synthesis and biological testing led to the identification of slightly or even more potent CFTR correctors (Chapter 3). In Chapter 4 the development of selective and potent inhibitors of the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase (DXS), using target-directed Dynamic Combinatorial Chemistry (tdDCC), as hit-identification strategy, was reported. Biochemical evaluation of several hit compounds amplified in the tdDCC experiment against M. tuberculosis DXS and D. radiodurans DXS afforded inhibitors with IC50 in the range of 30 microM \u2013 190 microM

Successful antiviral treatment of chronic hepatitis C in patients with rare comorbidities. Two case-reports

Antiviral therapy in patients suffering from chronic hepatitis C virus (HCV) infection and rare comorbidities cannot be easily started, as it can reduce the likelihood of a good therapeutic response with an increased frequency of side effects. We report two patients presenting unusual comorbidities associated with chronic C hepatitis: one with the Ehlers-Danlos Syndrome (EDS), a rare genetic disease caused by a defect in collagen synthesis, the other one with the Charcot Marie Tooth (CMT) disease, an uncommon but severe form of demyelinating peripheral neuropathy. Both patients were successfully treated with pegylated Interferon (Peg-IFN) and ribavirin (RBV) combined therapy, with the achievement of a sustained viral response (SVR) and a low occurrence of adverse effects. Up to now there are no reports of patients suffering from chronic C hepatitis associated with these uncommon but severe comorbidities treated with antiviral therapy. In conclusion, in such clinical situations, anti-HCV therapy may be started and tailored, especially if the patient is highly motivated and if optimal predictors of response (i.e. young age, favourable genotype and low baseline viraemia) do exist