Current opinion in pharmacology
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Curr Opin Pharmacol · Oct 2020
ReviewEmbracing diversity: how can broadly neutralizing antibodies effectively target a diverse HIV-1 reservoir?
Genetic diversity in the latent proviral reservoir of HIV-1 infected individuals poses a challenge to cure strategies. It has become increasingly evident that diversity increases proportionally with length of active infection, and that functional and/or sterilizing cure strategies will need to overcome this obstacle in individuals who initiated antiretroviral therapy (ART) during chronic infection. Analyzing the results of analytic treatment interruption (ATI) has allowed for the evaluation of such therapeutic strategies in HIV+ individuals. Strategies to overcome the genetic diversity of the HIV-1 reservoir include antibody combinations, pre-screening individuals for bNAb sensitivity, focusing on low-diversity individuals as well as targeting host proteins.
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Curr Opin Pharmacol · Apr 2020
ReviewNull hypothesis significance testing and effect sizes: can we 'effect' everything … or … anything?
The Null Hypothesis Significance Testing (NHST) paradigm is increasingly criticized. Estimation approaches such as point estimates and confidence intervals, while having limitations, provide better descriptions of results than P-values and statements about significance levels. Their use is supported by many statisticians. ⋯ Effect sizes should not be used to interpret results without accompanying limits, such as confidence intervals. New methods, especially Bayesian approaches, are being developed; however, no single method provides a simple answer. Rather there is a need to improve researchers understanding of the complex issues underlying experimental design, statistical analysis and interpretation of results.
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Curr Opin Pharmacol · Oct 2019
ReviewFocus on the essentials: tryptophan metabolism and the microbiome-gut-brain axis.
The gut-brain axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract, in which serotonin (5-HT) functions as a key neurotransmitter. Recent research has increasingly concentrated on tryptophan, the precursor to 5-HT and on the microbial regulation of tryptophan metabolism, with an emphasis on host-microbe control over kynurenine pathway metabolism and microbial-specific pathways that generate bioactive tryptophan metabolites. Here, we critically assess recent progress made towards a mechanistic understanding of the microbial regulation of tryptophan metabolism and microbiota-gut-brain axis homeostasis highlighting the role tryptophan metabolism plays in preclinical and clinical neuroscience and in the challenge to improve our understanding of how perturbed tryptophan metabolism contributes to stress-related psychiatric disorders.
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Chronic pruritus is a highly prevalent, debilitating disease, which is often refractory to conventional therapies. A step-wise, guideline-driven approach should be adopted in the management of these patients. ⋯ If these measures fail, and the origin of the pruritus remains unknown, cannot be treated or does not respond to therapy, systemic therapies as for example gabapentinoids, antidepressants, mu-opioid-receptor antagonists or, in case of inflammatory conditions, immunosuppressive drugs should be recommended. Novel agents, especially systemic monoclonal antibodies, neurokinin-1 receptor antagonists and opioid receptor modulators, are promising in providing relief in refractory cases.
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Curr Opin Pharmacol · Dec 2018
ReviewThe epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis.
Cystic fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR dysfunction is characterized by abnormal mucociliary transport due to a dehydrated airway surface liquid (ASL) and hyperviscous mucus, among other pathologies of host defense. ASL depletion is caused by the absence of CFTR mediated chloride secretion along with continued activity of the epithelial sodium channel (ENaC) activity, which can also be affected by CFTR mediated anion conductance. ⋯ Recent efforts have been made to develop novel, rationally designed therapeutics to produce-specific, long-lasting inhibition of ENaC activity in the airways while simultaneously minimizing off target fluid transport effects, systemic exposure and side effects. Such approaches comprise next-generation small molecule direct inhibitors, indirect channel-activating protease inhibitors, synthetic peptide analogs, and oligonucleotide-based therapies. These novel therapeutics represent an exciting step forward in the development of ENaC-directed therapies for CF.