Why 90% of clinical drug development fails and how to improve it?

Acta Pharmaceutica Sinica B, Год журнала: 2022, Номер 12(7), С. 3049 - 3062

Опубликована: Фев. 11, 2022

Ninety percent of clinical drug development fails despite implementation many successful strategies, which raised the question whether certain aspects in target validation and optimization are overlooked? Current overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity disease/normal tissues structure‒tissue exposure/selectivity–relationship (STR), may mislead candidate selection impact balance dose/efficacy/toxicity. We propose exposure/selectivity–activity relationship (STAR) to improve optimization, classifies candidates based on drug's potency/selectivity, exposure/selectivity, required dose for balancing efficacy/toxicity. Class I drugs have high specificity/potency needs low achieve superior efficacy/safety with success rate. II requires efficacy toxicity be cautiously evaluated. III relatively (adequate) manageable often overlooked. IV achieves inadequate efficacy/safety, should terminated early. STAR studies development.

Язык: Английский

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Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases

Redox Biology, Год журнала: 2021, Номер 42, С. 101901 - 101901

Опубликована: Фев. 21, 2021

Generation of reactive oxygen species and related oxidants is an inevitable consequence life. Proteins are major targets for oxidation reactions, because their rapid reaction rates with high abundance in cells, extracellular tissues, body fluids. Additionally, oxidative stress able to degrade lipids carbohydrates highly intermediates, which eventually attack proteins at various functional sites. Consequently, a wide variety distinct posttranslational protein modifications formed by oxidation, glycoxidation, lipoxidation. Reversible relevant physiological processes constitute signaling mechanisms ("redox signaling"), while non-reversible may contribute pathological situations several diseases. A rising number publications provide evidence involvement the onset progression diseases as well aging processes. Certain products chemically stable large quantity, makes them promising candidates become biomarkers damage. Moreover, progress development detection quantification methods facilitates analysis time effort contributes future applicability clinical routine. The present review outlines most important classes selected examples modifications, elucidates chemistry beyond formation discusses available analysis. Furthermore, relevance potential context disease summarized.

Язык: Английский

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Brain circuits for pain and its treatment

Science Translational Medicine, Год журнала: 2021, Номер 13(619)

Опубликована: Ноя. 10, 2021

Understanding the organization of brain’s pain circuits is critical for developing effective treatments patients suffering from chronic pain.

Язык: Английский

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Functional MRI Can Be Highly Reliable, but It Depends on What You Measure: A Commentary on Elliott et al. (2020)

Psychological Science, Год журнала: 2021, Номер 32(4), С. 622 - 626

Опубликована: Март 8, 2021

Язык: Английский

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A neuromarker for drug and food craving distinguishes drug users from non-users

Nature Neuroscience, Год журнала: 2022, Номер 26(2), С. 316 - 325

Опубликована: Дек. 19, 2022

Язык: Английский

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Design of stretchable and self-powered sensing device for portable and remote trace biomarkers detection

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 26, 2023

Timely and remote biomarker detection is highly desired in personalized medicine health protection but presents great challenges the devices reported so far. Here, we present a cost-effective, flexible self-powered sensing device for H2S analysis various application scenarios based on structure of galvanic cells. The mechanism attributed to change electrode potential resulting from chemical adsorption gas molecules surfaces. Intrinsically stretchable organohydrogels are used as solid-state electrolytes enable stable long-term operation under stretching deformation or environments. open-circuit exhibits high sensitivity, low limit, excellent selectivity H2S. Its non-invasive halitosis diagnosis identification meat spoilage demonstrated, emerging commercial value portable medical electronics food security. A wireless sensory system has also been developed monitoring with participation Bluetooth cloud technologies. This work breaks through shortcomings traditional chemiresistive sensors, offering direction theoretical foundation designing wearable sensors catering other stimulus requirements.

Язык: Английский

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Confronting Racism in All Forms of Pain Research: Reframing Study Designs

Journal of Pain, Год журнала: 2022, Номер 23(6), С. 893 - 912

Опубликована: Фев. 26, 2022

Язык: Английский

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First-in-human prediction of chronic pain state using intracranial neural biomarkers

Nature Neuroscience, Год журнала: 2023, Номер 26(6), С. 1090 - 1099

Опубликована: Май 22, 2023

Язык: Английский

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Molecular biomarkers for vascular cognitive impairment and dementia

Nature Reviews Neurology, Год журнала: 2023, Номер 19(12), С. 737 - 753

Опубликована: Ноя. 13, 2023

Язык: Английский

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β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

Pharmacological Reviews, Год журнала: 2023, Номер 75(5), С. 854 - 884

Опубликована: Апрель 7, 2023

The two beta-arrestins, beta-arrestin-1 and -2 (systematic names: arrestin-2 -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number cellular signaling pathways physiological functions. were discovered for their ability to disrupt via G protein-coupled receptors (GPCRs) binding activated receptors. However, it is now well recognized both beta-arrestins can also act as direct modulators numerous processes either GPCR-dependent or -independent mechanisms. Recent structural, biophysical, biochemical studies have provided novel insights into how bind GPCRs downstream effector proteins. Studies with beta-arrestin mutant mice identified pathophysiological regulated by and/or -2. Following brief summary recent structural studies, this review will primarily focus on beta-arrestin-regulated functions, particular central nervous system roles in carcinogenesis key metabolic including maintenance glucose energy homeostasis. This highlight potential therapeutic implications these discuss strategies could prove useful targeting specific purposes. Significance Statement structurally closely related evolutionarily highly conserved, emerged able vast array outcome cultured cells, complemented structure function, should pave way development classes therapeutically drugs capable regulating

Язык: Английский

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