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A Novel Strategy for the Discovery of Drug Targets: Integrating Clinical Evidence with Molecular Studies.
Kaneko, Shuji.
Afiliação
  • Kaneko S; Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University.
Biol Pharm Bull ; 47(2): 345-349, 2024.
Article em En | MEDLINE | ID: mdl-38296548
ABSTRACT
The mechanisms of several drugs remain unclear, limiting our understanding of how they exert their effects. Receptor affinities have not been comprehensively measured during drug development, and the safety investigations in humans are limited. Therefore, numerous unknown adverse and beneficial effects of drugs in humans persist. In this review, I highlight our achievements in identifying the unexpected beneficial effects of drugs through the analysis of real-world clinical data, which can contribute to drug repositioning and target finding. (1) Through the analysis of real-world data, we found that the anti-arrhythmic amiodarone induced interstitial lung disease, leading to fibrosis. Surprisingly, concurrent use of an anti-thrombin drug, dabigatran mitigated these adverse events. Pharmacological studies using animal models have mimicked this phenomenon and revealed the molecular mechanisms associated with the platelet-derived growth factor-alpha receptors. (2) The antidiabetic dipeptidyl-peptidase 4 inhibitors increased the risk of an autoimmune disease, bullous pemphigoid, which was reduced by the concomitant use of lisinopril. Pharmacological studies using human peripheral blood mononuclear cells have revealed that lisinopril suppressed the skin disorders by inhibiting the expression of cutaneous matrix metalloproteinase 9 in macrophages. (3) The antimicrobial fluoroquinolones increased the risk of tendinopathy, which was reduced by the concomitant use of dexamethasone. However, clinical guidelines have suggested that corticosteroid increases the risk of tendinopathy. Our investigation demonstrated that fluoroquinolones impaired tendon cells through DNA damage by generating reactive oxygen species. In contrast, dexamethasone exhibited an acute beneficial effect on tendon tissue by upregulating the expression of a radical scavenger, glutathione peroxidase 3.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucócitos Mononucleares / Tendinopatia Tipo de estudo: Guideline / Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Biol Pharm Bull Assunto da revista: BIOQUIMICA / FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucócitos Mononucleares / Tendinopatia Tipo de estudo: Guideline / Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Biol Pharm Bull Assunto da revista: BIOQUIMICA / FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article