Current status and future directions for diagnostic markers of drug-induced vascular injury

Brott, David; Jones, Huw B.; Gould, Sarah; Valentin, Jean Pierre; Evans, G. A.; Richardson, Rudy J.; Louden, Calvert

doi:10.3233/cbm-2005-1104

Cited by 15 publications

(18 citation statements)

References 59 publications

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“…In our studies, evaluation of SMA immunohistochemically shows decreased immunoreactivity in injured SMC of damaged arteries (Brott et al, 2005a). In drug-induced vascular injury, loss of SMA immunoreactivity specifically at the site of vascular damage raises the possibility that this protein qualifies as a potential diagnostic marker of drug-induced vascular injury.…”

Section: Smooth Muscle Actin As a Biomarker Of Smc Injurysupporting

confidence: 57%

Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents

et al. 2006

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In preclinical safety studies, drug-induced vascular injury can negatively impact candidate-drug selection because there are no obvious diagnostic markers for monitoring this pathology preclinically or clinically. Furthermore, our current understanding of the pathogenesis of this lesion is limited. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary target cells, smooth muscle (SMC) and endothelial cell (EC), are unknown. Evaluation of potential novel markers for clinical monitoring with a mechanistic underpinning would add value in risk assessment and risk management. This mini review focuses on the efforts and progress to identify diagnostic markers as well as understanding the mechanism of action in nonrodent drug-induced vascular injury.

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Section: Smooth Muscle Actin As a Biomarker Of Smc Injurysupporting

confidence: 57%

Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents

et al. 2006

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“…kidney), precipitating increases in cardiovascular‐related mortality and morbidity (Lewington et al ., 2002; Valentin et al ., 2009b; Chalmers and Arima, 2010). Likewise, vascular inflammation and injury is often reported in preclinical models (Brott et al ., 2005; Louden et al ., 2006), while the clinical relevance and consequence of these observations remains unclear, as compounds with a drug‐induced vascular injury liability have been successfully developed (e.g. potassium channel openers; phosphodiesterase inhibitors; endothelin receptor antagonists).…”

Section: What Are the Key Cardiovascular Safety Liabilities In Drug Dmentioning

confidence: 99%

“…However, some disorders can only be confirmed by histopathology such as necrosis, while others although observed preclinically, are of disputed relevance to the clinic (e.g. vascular inflammation and injury; Brott et al ., 2005; Louden et al ., 2006).…”

Section: How Good Are Preclinical and Clinical Strategies For Detectimentioning

confidence: 99%

How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?

Laverty

Benson

Cartwright

et al. 2011

British J Pharmacology

316

203

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Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post‐approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing ‘Cardiovascular Toxicity of Medicines’. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: Fully characterize the incidence, prevalence and impact of drug‐induced cardiovascular issues at all stages of the drug development process. Ascertain the predictive value of existing non‐clinical models and assays towards the clinical outcome. Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers.

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“…Immunohistochemistry and ISH, however, may be less sensitive and specific and are not as amenable to precise quantification as other molecular methods. IHC and ISH are particularly indicated to monitor the expression of biomarkers that are highly expressed in the tissue/cell of interest and that may be released as the result of cellular damage, such as smooth muscle actin (ACTA2), transgelin (TGLN), or miR-145 (Wiener et al 1996;Albassam et al 1999;Brott et al 2005; Supplemental Figure 1). These methods also may be used for biomarkers that are upregulated, that denote inflammatory cells, or markers that are deposited in the damaged vessels, such as complement, fibrin, or ICs (Supplemental Table 2).…”

Section: Characterization Of Divi and Biomarker Target Validation By mentioning

confidence: 99%

Nonclinical Safety Biomarkers of Drug-induced Vascular Injury

et al. 2014

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Better biomarkers are needed to identify, characterize, and/or monitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG developed a strategy based on the premise that biomarkers of DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic lexicon for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, and confirmation of target localization using immunohistochemistry and in situ hybridization are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI.

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Current status and future directions for diagnostic markers of drug-induced vascular injury

Cited by 15 publications

References 59 publications

Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents

Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents

How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?

Nonclinical Safety Biomarkers of Drug-induced Vascular Injury

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