Histopathology of Vascular Injury in Sprague-Dawley Rats Treated with Phosphodiesterase IV Inhibitor SCH 351591 or SCH 534385

Zhang, Jun; Snyder, Ronald D.; Herman, Eugene H.; Knapton, Alan; Honchel, Ronald; Miller, Talia; Espandiari, Parvaneh; Goodsaid, Federico; Rosenblum, Irwin Y.; Hanig, Joseph P.; Sistare, Frank D.; Weaver, James L.

doi:10.1177/0192623308322308

Cited by 30 publications

(48 citation statements)

References 44 publications

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“…Adventitial fibrosis and neovascularization can occur with chronic lesions, especially in large vessels, with differentiation of fibroblasts to myofibroblasts (Siow, Mallawaarachchi, and Weissberg 2003;Zalewski and Shi 1997). Rarely, plexiform vasculopathy, that is, the increased size and number of vasa vasorum, can be observed after chronic administration of vasoactive substances (Collins et al 1988;Nyska et al 1998;Westwood, Iswaran, and Greaves 1990;Zhang et al 2008). The INHAND terminology for the vascular system reflects the nomenclature of changes noted in other organs (Mann et al 2012).…”

Section: Anatomic Considerations and Divi Standard Terminologymentioning

confidence: 99%

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Scientific and Regulatory Policy Committee Points-to-consider Paper*

Frazier

Engelhardt

Fant³

et al. 2015

Toxicol Pathol

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Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment.

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Section: Anatomic Considerations and Divi Standard Terminologymentioning

confidence: 99%

“…After drug administration, EC morphology becomes characteristic for activation, as demonstrated by plump appearance, cuboidal shape, protrusion into the lumen, and prominent organelles, followed by apoptosis and eventually EC loss Zhang, Herman, Holt, et al 2002;Zhang et al 2008Zhang et al , 2010.…”

Section: Role Of Ec Activation In Vascular Injurymentioning

confidence: 99%

Scientific and Regulatory Policy Committee Points-to-consider Paper*

Frazier

Engelhardt

Fant³

et al. 2015

Toxicol Pathol

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“…Their development is frequently hampered by the induction of vascular toxicity in rat mesenteric tissue during preclinical studies. Histopathologically, mesenteric vascular injury is characterized by perivascular edema and mixed inflammatory cell infiltration associated with medial necrosis and hemorrhage (17). Whereas these vascular lesions in rats have been well characterized histologically, little is known about their pathogenesis, and in turn, sensitive and specific biomarkers for preclinical and clinical monitoring do not exist.…”

Section: Case Study 1: Drug-induced Vascular Injurymentioning

confidence: 99%

Identification and Elucidation of the Biology of Adverse Events: The Challenges of Safety Assessment and Translational Medicine

Turteltaub

Davis

Burns‐Naas

et al. 2011

Clinical Cancer Research

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There has been an explosion of technology-enabled scientific insight into the basic biology of the causes of adverse events. This has been driven, in part, by the development of the various "omics" tools (e.g., genomics, proteomics, and metabolomics) and associated bioinformatics platforms. Meanwhile, for decades, changes in preclinical testing protocols and guidelines have been limited. Preclinical safety testing currently relies heavily on the use of outdated animal models. Application of systems biology methods to evaluation of toxicities in oncology treatments can accelerate the introduction of safe, effective drugs. Systems biology adds insights regarding the causes and mechanisms of adverse effects, provides important and actionable information to help understand the risks and benefits to humans, focuses testing on methods that add value to the safety testing process, and leads to modifications of chemical entities to reduce liabilities during development. Leveraging emerging technologies, such as genomics and proteomics, may make preclinical safety testing more efficient and accurate and lead to better safety decisions. The development of a U.S. Food and Drug Administration guidance document on the use of systems biology in clinical testing would greatly benefit the development of drugs for oncology by communicating the potential application of specific methodologies, providing a framework for qualification and application of systems biology outcomes, and providing insight into the challenges and limitations of systems biology in the regulatory decision-making process. Clin Cancer Res; 17(21); 6641-5. Ó2011 AACR. Introductory NoteAt the 2010 Conference on Clinical Cancer Research, co-convened by Friends of Cancer Research and the Engelberg Center for Health Care Reform at the Brookings Institution, participants explored 4 pressing new challenges in the field. Articles summarizing the panel's recommendations on each of these topics are featured in this issue of Clinical Cancer Research (1-4). Gaps in Current Testing and Safety Assessment ParadigmsThe toxicity of new oncology drugs is a leading cause of pharmaceutical attrition and a major impediment to efficient and successful drug development. Safety, or lack thereof, is also a major factor in regulatory decisions involving drug approval, labeling, risk evaluation, and mitigation and even withdrawal from the marketplace. The current battery of preclinical safety studies required to support the clinical development of new drugs and marketing approval is mapped out in International Conference on Harmonisation (ICH) guidelines that include ICH M3, E14, and S1 to S9 (5). In addition, various other documents from regulatory agencies provide recommendations regarding specific toxicities or adverse events, such as hepatotoxicity (6). However, these testing methods and risk assessments have not kept pace with the rapid evolution of technology, biomedical research, and knowledge generation. For example, the studies required to meet international regulatory...

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“…Serum for biomarker analysis and tissues for histopathology were collected and stored as previously described (J. Zhang et al 2008). …”

Section: In Vivo Studiesmentioning

confidence: 99%

Early Events in Vascular Injury in the Rat Induced by the Phosphodiesterase IV Inhibitor SCH 351591

et al. 2010

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Treatment with drugs from multiple classes induces vascular injury with medial necrosis, hemorrhage, endothelial damage, and inflammation. Previous research has suggested early events might be occurring well in advance of the full lesions that appear forty-eight to seventy-two hours after dosing with SCH 351591, a PDE IV inhibitor. This study was performed to study early events in detail. Rats were dosed with 20 mg/kg of drug by gavage and sacrificed at times between fifteen and 240 minutes after dosing. Tissues were collected for histopathological analysis and gene expression studies. Serum was collected for biomarker analysis. The data from biomarker analysis showed a three-part response with an early phase that was maximal at fifteen to thirty minutes, a second phase from forty-five to 180 minutes, and the third phase that was starting to rise at four hours. The first phase included increases in lymphocytes, serum histamine, and serum nitrite. The second phase shows continued elevation of serum nitrite. The third phase was marked by an increase in serum GRO/CINC-1. At fifteen minutes, histopathology showed activation of mast cells, but not degranulation. Increases in endothelial activation and perivascular inflammatory cells were first apparent at thirty minutes and increased through 240 minutes.

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Histopathology of Vascular Injury in Sprague-Dawley Rats Treated with Phosphodiesterase IV Inhibitor SCH 351591 or SCH 534385

Cited by 30 publications

References 44 publications

Scientific and Regulatory Policy Committee Points-to-consider Paper*

Scientific and Regulatory Policy Committee Points-to-consider Paper*

Identification and Elucidation of the Biology of Adverse Events: The Challenges of Safety Assessment and Translational Medicine

Early Events in Vascular Injury in the Rat Induced by the Phosphodiesterase IV Inhibitor SCH 351591

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