Alfred Tonelli

Publications (5)13.42 Total impact

• Article: Nonclinical safety assessment of a synthetic peptide thrombopoietin agonist: effects on platelets, bone homeostasis, and immunogenicity and the implications for clinical safety monitoring of adverse bone effects.

  Elaine Knight, Gary Eichenbaum, Verna Hillsamer, Tony Greway, Alfred Tonelli, Helen Han-Hsu, Cindy Zakszewski, Edward Yurkow, Umesh Shukla, David End, Calvert Louden
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  ABSTRACT: RWJ-800088 is a novel, potent polyethylene glycol (PEG)-conjugated thrombopoietin (TPO) mimetic that increases platelet levels and protects against thrombocytopenia. A nonclinical safety program was customized for this peptide that takes into account its protein-like structure, synthetic chemical nature, agonist pharmacologic activity, and mode of administration. In repeat-dose toxicity studies, the salient findings were dose-related increases in circulating platelet counts, mean platelet volume, and megakaryocytes in the bone marrow with no antibody formation. Reversible myelofibrosis and hyperostosis were observed in rats, but not dogs, when the circulating platelet levels exceeded 3× those of vehicle controls. The bone effects were due to the exaggerated pharmacologic effect and excessive stimulation and elevation of megakaryocytes by TPO, which results in intramedullary proliferation of fibroblasts and mesenchymal cells followed by osseous metaplasia. These findings support the use of platelet elevations of >3× as a stopping criterion to prevent potential adverse bone-related effects in humans.
  International Journal of Toxicology 08/2011; 30(4):385-404. · 1.28 Impact Factor
• Article: Unexpected nasal changes in rats related to reflux after gavage dosing.

  Siegrid Damsch, Gary Eichenbaum, Adriana Looszova, Lieve Lammens, Bianca Feyen, Kathleen Van den Bulck, Elaine Knight, Michael Kelley, Alfred Tonelli
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  ABSTRACT: In a three-week oral gavage toxicity study in rats, a high incidence of respiratory symptoms and high mortality was noted in compound-dosed rats only. Because of audible respiration, an effect in the upper respiratory tract was suspected and the nasal cavity was included for examination. Histology revealed extensive necrosis and purulent inflammation within the nasal passages, indicative of direct irritation. Since posterior nasal regions were most affected, with food material present within the inflammatory exudates, reflux and retrograde aspiration of irritant material (possibly stomach contents with test formulation) into the nasal cavity were suspected. Lowering the dose volume and fasting the rats prior to gavage dosing substantially reduced the respiratory effects and mortality. The current article focuses on the histological changes in the nasal cavity indicative of gavage-related reflux and provides guidance on differentiation between technical gavage error and gavage-related reflux.
  Toxicologic Pathology 01/2011; 39(2):337-47. · 1.91 Impact Factor
• Article: Gavage-related reflux in rats: identification, pathogenesis, and toxicological implications (review).

  Siegrid Damsch, Gary Eichenbaum, Alfred Tonelli, Lieve Lammens, Kathleen Van den Bulck, Bianca Feyen, John Vandenberghe, Anton Megens, Elaine Knight, Michael Kelley
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  ABSTRACT: After oral gavage dosing of rats, reflux may occur, resulting in serious respiratory effects and mortality. Published information on gavage-related reflux is limited, as it has not yet been a focus of research. Nevertheless, it represents a recurrent challenge in daily toxicology practice of oral gavage dosing. The absence of clear guidance and criteria for the identification and management of reflux-induced effects can limit the ability to properly interpret toxicity study results. The review presented herein includes an overview of experimental data from gavage studies in rats, in which reflux was observed, and provides a comprehensive analysis of the literature on reflux in general and the different potential pathways contributing to gavage-related reflux in rats. The article aims to increase the awareness and understanding of the pathogenesis of gavage-related reflux and provides guidance on identification of potential risk factors, as well as interpretation of histological changes and their toxicological relevance. Furthermore, differentiation of reflux-induced effects from direct compound-related toxicity and from gavage errors is addressed in particular, and the importance of nasal histology is discussed.
  Toxicologic Pathology 01/2011; 39(2):348-60. · 1.91 Impact Factor
• Article: Why I love metabolites in safety testing (MIST): a light-hearted historical perspective.

  Alfred Tonelli
  Bioanalysis 07/2009; 1(4):683-5. · 3.22 Impact Factor
• Source

  Available from: Subrahmanyam Vangala

  Article: Biomarkers, metabonomics, and drug development: can inborn errors of metabolism help in understanding drug toxicity?

  Subrahmanyam Vangala, Alfred Tonelli
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  ABSTRACT: Application of "omics" technology during drug discovery and development is rapidly evolving. This review evaluates the current status and future role of "metabonomics" as a tool in the drug development process to reduce the safety-related attrition rates and bridge the gaps between preclinical and clinical, and clinical and market. Particularly, the review looks at the knowledge gap between the pharmaceutical industry and pediatric hospitals, where metabonomics has been successfully applied to screen and treat newborn babies with inborn errors of metabolism. An attempt has been made to relate the clinical pathology associated with inborn errors of metabolism with those of drug-induced pathology. It is proposed that extending the metabonomic biomarkers used in pediatric hospitals, as "advanced clinical chemistry" for preclinical and clinical drug development, is immediately warranted for better safety assessment of drug candidates. The latest advances in mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy should help replace the traditional approaches of laboratory clinical chemistry and move the safety evaluation of drug candidates into the new millennium.
  The AAPS Journal 02/2007; 9(3):E284-97. · 5.09 Impact Factor