Daniel Crona

University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

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Publications (10)25.57 Total impact

  • Daniel J. Crona, Young E. Whang
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    ABSTRACT: Posterior reversible encephalopathy syndrome (PRES) is a clinical/radiological syndrome characterized by symptoms that can include seizure, headache, impaired vision and hypertension, and can be confirmed by magnetic resonance imaging. Numerous reports have emerged that describe PRES in cancer patients. The list of medications linked to PRES can include traditional cytotoxic chemotherapeutics (e.g., cisplatin, cyclophosphamide, and high-dose corticosteroids), newer agents that target the vascular endothelial growth factor pathway (e.g., bevacizumab, sunitinib, and pazopanib), and supportive care mediations (e.g., granulocyte colony stimulating factors and erythropoietin). We report, for the first time, a case of PRES that is secondary to treatment with enzalutamide, a potent androgen receptor antagonist used in the treatment of metastatic castration-resistant prostate cancer. Enzalutamide is approved for the treatment of both docetaxel-pretreated and chemotherapy-naïve metastatic castration-resistant prostate cancer. Enzalutamide has been previously linked to the increased risk of seizures. Clinicians should be aware that, in rare cases, patients treated with enzalutamide could potentially be at risk for PRES. If symptoms suggestive of PRES arise in patients receiving enzalutamide, the drug should be discontinued immediately and the diagnostic process should be initiated.
    Investigational New Drugs 12/2014; · 3.50 Impact Factor
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    ABSTRACT: Purpose:Identify and summarize articles that describe the value that pharmacy residency training offers to sponsoring health systems.Summary:There is a tremendous gap between the number of resident applicants and the number of pharmacy residencies available. Informing health-system administration executives about the proven value of residency training is key to expanding the number of available positions. To address this disparity, a comprehensive and systematic literature search to identify publications highlighting the value that pharmacy residency training provides to the sponsor hospital or health system was conducted. Articles were identified through query of PubMed and SciVerse SCOPUS and through review of bibliographies from relevant articles. Twenty articles were identified and summarized in this annotated bibliography that demonstrate perceived and quantitative value of pharmacy residency training for health systems that sponsor residency training.Conclusion:Pharmacy residency training programs are essential for pharmacists that will primarily engage in direct patient care activities. This annotated bibliography includes key publications that provide evidence of the value that pharmacy residents provide to the sponsoring health system. This manuscript will aid prospective residency directors interested in developing new residency positions at new institutions or for residency program directors interested in expanding the total number of resident positions available at the existing sites.
    Journal of Pharmacy Practice 03/2014;
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    ABSTRACT: To review currently available literature on the oral multikinase inhibitor regorafenib and its role in the treatment of metastatic colorectal cancer (mCRC), and imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GISTs). A comprehensive literature search was performed of PubMed/MEDLINE and American Society of Clinical Oncology (ASCO) abstracts (through August 2013). Preclinical pharmacological and phase I to III trials data analyzing regorafenib efficacy and safety in mCRC or imatinib- and sunitinib-resistant GIST patients were evaluated. All available English-language, peer-reviewed articles and ASCO abstracts with relevant information were reviewed. Regorafenib was approved for mCRC in September 2012 and for imatinib- and sunitinib-resistant GISTs in February 2013. Regorafenib is an inhibitor of stromal, angiogenic, and oncogenic receptor tyrosine kinases, as well as the RAF/MEK/ERK signaling pathway. Phase III CORRECT (Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer) trial data demonstrated an overall survival benefit for mCRC patients treated with regorafenib (6.4 vs 5.0 months; P = .0052). Phase III GRID (Gastrointestinal Stromal Tumors After Failure of Imatinib and Sunitinib) trial data revealed a progression-free survival benefit in imatinib- and sunitinib-resistant GIST patients (4.8 vs 0.9 months; P < .0001). Its adverse event (AE) profile is comparable to that of other multikinase inhibitors. The most commonly observed grade ≥3 AEs included hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue. Regorafenib is a novel oral multikinase inhibitor that has shown promising results for patients with advanced, unresectable or metastatic treatment-refractory CRCs or imatinib- and sunitinib-resistant GISTs.
    Annals of Pharmacotherapy 11/2013; · 2.92 Impact Factor
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    20th Annual Southeast SAS Users Group Conference; 10/2012
  • Daniel Crona, Federico Innocenti
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    ABSTRACT: The systemic treatment of cancer with traditional cytotoxic chemotherapeutic agents and more targeted agents is often complicated by the onset of adverse drug reactions. Pharmacogenetic prediction of adverse drug reactions might have consequences for dosing and efficacy. This review discusses relevant examples where the germline variant-toxicity relationship has been validated as an initial step in developing clinically useful pharmacogenetic markers and provides examples where germline variants have influenced dosing strategies and/or survival or other outcomes of efficacy. This review will also provide insight into the reasons why more pharmacogenetic markers have not been routinely integrated into clinical practice.
    Biomarkers in Medicine 06/2012; 6(3):349-62. · 3.22 Impact Factor
  • Daniel Crona, Robert MacLaren
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    ABSTRACT: Altered concentrations of ghrelin, motilin, and cholecystokinin (CCK) may contribute to gastric hypomotility. The aims of this study were to evaluate the concentrations of these hormones in patients tolerant and intolerant to gastric nutrition, assess the influence of prokinetic therapy on these hormone concentrations, determine the associations between these mediators and gastric emptying, and evaluate whether inflammation influences their concentrations. Post hoc analyses of 2 prospective studies that enrolled 20 critically ill patients with an aspirated gastric residual (GR) >150 mL while receiving gastric enteral nutrition (intolerant group) and 10 critically ill patients with minimal GR (tolerant group). Patients with intolerance were also assessed 1 day after prokinetic therapy. Fasting serum concentrations of total ghrelin, acyl ghrelin (active), des-acyl ghrelin (inactive), motilin, CCK, and tumor necrosis factor (TNF)-α were determined. Gastric emptying was assessed concurrently using the acetaminophen absorption method. Compared to the tolerant group, the intolerant group had higher total ghrelin (1324.8 ± 1204.6 vs 285.1 ± 132.5 pg/mL; P < .001), lower acyl ghrelin (70.5 ± 65.4 vs 208.5 ± 186.9 pg/mL; P < .05), and lower acyl ghrelin to des-acyl ghrelin ratio (1.11 ± 1.35 vs 3.47 ± 3.21 pg/mL; P < .05). Concentrations of other hormones and TNF-α were similar. Despite accelerated gastric emptying after prokinetic therapy, concentrations of all hormones and TNF-α were similar to baseline values. Hormone concentrations were not associated with gastric emptying or TNF-α. Patients intolerant to gastric nutrition generate less acyl ghrelin, which may contribute to gastric hypomotility. Intolerance is not associated with altered concentrations of other hormones. Hormone concentrations are not influenced by prokinetic therapy.
    Journal of Parenteral and Enteral Nutrition 07/2011; 36(2):189-96. · 2.49 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown. In vivo experiments were performed on adult mice with conditional endothelial-specific expression of the truncation mutation Bmpr2delx4+, with age-matched transactivator-only mice as controls. Phenotype was assessed by RVSP, counts of muscularized vessels and proliferating cells, and staining for thromboses, inflammatory cells, and apoptotic cells. The effects of BMPR2 knockdown in PMVEC by siRNA on rates of apoptosis were assessed. Affymetrix expression arrays were performed on PMVEC isolated and cultured from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2delx4+ or Bmpr2R899X mutation. Transgenic mice showed increased RVSP and corresponding muscularization of small vessels, with histologic alterations including thrombosis, increased inflammatory cells, increased proliferating cells, and a moderate increase in apoptotic cells. Expression arrays showed alterations in specific pathways consistent with the histologic changes. Bmpr2delx4+ and Bmpr2R899X mutations resulted in very similar alterations in proliferation, apoptosis, metabolism, and adhesion; Bmpr2delx4+ cells showed upregulation of platelet adhesion genes and cytokines not seen in Bmpr2R899X PMVEC. Bmpr2 mutation in PMVEC does not cause a loss of differentiation markers as was seen with Bmpr2 mutation in smooth muscle cells. Bmpr2 mutation in PMVEC in vivo may drive PAH through multiple, potentially independent, downstream mechanisms, including proliferation, apoptosis, inflammation, and thrombosis.
    Respiratory research 06/2011; 12:84. · 3.64 Impact Factor
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    ABSTRACT: While modulation of the serotonin transporter (5HTT) has shown to be a risk factor for pulmonary arterial hypertension for almost 40 years, there is a lack of in vivo data about the broad molecular effects of pulmonary inhibition of 5HTT. Previous studies have suggested effects on inflammation, proliferation, and vasoconstriction. The goal of this study was to determine which of these were supported by alterations in gene expression in serotonin transporter knockout mice. Eight week old normoxic mice with a 5-HTT knock-out (5HTT-/-) and their heterozygote(5HTT+/-) or wild-type(5HTT+/+) littermates had right ventricular systolic pressure(RVSP) assessed, lungs collected for RNA, pooled, and used in duplicate in Affymetrix array analysis. Representative genes were confirmed by quantitative RT-PCR and western blot. RVSP was normal in all groups. Only 124 genes were reliably changed between 5HTT-/- and 5HTT+/+ mice. More than half of these were either involved in inflammatory response or muscle function and organization; in addition, some matrix, heme oxygenase, developmental, and energy metabolism genes showed altered expression. Quantitative RT-PCR for examples from each major group confirmed changes seen by array, with an intermediate level in 5HTT +/- mice. These results for the first time show the in vivo effects of 5HTT knockout in lungs, and show that many of the downstream mechanisms suggested by cell culture and ex vivo experiments are also operational in vivo. This suggests that the effect of 5HTT on pulmonary vascular function arises from its impact on several systems, including vasoreactivity, proliferation, and immune function.
    BMC Pulmonary Medicine 06/2009; 9:19. · 2.76 Impact Factor
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    ABSTRACT: Familial pulmonary arterial hypertension (PAH) is associated with mutations in bone morphogenetic protein type II receptor (BMPR2). Many of these mutations occur in the BMPR2 tail domain, leaving the SMAD functions intact. To determine the in vivo consequences of BMPR2 tail domain mutation, we created a smooth muscle-specific doxycycline-inducible BMPR2 mutation with an arginine to termination mutation at amino acid 899. When these SM22-rtTA x TetO(7)-BMPR2(R899X) mice had transgene induced for 9 wk, starting at 4 wk of age, they universally developed pulmonary vascular pruning as assessed by fluorescent microangiography. Approximately one-third of the time, the induced animals developed elevated right ventricular systolic pressures (RVSP), associated with extensive pruning, muscularization of small pulmonary vessels, and development of large structural pulmonary vascular changes. These lesions included large numbers of macrophages and T cells in their adventitial compartment as well as CD133-positive cells in the lumen. Small vessels filled with CD45-positive and sometimes CD3-positive cells were a common feature in all SM22-rtTA x TetO(7)-BMPR2(R899X) mice. Gene array experiments show changes in stress response, muscle organization and function, proliferation, and apoptosis and developmental pathways before RVSP increases. Our results show that the primary phenotypic result of BMPR2 tail domain mutation in smooth muscle is pulmonary vascular pruning leading to elevated RVSP, associated with early dysregulation in multiple pathways with clear relevance to PAH. This model should be useful to the research community in examining early molecular and physical events in the development of PAH and as a platform to validate potential treatments.
    AJP Lung Cellular and Molecular Physiology 09/2008; 295(5):L744-55. · 3.52 Impact Factor
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    ABSTRACT: Idiopathic pulmonary arterial hypertension (IPAH) in human patients is associated with mutations in type 2 receptor for the bone morphogenic protein pathway (BMPR2). Mice expressing an inducible dominant negative form of BMPR2 in smooth muscle develop elevated right ventricular pressures when the transgene is activated. We hypothesized that transcriptional changes in these mice may allow insight into the early molecular events leading to IPAH. Microarray analysis was used to examine the transcriptional changes induced in whole lung by loss of normal smooth muscle cell (SMC) BMPR2 signaling in adult male or female mice (12 wk at time of death) expressing the transgene for either 1 or 8 wk. Our key results include a decrease in markers of smooth muscle differentiation, an increase in cytokines and markers of immune response, particularly in female mice, and a decrease in angiogenesis-related genes. These broad patterns of gene expression appear as early as 1 wk and are well established by 8 wk. Results were confirmed by quantitative RT-PCR to RNA from individual mice. Primary pulmonary artery SMC cultures transfected with small interfering RNA to BMPR2 also show loss of SMC markers myosin heavy chain 11 and calponin by quantitative RT-PCR and Western blot. These studies show classes of genes differentially regulated in response to loss of BMPR2 in SMC in vivo with clear relevance to the IPAH disease process, suggesting that the relevance of BMPR2 dysregulation may extend beyond proliferation.
    AJP Lung Cellular and Molecular Physiology 07/2007; 292(6):L1556-63. · 3.52 Impact Factor

Publication Stats

125 Citations
25.57 Total Impact Points


  • 2011–2012
    • University of North Carolina at Chapel Hill
      • Institute of Pharmacogenomics and Individualized Therapy
      Chapel Hill, NC, United States
    • Vanderbilt University
      • Division of Allergy, Pulmonary and Critical Care
      Nashville, MI, United States