Application of pharmacogenomics for trauma and critical care patients: A case report.

BACKGROUND: Pharmacogenomics is increasingly becoming a valuable tool for improving health outcomes, reducing health care costs and avoiding adverse drug reactions. While application of pharmacogenomics is quite common in oncology and cardiology, routine use of this technology is rare in certain other fields including Trauma and Critical Care Surgery. We are testing feasibility of applying pharmacogenomic testing to improve therapeutic outcomes of trauma and acute care patients at MercyOne Medical Center in Des Moines, IA. METHODS: Trauma patients admitted to the hospital with projected stay of >5 days, or with admission extended due to failed multiple trials of medication volunteered to participate in this IRB-approved study. Effectiveness of medical therapy was evaluated using standard pain scores recorded prior to admission of any pain medication to conscious and competent patients. Pharmacogenomic results were obtained from commercial providers within 3-5 days and used to alter medical therapy as needed. RESULTS: An 18-year-old African American male, admitted for gunshot wounds to the neck, exhibited an ASIA A spinal cord injury, with no sensation or movement of his extremities, persistent nausea with emesis and a history of depression. He also developed gastritis with hematemesis. In addition to all standard trauma procedures, he received standard doses of tramadol, oxycodone or hydrocodone, ondansetron, citalopram, and intravenous protonix daily. He reported no pain relief. The patient's pharmacogenomic analysis revealed his ultrarapid and rapid genotype for CYP2D6 and CYP2C19 respectively, allowing us to choose dilaudid resulting in immediate improvement of his pain scores. Additionally, using metoclopramide, duloxetine and famotidine led to immediate improvement or complete resolution of symptoms. CONCLUSION: Pharmacogenomics testing is a useful tool for selecting appropriate pain management of trauma patients with expected hospital stay ≥5 days. Additionally, standard pharmacogenomic panels allow tailoring medical therapy to common conditions associated with traumatic injury.

Addition of Allopurinol for Altering Thiopurine Metabolism to Optimize Therapy in Patients with Inflammatory Bowel Disease.

Thiopurine drugs, including azathioprine and 6-mercaptopurine, are used commonly in patients with inflammatory bowel disease for maintenance of remission. Although generally well tolerated, adverse effects lead to discontinuation in a significant minority of patients. Pharmacogenomic studies have suggested that metabolic breakdown of azathioprine in an individual is genetically determined. Coupled with the fact that certain thiopurine metabolites, notably 6-thioguanine nucleotide and 6-methylmercaptopurine, are associated with antiinflammatory effects and adverse effects, respectively, some investigators have examined intentionally shunting the metabolism of azathioprine toward increasing 6-thioguanine nucleotide levels by using low doses of the xanthine oxidoreductase inhibitor allopurinol to improve efficacy and decrease toxicity of azathioprine in patients with inflammatory bowel disease. We performed a search of the MEDLINE and Embase databases for basic and clinical research reports of this modality. Pertinent articles were retrieved, reviewed, and assessed by the authors. Case series, cohort studies, and one randomized trial have investigated adding allopurinol to azathioprine therapy in patients with inflammatory bowel disease. Most reports primarily examined metabolite levels in these patients. In general, the literature suggests that this modality was successful at significantly increasing 6-thioguanine nucleotide levels while decreasing 6-methylmercaptopurine levels. Several small reports have suggested that patients with increased 6-thioguanine nucleotide levels had improved symptoms or symptom remission. Adverse effects and discontinuation rates remained similar or were improved in patients who were taking a thiopurine and started allopurinol. In conclusion, the addition of allopurinol may be an option for optimizing thiopurine metabolite production in select patients with low 6-thioguanine nucleotide levels. Appropriate care and monitoring of these patients are mandatory to prevent neutropenia or other adverse effects.

Recent Advances in Application of Pharmacogenomics for Biotherapeutics.

Biotherapeutics (BTs), one of the fastest growing classes of drug molecules, offer several advantages over the traditional small molecule pharmaceuticals because of their relatively high specificity, low off-target effects, and biocompatible metabolism, in addition to legal and logistic advantages. However, their clinical utility is limited, among other things, by their high immunogenic potential and/or variable therapeutic efficacy in different patient populations. Both of these issues, also commonly experienced with small molecule drugs, have been addressed effectively in a number of cases by the successful application of pharmacogenomic tools and approaches. In this introductory article of the special issue, we review the current state of application of pharmacogenomics to BTs and offer suggestions for further expansion of the field.

Clinical Trials of Poly(ADP-Ribose) Polymerase Inhibitors for Cancer Therapy: A Review.

Poly(ADP-Ribose) Polymerase (PARP) is a family of enzymes involved in DNA repair, genome stability, cellular energy metabolism and cell division. Inhibition of PARP-1, the well characterized member of this family, has been explored as a strategy for enhancing anti-cancer activity of existing drugs and for developing new drugs. Recently unique enzymatic properties and biological functions of PARP-2 and PARP-3 have been discovered, further expanding the utility of PARP as a target for cancer pharmacotherapy. We compare and contrast the structural and enzymatic properties of these three members of the PARP family. Interactions of these enzymes with proteins specific to different DNA repair pathways are summarized. Further, we evaluate progress on development of PARP inhibitors as anticancer agents. Results of Phase I and Phase II clinical trials of seven PARP inhibitors, used alone or in combination with known anticancer agents are reviewed highlighting common observations regarding the maximum tolerable dose, adverse reactions profile, PARP inhibition and anticancer effects. While further clinical studies are warranted, based on current data, Olaparib (Ola), Veliparib (Veli) and Rucaparib (Ruca) offer considerable potential. Prolonged exposure to Ola and Veli leads to resistant cancer cells, primarily through restoration of the HR pathway, overexpression of the P-glycoprotein efflux pump or modulation of PARP expression. Some resistant cancer cells continue to respond to platinum based drugs, encouraging further development of PARP inhibitors for cancer treatment. Future course of this research, specifically focusing on use of PARP inhibition as a strategy for personalized cancer therapy, is discussed.

Determinants of immunogenic response to protein therapeutics.

Protein therapeutics occupy a very significant position in the biopharmaceutical market. In addition to the preclinical, clinical and post marketing challenges common to other drugs, unwanted immunogenicity is known to affect efficacy and/or safety of most biotherapeutics. A standard set of immunogenicity risk factors are routinely used to inform monitoring strategies in clinical studies. A number of in-silico, in vivo and in vitro approaches have also been employed to predict immunogenicity of biotherapeutics, but with limited success. Emerging data also indicates the role of immune tolerance mechanisms and impact of several product-related factors on modulating host immune responses. Thus, a comprehensive discussion of the impact of innate and adaptive mechanisms and molecules involved in induction of host immune responses on immunogenicity of protein therapeutics is needed. A detailed understanding of these issues is essential in order to fully exploit the therapeutic potential of this class of drugs. This Roundtable Session was designed to provide a common platform for discussing basic immunobiological and pharmacological issues related to the role of biotherapeutic-associated risk factors, as well as host immune system in immunogenicity against protein therapeutics. The session included overview presentations from three speakers, followed by a panel discussion with audience participation.

Recombinant expression of maize nucleotide excision repair protein Rad23 in Escherichia coli.

Nucleotide excision is a highly conserved DNA repair pathway for correcting DNA lesions that cause distortion of the double helical structure. The protein heterodimer XPC-Rad23 is involved in recognition of and binding to such lesions. We have isolated full-length cDNAs encoding two different members of the maize Rad23 family. The deduced amino acid sequences of both maize orthologues show a high degree of homology to plant and animal Rad23 proteins. The cDNA encoding maize Rad23A was cloned as an in-frame C-terminal fusion of glutathione S-transferase. This chimera was expressed in Escherichia coli as a soluble protein and purified to homogeneity using glutathione-agarose followed by MonoQ column chromatography. Purified recombinant maize Rad23 protein was used to generate polyclonal antibodies that cross-react with a approximately 48-kDa protein in extracts from plant as well as mammalian cells. The purified recombinant protein and antibodies would be useful reagents to study the biochemistry of nucleotide excision repair in plants.