Pharmacogenomics in cardiovascular disorders: Steps in approaching personalized medicine in cardiovascular medicine

Christopher Barone, Shaymaa S Mousa, Shaker A MousaThe Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USAAbstract: Some of the most commonly prescribed medications are those for cardiovascular maladies. The beneficial effects of these medications have been well documented. However, there can be substantial variation in response to these medications among patients, which may be due to genetic variation. For this reason pharmacogenomic studies are emerging across all aspects of cardiovascular medicine. The goal of pharmacogenomics is to tailor treatment to an individual’s genetic makeup in order to improve the benefit-to-risk ratio. This review examines the potential pharmacogenomic parameters which may lead to a future of personalized medicine. For example, it has been found that patients with CYP2C9 and VKORC1 gene variations have a different response to warfarin. Other studies looking at β-blockers, ACE inhibitors, ARBs, diuretics and statins have shown some results linking genetic variations to pharmacologic response. However these studies have not impacted clinical use yet, unlike warfarin findings, as the small retrospective studies need to be followed up by larger prospective studies for definitive results.Keywords: cardiovascular, pharmacogenomics, genetics, cardiovascular medicine, personalized medicine, polymorphis

Polycystic ovary syndrome and its impact on women’s quality of life: More than just an endocrine disorder

In the past, polycystic ovary syndrome has been looked at primarily as an endocrine disorder. Studies now show that polycystic ovary syndrome is a metabolic, hormonal, and psychosocial disorder that impacts a patient’s quality of life. It is extremely important to holistically treat these patients early on to help them deal with the emotional stress that is often overlooked with polycystic ovary syndrome. Early diagnosis and long term management can help control polycystic ovary syndrome so that women can still live a healthy active life and avoid long-term complications such as metabolic syndrome and cardiovascular diseases

Tetraiodothyroacetic acid (Tetrac) and nanoparticulate tetrac arrest growth of medullary carcinoma of the thyroid

Context: Tetraiodothyroacetic acid (tetrac) blocks angiogenic and tumor cell proliferation actions of thyroid hormone initiated at the cell surface hormone receptor on integrin alpha v beta 3. Tetrac also inhibits angiogenesis initiated by vascular endothelial growth factor and basic fibroblast growth factor. Objective: We tested antiangiogenic and antiproliferative efficacy of tetrac and tetrac nanoparticles (tetrac NP) against human medullary thyroid carcinoma (h-MTC) implants in the chick chorioallantoic membrane (CAM) and h-MTC xenografts in the nude mouse. Design: h-MTCcells were implanted in the CAM model (n = 8 per group); effects of tetrac and tetrac NP at 1 mu g/CAM were determined on tumor angiogenesis and tumor growth after 8 d. h-MTC cells were also implanted sc in nude mice (n = 6 animals per group), and actions on established tumor growth of unmodified tetrac and tetrac NP ip were determined. Results: In the CAM, tetrac and tetrac NP inhibited tumor growth and tumor-associated angiogenesis. In the nude mouse xenograft model, established 450-500 mm(3) h-MTC tumors were reduced in size over 21 d by both tetrac formulations to less than the initial cell mass (100 mm(3)). Tumor tissue hemoglobin content of xenografts decreased by 66% over the course of administration of each drug. RNA microarray and quantitative real-time PCR of tumor cell mRNAs revealed that both tetrac formulations significantly induced antiangiogenic thrombospondin 1 and apoptosis activator gene expression. Conclusions: Acting via a cell surface receptor, tetrac and tetrac NP inhibit growth of h-MTC cells and associated angiogenesis in CAM and mouse xenograft models.Charitable Leadership Foundation/Medical Technology Acceleration ProgramPharmaceutical Research Institute of Albany College of Pharmac

Pharmacogenomics in osteoporosis: Steps toward personalized medicine

Robert Greene1, Shaymaa S Mousa, Mohamed Ardawi2, Mohamed Qari2, Shaker A Mousa11The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; 2Center of Excellence in Osteoporosis Research, King Abdul Aziz University, Jeddah, Saudi ArabiaAbstract: Osteoporosis is a complicated and preventable disease with major morbidity complications that affects millions of people. In the last 15 years, there have been numerous studies and research in the new fields of pharmacogenetics and pharmacogenomics related to osteoporosis. Numerous “candidate genes” have been identified and have been found to be associated with osteoporosis as well as the treatment of osteoporosis. Many studies have found conflicting results on different polymorphisms and whether or not they are related to bone mineral density and osteoporosis. There is a need for larger and better designed pharmacogenomic studies related to osteoporosis incorporating a greater variety of candidate genes. The evaluation of osteoporosis and fracture risk is moving from a risk stratification approach to a more individualized approach, in which an individual’s absolute risk of fracture is evaluable as a constellation of the individual’s environmental exposure and genetic makeup. Therefore, the identification of gene variants associated with osteoporosis phenotypes or response to therapy might help individualize the prognosis, treatment, and prevention of fracture. This review focuses on major candidate genes and what needs to be done to take the genetics of osteoporosis and incorporate them into the pharmacogenomics of the management of osteoporosis.Keywords: pharmacogenomics, osteoporosis, VDR, ER-alpha, CYP19 Gene, LRP5, COLIA1, polymorphisms, genetic

Tetraiodothyroacetic acid and tetraiodothyroacetic acid nanoparticle effectively inhibit the growth of human follicular thyroid cell carcinoma

Background: Tetraiodothyroacetic acid (tetrac) is a deaminated analogue of L-thyroxine that blocks the actions of L-thyroxine and 3,5,3'-triiodo-L-thyronine at the cell surface receptor for thyroid hormone on integrin alpha v beta 3. Tetrac blocks the proliferative effects of thyroid hormone on tumor cells and the proangiogenesis actions of the hormone. In the absence of thyroid hormone, tetrac also blocks angiogenesis induced by various growth factors. Covalently linked to poly(lactide-co-glycolide), tetrac nanoparticles (tetrac NP) do not gain access to the cell interior and act exclusively at the integrin receptor. Here, the activity of tetrac and tetrac NP against follicular thyroid carcinoma (FTC)-236 cells was studied in two models: (1) tumor cell implants in the chick chorioallantoic membrane (CAM) system and (2) xenografts in the nude mouse. Methods: FTC-236 cells (10(6)) were implanted in the CAM (n = 8 each for control, and for tetrac and tetrac NP, both at 1 mu g/CAM) and the actions of tetrac and tetrac NP were determined after 8 days on tumor-related angiogenesis and tumor growth. Xenografts of 10(7) FTC-236 cells were implanted in nude mice (n = 8 per group). Tetrac or tetrac NP was administered intraperitoneal (1 mg/kg and 1 mg tetrac equivalent/kg, respectively) every other day for 32 days beginning on day 10, when tumor volume was 200-250 mm(3). Animals were monitored after discontinuation of treatment up to day 40. Results: In the CAM paradigm, tetrac and tetrac NP arrested tumor-related angiogenesis and tumor growth. In the xenograft model, tetrac and tetrac NP promptly and progressively reduced tumor volume (p < 0.01) over 32 days. There was some regrowth of tumor after interruption of tetrac treatment, but at day 40, tumor volume and tumor weight at sacrifice were 45-55% below those of controls (p < 0.01). Animal weight gain was comparable in the control and treatment groups of animals. Conclusions: Tetrac and tetrac NP effectively arrest FTC-236 cell tumor growth in the CAM and xenograft models, suggesting its potential utility against FTC

Correction: Block et al. Fluorinated Analogs of Organosulfur Compounds from Garlic (<i>Allium sativum</i>): Synthesis, Chemistry and Anti-Angiogenesis and Antithrombotic Studies. <i>Molecules</i> 2017, <i>22</i>, 2081

In the original publication [...

Fluorinated Analogs of Organosulfur Compounds from Garlic (Allium sativum): Synthesis, Chemistry and Anti-Angiogenesis and Antithrombotic Studies

We describe the synthesis, reactivity, and antithrombotic and anti-angiogenesis activity of difluoroallicin (S-(2-fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate) and S-2-fluoro-2-propenyl-l-cysteine, both easily prepared from commercially available 3-chloro-2-fluoroprop-1-ene, as well as the synthesis of 1,2-bis(2-fluoroallyl)disulfane, 5-fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin, trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoroallyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane), and a bis(2-fluoroallyl)polysulfane mixture. All tested organosulfur compounds demonstrated effective inhibition of either FGF or VEG-mediated angiogenesis (anti-angiogenesis activity) in the chick chorioallantoic membrane (CAM) or the mouse Matrigel® models. No embryo mortality was observed. Difluoroallicin demonstrated greater inhibition (p &lt; 0.01) versus organosulfur compounds tested. Difluoroallicin demonstrated dose-dependent inhibition of angiogenesis in the mouse Matrigel® model, with maximal inhibition at 0.01 mg/implant. Allicin and difluoroallicin showed an effective antiplatelet effect in suppressing platelet aggregation compared to other organosulfur compounds tested. In platelet/fibrin clotting (anti-coagulant activity), difluoroallicin showed concentration-dependent inhibition of clot strength compared to allicin and the other organosulfur compounds tested