Spyros Deftereos

Literature mining, ontologies and information visualization for drug repurposing

The immense growth of MEDLINE coupled with the realization that a vast amount of biomedical knowledge is recorded in free-text format, has led to the appearance of a large number of literature mining techniques aiming to extract biomedical terms and their inter-relations from the scientific literature. Ontologies have been extensively utilized in the biomedical domain either as controlled vocabularies or to provide the framework for mapping relations between concepts in biology and medicine. Literature-based approaches and ontologies have been used in the past for the purpose of hypothesis generation in connection with drug discovery. Here, we review the application of literature mining and ontology modeling and traversal to the area of drug repurposing (DR). In recent years, DR has emerged as a noteworthy alternative to the traditional drug development process, in response to the decreased productivity of the biopharmaceutical industry. Thus, systematic approaches to DR have been developed, involving a variety of in silico, genomic and high-throughput screening technologies. Attempts to integrate literature mining with other types of data arising from the use of these technologies as well as visualization tools assisting in the discovery of novel associations between existing drugs and new indications will also be presented.

Drug repurposing and adverse event prediction using high-throughput literature analysis.

Drug repurposing is the process of using existing drugs in indications other than the ones they were originally designed for. It is an area of significant recent activity due to the mounting costs of traditional drug development and scarcity of new chemical entities brought to the market by bio‐pharmaceutical companies. By selecting drugs that already satisfy basic toxicity, ADME and related criteria, drug repurposing promises to deliver significant value at reduced cost and in dramatically shorter time frames than is normally the case for the drug development process. The same process that results in drug repurposing can also be used for the prediction of adverse events of known or novel drugs. The analytics method is based on the description of the mechanism of action of a drug, which is then compared to the molecular mechanisms underlying all known adverse events. This review will focus on those approaches to drug repurposing and adverse event prediction that are based on the biomedical literature. Such approaches typically begin with an analysis of the literature and aim to reveal indirect relationships among seemingly unconnected biomedical entities such as genes, signaling pathways, physiological processes, and diseases. Networks of associations of these entities allow the uncovering of the molecular mechanisms underlying a disease, better understanding of the biological effects of a drug and the evaluation of its benefit/risk profile. In silico results can be tested in relevant cellular and animal models and, eventually, in clinical trials. WIREs Syst Biol Med 2011 3 323–334 DOI: 10.1002/wsbm.147

Reversal of heart failure in thalassemia major by combined chelation therapy: a case report

Abstract:  In patients with thalassemia major (TM) who are non‐compliant with long‐term desferrioxamine (DFO) chelation, survival is limited mainly because of cardiac complications of transfusional hemosiderosis. Combined chelation therapy with DFO and deferiprone has maximized the efficacy of the therapy and reduced cardiological complications. The aim of this report is to present the results of this combination in a desperate case of heart failure.

From depression to neurodegeneration and heart failure: re-examining the potential of MAO inhibitors

Initially introduced in the 1950s for treating depression, monoamine oxidase (MAO) inhibitors were gradually abandoned, mainly owing to their potential for drug–drug and drug–food interactions, the most widely known being with tyramine-containing food (the ‘cheese’ effect). Since then, more selective MAO-A or MAO-B inhibitors have been developed with substantially reduced risks, and have been approved for the treatment of depression and Parkinson’s disease, respectively. Recent research suggests that some of these drugs also have neuroprotective properties, while preclinical evidence expands the spectrum of potential indications to heart failure, renal diseases and multiple sclerosis. In this article, the authors review the relevance of MAO isoforms to disease, and they also outline current research and development efforts in this class of drugs, including newer multipotent compounds.

Hypothyroidism Is a Risk Factor for New-Onset Diabetes: A Cohort Study

OBJECTIVE To identify risk factors for the development of statin-associated diabetes mellitus (DM). RESEARCH DESIGN AND METHODS The study was conducted in two phases. Phase one involved high-throughput in silico processing of a large amount of biomedical data to identify risk factors for the development of statin-associated DM. In phase two, the most prominent risk factor identified was confirmed in an observational cohort study at Clalit, the largest health care organization in Israel. Time-dependent Poisson regression multivariable models were performed to assess rate ratios (RRs) with 95% CIs for DM occurrence. RESULTS A total of 39,263 statin nonusers were matched by propensity score to 20,334 highly compliant statin initiators in 2004–2005 and followed until the end of 2010. Within 59,597 statin users and nonusers in a multivariable model, hypothyroidism and subclinical hypothyroidism carried an increased risk for DM (RR 1.53 [95% CI 1.31–1.79] and 1.75 [1.40–2.18], respectively). Hypothyroidism increased DM risk irrespective of statin treatment (RR 2.06 [1.42–2.99] and 1.66 [1.05–2.64] in statin users and nonusers, respectively). Subclinical hypothyroidism risk for DM was prominent only upon statin use (RR 1.94 [1.13–3.34] and 1.20 [0.52–2.75] in statin users and nonusers, respectively). Patients with hypothyroidism treated with thyroid hormone replacement therapy were not at increased risk for DM. CONCLUSIONS Hypothyroidism is a risk factor for DM. Subclinical hypothyroidism-associated risk for DM is prominent only upon statin use. Identifying and treating hypothyroidism and subclinical hypothyroidism might reduce DM risk. Future clinical studies are needed to confirm the findings.

Hypocalcemic heart failure in thalassemic patients.

Hypocalcemic cardiomyopathy in primary or secondary hypoparathyroidism is usually refractory to conventional treatment of cardiac failure. We report the case of a thalassemic patient with severe cardiac failure that might have been attributed to several factors, such as hemosiderosis, hypomagnesemia, and hypocalcemia, refractory to conventional cardiac therapy. Cardiac echocardiography showed impaired biventricular performance, and laboratory analyses revealed hypoparathyroidism due to hemosiderosis. When concomitant treatment of heart failure and calcium supplementation was initiated, correction of hypocalcemia resulted in clinical and laboratory improvement, providing strong evidence in support of our hypothesis about hypocalcemic myocardiopathy.

Intensive Chelation Therapy in β-Thalassemia and Possible Adverse Cardiac Effects of Desferrioxamine

Combination chelation therapy with desferrioxamine and deferiprone has recently been suggested as a more effective tissue iron—chelating treatment for transfusion-dependent β-thalassemia patients, although a standard dosage protocol has not yet been established. We describe a thalassemia major patient who had been treated with combination therapy with desferrioxamine and deferiprone and who was referred to us for faintness and dizziness associated with electrocardiographic ST-T changes and arrhythmia. A brief interruption of the treatment and a subsequent decrease in the drug doses caused the reversion of symptoms and findings. This response prompted us to speculate that a causal relationship existed between the observed abnormalities and the intensive chelation therapy. The possibility of this electrical instability as an adverse cardiac event occurring in the context of treatment with these chelating agents raises questions about the time of application of this therapy, the regimen dosages, and follow-up of such patients.

Does Heterozygous β-Thalassemia Confer a Protection against Coronary Artery Disease?

Abstract: Six hundred and thirty‐eight patients who presented with clinical symptoms and/or electrocardiographic findings suggestive of stable angina pectoris were studied; they were also investigated by coronary arteriography. Hemoglobin electrophoresis was performed on all patients to detect the presence of the β‐thalassemia trait. Results were analyzed by logistic regression analysis to determine whether the latter confers any protective effect against advanced coronary artery disease (aCAD; defined as the presence of atheromas in coronary arteries, resulting in stenosis at least 70%). WeThe role of the currently accepted risk factors (smoking, hypertension, hypercholesterolemia, and diabetes) in developing aCAD were reconfirmed, while at the same time it was found that β‐thalassemia heterozygosity is associated with a reduced risk against aCAD (odds ratio 0.39, 95% confidence interval 0.16‐0.98). The lipoprotein and blood rheology profile of these individuals may be the underlying causes of this protective effect.

Unstable angina associated with coronary arterial calcification in a thalassemia intermedia patient with a pseudoxanthoma elasticum‐like syndrome

Abstract: The coexistence of a pseudoxanthoma elasticum (PXE)‐like syndrome in β‐thalassemia and other hemoglobinopathies is a recently established clinical entity that has been observed with a significant frequency and related to some severe, even life‐threatening complications. We present here a thalassemia intermedia patient who developed unstable angina in a setting of severe anemia and PXE‐related coronary arterial calcification. Besides the clinical significance of this PXE‐like syndrome, its acquired nature may introduce some new thoughts regarding the pathogenesis of atherosclerosis.

The patient with rhabdomyolysis: Have you considered quail poisoning?

THE CASES Patient 1: A 62-year-old woman was admitted with nausea, vomiting, weakness and leg muscle pain. The symptoms had begun 7 hours after a meal of fresh roasted quail. She was not taking any medications, had no allergies to food or medications and did not use alcohol, cigarettes or illicit