Current Medicinal Chemistry - Volume 18, Issue 23, 2011

Following their introduction in the late 1980's cardiac troponins (cTn) have become a “cornerstone” within the diagnosis and management of acute coronary syndrome (ACS) [1]. Since the initial introduction of cTn assays many manufacturers have improved the sensitivity of their assays, which in turn has lead to a reduction in the recognized clinical cut-offs for ACS. The ongoing development of high sensitive assays in an attempt to further improve the analytical performance provides significant challenge within the clinical/laboratory setting. The first paper in this special edition by Gaze [2] provides insight into some of the issues associated with the assessment and interpretation of cTn data in relation to both currently available assays, and also future potential developments. Although cTn release has become synonymous with cardiac damage it is important to note that not all release of cTn is related to acute myocardial infarction (AMI). Indeed, a number of other secondary-ischemic and non-ischemic conditions have been identified that also result in cTn release, all of which are associated with poor patient prognosis [2]. Exercise, and specifically prolonged exercise is presently the only known stimulus for cTn release that does not appear to be related to poor outcome. In order to demonstrate and to characterize the various exercise stimuli that result in cTn release Williams et al. [3] and Nie et al. [4] present original data from two very different exercise studies. These studies show that exercise cTn release is not only restricted to highly trained endurance athletes following ultra-endurance exercise, but can also occur in adolescents completing moderate duration exercise. These data build on previous work demonstrating cTn release following as little as 30 minutes of exercise [5]. The fact that relatively short duration activity elicits a post-exercise release of cTn, coupled with the manufacturers' drive to increase assay sensitivity means that there is increasing potential for a significant elevation in the false-positive diagnosis of ACS. The risk of falsepositives is increased further as it is well known that exercise is a potent trigger for ACS [6], accordingly a real threat exists for clinical confusion if hospital admission is preceded by strenuous exercise [7]. Using a case-study approach in the last paper of this special edition, Eijsvogels et al. [8] highlight a number of real-life situations that may result in clinical dilemma and offer practical advice on how patients presenting with elevations in cTn following a bout of exercise may be clinically managed.

Cardiac troponins (cTn) are considered to be the ‘gold standard’ biomarker for the diagnosis of acute coronary syndrome (ACS); a pathological spectrum which includes cardiac ischemia, angina, myocardial infarction and ultimately cardiac failure. The growing evidence base for the diagnostic and prognostic use of cTn in ACS has resulted in a universal redefinition of acute myocardial infarction (AMI). Recently a number of immunoassays with claims of superior sensitivity have been produced. The analytical and clinical performance of these assays require appropriate evaluation. Sensitive assays can be used for diagnosis in the first few hours after an ischemic episode. Early elevations in cTn are prognostic. A single time point for cTn testing may be useful for rule out, however such a strategy does not detect the rising and falling pattern required for diagnosis as suggested in the universal definition of AMI. The newer assays demonstrate low level cTn positivity in apparently healthy people. In addition, the sensitive assays detect more cTn positive patients who do not have a final diagnosis of ACS. It is unknown if such mild elevations in cTn detected by sensitive assays are of clinical concern. What is certain is that AMI remains a clinical not a biochemical diagnosis and interpretation of cTn concentrations should be made according to the clinical context. This review highlights the development of the sensitive assays, documents their analytical and clinical performance and reviews the usefulness of cTn elevation in non-ACS conditions.

Prolonged strenuous exercise is associated with the appearance of biomarkers of cardiac cell damage and a decline in cardiac function during recovery. Few studies have assessed repeated bouts of prolonged exercise and whether this results in further biomarker accumulation and greater dysfunction. Further, it may be useful to describe the changes in a range of biomarkers that may provide additional insight into the clinical significance of cardiac biomarker release. Four highly trained cyclists completed the 4800 km Race Across America (RAAM) in 7 days. Venous blood samples and echocardiograms were taken prior to, every 24 hours during and immediately after the RAAM. Venous blood was analysed for cardiac troponin I (cTnI), creatine kinase MB (CK-MB), fatty acid binding protein (HFABP), glycogen phosphorylase BB (GPBB) and N-Terminal Brain Natriuretic Peptide (NTproBNP). Echocardiograms allowed analysis of septal, left ventricular free wall and right ventricular free wall tissue velocities during systole and diastole. Before the RAAM cTnI levels were below the assay detection level (0.02 ng.ml-1). In three riders cTnI peaked on day one (0.03 ng.ml-1) and returned below detection levels post race. In the 4th rider cTnI peaked on day 5 (0.08 ng.ml-1) and was still elevated post-race. Both CK-MB and H-FABP were increased during the RAAM in all 4 cyclists. In three riders H-FABP peaked on day one (3.49 to 5.09 ng.ml-1) and declined over the rest of the RAAM. In the final rider H-FABP peaked on day two (5.90 ng.ml-1) and then dropped back to baseline by the post-RAAM assessment. Interestingly, changes in H-FABP mirrored, temporally, changes in CK-MB in places and this may reflect an association with skeletal muscle damage. Data for GPBB value to (2.9 - 149.6 ng.ml-1) and NTproBNP value to (27.3 - 310.0 ng.L-1) were variable but again was elevated in all riders during the course of the RAAM. Changes in ventricular wall tissue velocities were minor and not cumulative. Peak atrial diastolic tissue velocity in the left ventricular free wall increased (P < 0.05) from 11 to 18 cm.s-1 over the last two race days but this did not significantly impact the ratio of early to late diastolic wall motion. Cardiac biomarkers were elevated during the completion of the RAAM in all 4 cyclist but changes were not cumulative which suggest that the hearts of the cyclists coped well with the extreme cardiac work demanded by this ultra-endurance exercise challenge.

Objectives: Post-exercise cardiac troponin T (cTnT) release has been widely reported in adult athletes but limited data is available for adolescents. The aim of this study was to determine the incidence and magnitude of cTnT appearance in a large group of adolescent runners, and to determine any association between cTnT release and personal characteristics of adolescents. Methods: We recruited 63 adolescent runners (mean±SD: age 16.4±1.5 years; 10 females) who all completed a simulated half-marathon race (an all-out 21-km run) during routine training. Personal data collected included age, training history, 21-km run performance as well as pre-post exercise serum cTnT levels. Serum cTnT was assayed using a 3rd generation assay. Results: At pre-exercise, cTnT concentrations were below the 0.01 μg/L cTnT detection limit of assay in 58/63 runners. The post-exercise cTnT level (range: <0.01-1.36 μg/L) was significantly (p<0.001) greater than that of the pre-exercise (range: <0.01-0.02 μg/L). After the exercise, 57 (90%) and 44 (70%) subjects had cTnT concentrations above the detection: 0.01, and clinical thresholds: 0.05 μg/L, respectively. Post-exercise cTnT was inversely correlated with training years (r=-0.25, p<0.05) and age (r=-0.31, p<0.05). Compared with runners who had trained for ≥ 3 years, runners with less training experience demonstrated increased post-race cTnT levels (p<0.01). Conclusion: cTnT increases are virtually universal among adolescent runners following a 21-km run during routine training and can reach levels typically diagnostic for acute myocardial infarction potentially initiating diagnostic dilemmas. Adolescents with less training experience had higher post-exercise cTnT.

Exercise training represents a successful and powerful strategy to prevent future cardiovascular disease. Paradoxically, performance of exercise is also associated with an increased risk of acute cardiac events. Accordingly, patients may present to hospital with cardiac symptoms following a bout of unaccustomed physical effort (e.g. exercise). Current guidelines for the identification of an acute myocardial infarction (AMI) importantly depend on the presence of cardiac troponin as a highly sensitive marker of cardiac damage. However, a number of studies have reported elevated cardiac troponin levels in asymptomatic, healthy subjects after endurance exercise (such as a marathon, prolonged cycling or prolonged walking). These observations indicate that elevated cardiac troponin levels can be the result of cardiac ischemia, and subsequent necrosis, but also may be related to strenuous exercise. In this paper, we present three different clinical cases of post-exercise elevations in cardiac troponins, each with a distinct clinical presentation. These case studies emphasize that a detailed assessment of all symptoms and a thorough patient-history are prerequisite for accurate interpretation of a positive cardiac troponin test following exercise.

Malignancy-associated hypercalcemia (MAH) is one of the clinical emergencies in medical oncology, arising early or, more often, during the late phases of disease. Prevalence cannot be estimated accurately because previous figures of 5-30% of all cancer patients have progressively reduced thanks to the widespread use of bisphosphonates for the prevention of skeletal events. The classic distinction of humoral vs. osteolytic hypercalcemia is still relevant from an etiological point of view, but should not be considered as a rigid alternative since both mechanisms may be active in the same patients and the activation of the RANKL pathway is a common pathogenetic mechanism. Parathyroid hormone-related protein mimics the effects of PTH on the bone and kidney (tubular calcium resorption) and may represent an attractive druggable target, but additional agents (cytokines or other mediators) as well as ectopic production of 1,25(OH)2D3 may give an important contribution to humoral hypercalcemia. Conversely, bone invasion by cancer cells determines massive bone reabsorption due to the release of proteolytic enzymes and pro-osteolytic agents with paracrine activity on adjacent bone and stromal cells. When cancer patients develop headache, confusion, de-hydration and tremors hypercalcemia should be suspected although slow rise of calcium levels may produce more indolent symptoms. Bisphosphonates (with or without hydration and diuretics) may efficiently control MAH but only if an active treatment for the underlying cancer is promptly started. The anti-RANKL monoclonal antibody denosumab represents a novel agent able to revert the vicious cycle of bone metastases and data from phase III studies are currently showing promising activity in reverting bone resorption with manageable toxicity.

Botulinum toxin (BoNT) has been increasingly used in the interventional treatment of several disorders; the use of this agent has extended to a plethora of conditions including focal dystonia, spasticity, inappropriate contraction in most gastrointestinal sphincters, eye movement disorders, hyperhidrosis, genitourinary disorders and aesthetically undesirable hyperfunctional facial lines. In addition, BoNT is being investigated for the control of pain, and for the management of tension or migraine headaches and myofascial pain syndrome. Benign prostatic hyperplasia (BPH) is a common condition in ageing men; the goal of therapy is to reduce the lower urinary tract symptoms (LUTS) associated with BPH and to improve the quality of life. However, medical treatment, including drugs that relax smooth muscle within the prostate and drugs that shrink the gland are not totally effective or without complications. The standard surgical treatment for BPH is progressively changing to minimally invasive therapies, but none of them has provided clear results. The use of BoNT-A to inhibit the autonomic efferent effects on prostate growth and contraction, and inhibit the abnormal afferent effects on prostate sensation, might be an alternative treatment for BPH. BoNT injections have several advantages over drugs and surgical therapies in the management of intractable or chronic disease; systemic pharmacologic effects are rare, permanent destruction of tissue does not occur, and graded degrees of relaxation may be achieved by varying the dose injected. In this paper, clinical experience over the last years with BoNT in BPH impaired patients will be illustrated.

The apoptotic phenomena observed in tissues which are subdued to ischemia and then to technical therapeutics of perfusion keep causing serious problems in the patient's clinical recovery. Then, they constitute a challenge to resolve. The objective of this work is to discuss the intracellular mechanisms that lead cells to apoptosis during the ischemia-reperfusion process, taking into consideration that these phenomena are observable in a simple microorganism as the yeast Saccharomyces cerevisiae. Yeast provide an alternative study system in which the effects of certain cytoprotective drugs can be evaluated. The results can then be extrapolated to other types of cells. Several works have focused on the role of mitochondria in the apoptotic processes of cellular necrosis. One of the main factors responsible for this process is the unregulated opening of the permeability barrier. The inner membrane thus allows the unrestricted passage of ions and the release of apoptotic mediators from the inner membrane space towards the cytosol. Also, there is an increase in the level of reactive oxygen species (ROS) and the uncoupling of oxidative phosphorylation, which lead to the reversal of ATP synthesis to ATP hydrolysis. The driving cause of this complex process is the opening of an non-specific pore located in the mitochondrial membrane, denominated mammalian permeability transition pore (mPTP), which is also expressed in yeast (yPTP). From the functional point of view, the yeast pore presents some of the characteristics observed in mammals, and is similar in the defensive response against the deleterious mechanisms caused by oxidative stress. An increasing body of evidence supports the concept that the pharmacological inhibition of the mPTP is an actual and promising strategy for the protection of tissues in ischemic situations in order to avoid the damage induced by perfusion.

Hypercalcemia is a relatively common clinical problem, mainly (>90%) related to primary hyperparathyroidism (HPT) and malignancies. The anatomical and functional imaging techniques available for locating enlarged parathyroid glands include ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine imaging techniques. The most commonly employed are US and parathyroid scintigraphy, while CT, MRI, positron emission tomography (PET)/CT, and selective venous sampling are generally used in patients with persistent or recurrent HPT, or when findings of non-invasive studies are negative or conflicting. The reported accuracy is 57-93%, 54-93%, and up to 95% for US, 99mTc-sestamibi scintigraphy, and the two modalities combined, respectively. A multimodality approach (x-ray, whole-body scintigraphy, CT, MRI, and PET) is usually recommended for whole body assessment in cases of cancer-induced hypercalcemia (CIH). Imaging studies should evaluate each organ (i.e. breast, kidney, prostate, parathyroid) potentially involved in the pathogenesis of hypercalcemia in patients with CIH. In cases of skeletal metastases, when findings on plain x-ray or bone scans are uncertain, any unexplained region of abnormal uptake should be examined by MRI and/or 18F-fluoro-2- deoxyglucose (FDG)-PET/CT, which has proved more accurate than classical bone scintigraphy, especially for dealing with hematologic malignancies. A number of radionuclide tracers, other than 18F-FDG, are available for use in selected cases to locate specific tumors (i.e. 68Ga for neuroendocrine tumors). This is a review of recently published information on the imaging techniques currently available for patients with hypercalcemia.

Traditional nonsteroidal anti-inflammatory drugs, tNSAIDs, are effective medication for prevention of ischemic events and treatment of pain, fever and inflammation. However their use associates with a significant risk to develop gastrointestinal and cardiovascular complications. Low doses of acetyl salicylic acid (ASA) and effective doses of tNSAIDs associate with a 2-6 fold increase in the risk of gastrointestinal bleeding. ASA and tNSAIDs inhibit cyclooxygenases (COXs). The COX exists at least in two isoforms, COX-1 and COX-2. Selective inhibitors of COX-2, the coxibs, spares the gastrointestinal tract while exert anti-inflammatory and analgesic effects. However, coxibs increase the risk of thrombo-embolic events. Nitric oxide (NO) and hydrogen sulfide (H2S), are potent vasodilatory agents that maintain mucosal integrity in the gastrointestinal tract. Hybrid molecules generated by coupling a NO or H2S releasing moiety to ASA or tNSAIDs has resulted into new classes of NSAIDs. These agents, the NO-releasing NSAIDs, or CINOD, and the H2Sreleasing NSAIDs are currently investigated as a potential alternative to tNSAIDs and coxibs. Naproxcinod has been the first, and so far the only, CINOD investigated in clinical trials. These studies have shown a slightly improvement in gastrointestinal tolerability in comparison to naproxen in surrogate endpoints (number of gastric and duodenal ulcers) and a significant reduction in the risk of destabilization of blood pressure control in patients with osteoarthosis taking anti-hypertensive medications in comparison to either naproxen and rofecoxib. The lack of outcome studies, however, has precluded the approval of naproxcinod by the Food and Drug Administration leading to a voluntary withdrawn of an application to the EMEA in May 2011. NSAIDs that releases H2S as a mechanism supporting an intrinsic gastrointestinal and cardiovascular safety are being investigated in preclinical models. Either naproxen and diclofenac hybrids have been reported to cause less gastrointestinal injury than parent NSAIDs. These novel chemical entities exert a variety of beneficial effects in rodent models of cardiovascular and metabolic disorders through a mechanism that might involve the release of H2S and/or by exerting anti-oxidant effects. The beneficial role these mechanisms in clinical settings await a proof-of-concept study

Renin-angiotensin II-aldosterone axis has long been known as a regulator of blood pressure and fluid homeostasis. Yet, local renin-angiotensin II systems have been discovered and novel actions of angiotensin II (AngII) have emerged among which its ability to act as a immunomodulator and profibrotic molecule. The enzyme responsible for its synthesis, Angiotensin-converting-enzyme (ACE), is present in high concentrations in lung tissue. In the present paper, we review data from studies of the past decade that implicate AngII and functional polymorphisms of the ACE gene that increase ACE activity with increased susceptibility for asthma and chronic obstructive pulmonary disease (COPD) and for pulmonary hypertension. Moreover, drugs that inhibit the synthesis of AngII (ACE inhibitors) or that antagonize its actions on its receptors (Angiotensin II receptor blockers -ARBs) have been shown to provide beneficial effects. Another recent discovery reviewed is the presence of a homologue of ACE, ACE2, which cleaves a single amino acid from AngII and forms a heptapeptide with vasodilatory actions, Ang 1-7. The balance between ACE and ACE2 is crucial for controlling AngII levels. ACE and ACE2 also appear to modify the severity of Acute Respiratory Distress Syndrome (ARDS), with ACE2 playing a protective role. Finally, mention is made to the recent discovery of ACE2 as a receptor for the SARS Corona Virus.

Quantum dot (QD) has been extensively investigated as a nanoprobe to replace conventional organic dyes due to its unique optical properties. However, nanotoxicity of QD greatly hampers its biomedical applications, particularly in in vivo imaging. It is critical to functionalize QD and/or composite QD with other functional materials for biocompatibility, multifunction and expanded applications. In this review, advances of QD-based nanocomposites are addressed with emphasis of their synthesis, fundamental understanding and applications in biosensor, multimodal imaging, drug delivery, diagnostics and cancer therapy. Some specific QD-based bionanosystems and future development directions are also discussed.

Calcium is essential for many metabolic process, including nerve function, muscle contraction, and blood clotting. The metabolic pathways that contribute to maintain serum calcium levels are bone remodeling processes, intestinal absorption and secretion, and renal handling, but hypercalcemia occurs when at least 2 of these 3 metabolic pathways are altered. Calcium metabolism mainly depends on the activity of parathyroid hormone (PTH). Its secretion is strictly controlled by the ionized serum calcium levels through a negative feed-back, which is achieved by the activation of calcium-sensing receptors (CaSRs) mainly expressed on the surface of the parathyroid cells. The PTH receptor in bone and kidney is now referred as PTHR1. The balance of PTH, calcitonin, and vitamin D has long been considered the main regulator of calcium metabolism, but the function of other actors, such as fibroblast growth factor-23 (FGF-23), Klotho, and TPRV5 should be considered. Primary hyperparathyroidism and malignancy are the most common causes of hypercalcemia, accounting for more than 90% of cases. Uncontrolled hypercalcemia may cause renal impairment, both temporary (alteration of renal tubular function) and progressive (relapsing nephrolithiasis), leading to a progressive loss of renal function, as well as severe bone diseases, and heart damages. Advances in the understanding of all actors of calcium homeostasis will be crucial, having several practical consequences in the treatment and prevention of hypercalcemia. This would allow to move from a support therapy, sometimes ineffective, to a specific and addressed therapy, especially in patients with chronic hypercalcemic conditions unsuitable for surgery.

Sialic acids are one of the important constituents of glycoconjugates in the deuterostome lineage of animals and microorganisms. Siglecs (Sialic acid-binding immunoglobulin like lectins) are a family of cell-surface receptor proteins that recognize sialylated glycoconjugates as ligands. To date, 15 Siglecs have been described in humans and are mainly known as regulators of the immune system. Several of the Siglecs are emerging as potential targets for the treatment of some inflammatory, autoimmune, allergic, neurodegenerative and infectious diseases. In addition to antibody mediated therapy, high-affinity ligand-based probes of Siglec receptors would represent invaluable tools to effectively address therapeutic opportunities of Sialic acid-mediated Siglec recognition. This review discusses some aspects of structure and function of Siglec receptors, and concisely summarizes up-to-date progress on the identification of sialic acid based high-affinity ligands of certain well explored Siglec receptors.

Discovery, isolation, characterisation and pre-clinical and clinical trials of plant- or animal-derived drugs displaying pharmacological activities continue to develop and enlarge. Cancer chemotherapy is one of the most promising areas for these drugs. Since a very long time, nature has been an attractive source of potential medicinal agents for human use. The deep sea is becoming a novel and potently appealing source for new drugs, as well as shallow waters. This interest is mainly related to the terrific chemical diversity found in the vast number of plants and animal species, as well as in the microbial world. During the evolution, a rich source of biologically active compounds is developed in the depths of the sea, often reflecting ecological adaptation. Most of them (toxins) are developed to allow survival and flourishing acting against predators and parasites. Recent progress in Scuba diving, hitech/biotechnological and procedural advances in structure clarification, organic synthesis and biological assay determined the characterisation and preclinical/clinical evaluation of novel anticancer drugs. The aim of this review is to provide a description of their discovery, mode of action and clinical application.

Neuropilins comprise two homologous widely-expressed single-pass plasma membrane receptors (Nrp1 and Nrp2), originally identified for binding secreted Semaphorins and Vascular Endothelial Growth Factors (in association with Plexins and VEGF-Receptors). Semaphorins have been implicated with opposite functions in cancer: either as putative tumor suppressors and anti-angiogenic factors, or mediating tumour angiogenesis, invasion and metastasis. Moreover, due to their implication in VEGF signaling, neuropilins regulate vascular development and tumor angiogenesis. Recent evidence further suggests a role of neuropilins in cancer progression due to their interaction with receptor tyrosine kinases, adhesion molecules, and integrins. Furthermore, neuropilins have been implicated in response to additional growth factors, such as Hepatocyte Growth Factor, Fibroblast Growth Factor, Transforming Growth Factor beta, Galectin, etc. Altogether, these data seem to qualify neuropilins as signaling platforms on the cell surface, potentially capable of regulating cancer cells, as well as cells of the tumor microenvironment. Intriguingly, clinical-pathological data often indicate a correlation between increased expression of neuropilins and advanced stage tumors with poor prognosis. In this article, we will review the current experimental evidence about the functional role of neuropilins in cancer and the underlying molecular mechanisms.

Benign prostatic hyperplasia (BPH) is a kind of common noncancerous prostate gland enlargement with growing tendency in recent years. 5α-reductase is the key enzyme responsible for dihydrotestosterone biosynthesis and has been considered as an important target for designing inhibitors as potent therapeutic agents for BPH. Finasteride, the first steroidal 5α-reductase inhibitor, has been marketed worldwide as a drug for BPH. During these years, many other novel types of 5α-reductase inhibitors are being studied. This review summarizes recent advancement in steroidal 5α-reductase inhibitors.

Chinese medicine has a long history of several thousand years. The main form of Traditional Chinese Medicine (TCM) is composite, i.e. a mixture of up to 10 medicinal products. Thus a composite prescription of 4-5 kinds of Chinese medicinal products may contain several hundred kinds of chemical composition. The active ingredients and clinical efficacy of which are difficult to characterize. We aim to review the Chinese literature of TCMs with neuroprotective effects. We illustrate with our study on Pien Tze Huang (PZH) the use of in vivo tests in the study of composite TCM. Our results show evidence that PZH might have neuropreventive effects in rats.