Current Medicinal Chemistry - Volume 14, Issue 13, 2007

N-BP, rapamycin and its derivatives have been originally developed respectively as anti-resorptive and anti-fungal agents. In fact, in vitro and in vivo experiments demonstrated that these compounds are multi-functional molecules exerting their effects on tumour cell growth and bone remodelling. The major challenge in treating cancer relates to mutations in key genes such as p53, Rb or proteins affecting caspase signalling carried by many tumour cells. Whether nitrogen containing bisphosphonates (N-BP) are potent bone inhibitors, they also inhibit tumour cell proliferation and increase atypical apoptosis of bone tumour cells regardless of the p53 and Rb status. N-BP may be then considered as effective therapeutic agents in clinical trials of bone tumours. Rapamycin and its derivatives inhibit mTOR dependent mRNA translation both in osteoclasts and tumour cells. Cellular physiological mechanisms regulated by mTOR integrate many environmental parameters including growth factors, hormones, cytokines, amino acids, energy availability and cellular stresses that are coupled with cell cycle progression and cell growth. Rapamycin and its derivatives as well as N-BP must be considered as bi-(multi) functional molecules affecting simultaneously bone and tumour metabolisms. The present survey describes these two molecular families and discusses their therapeutic interests for primary bone tumours and bone metastases.

Immunosenescence is characterized by a peculiar remodeling of the immune system, mainly induced by lifelong antigenic burden and oxidative stress. Apoptosis or programmed cell death plays a central role in the ageing process. Both recurrent antigenic stimulations and oxidative metabolism by-products, impinging upon the immune system, modify the apoptotic capability of lymphocytes, driving immunosenescence. The apoptosis remodeling, in addition to inflamm-ageing, i.e. the upregulation of anti-stress responses and inflammatory cytokines, represents one of the major determinants of ageing rate and longevity, as well as of the most common age-related diseases. The cells of the immune system undergo two different kinds of apoptotic processes: activation-induced cell death (AICD), geared towards the elimination of unnecessary lymphocytes following clonal expansion, and damage-induced cell death (DICD), particularly important for preventing the onset of neoplastic proliferations. During senescence these apoptotic pathways are differentially modulated, with variable impacts on the ageing process. A correct modulation of apoptosis may be useful for prolonging the lifespan or at least reducing age-related degenerative, inflammatory and neoplastic diseases whose incidence increases with age. This review focuses on the role of AICD and DICD dysfunction in the ageing process and highlights emerging anti-ageing therapeutical strategies offered by apoptosis re-modulation. The challenge for the future is to identify factors and signals that regulate apoptotic processes and determine if selective apoptosis manipulation in specific lymphocyte subsets could preserve immune function in the elderly, contributing to successful ageing.

Growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is not only involved in the regulation of somatic growth but also has important physiological functions in adults. Several studies have shown that GH deficiency in adults is associated with abnormalities in body composition, metabolic derangements, and suboptimal physical performance. Furthermore, GH/IGF-I axis plays an important role in the maintenance of heart structure and function. Until recently, GH therapy was only used to treat short stature children, with or without established GH deficiency, and it remains common practice to discontinue GH replacement therapy when final height is achieved. Acromegaly, entity characterized by GH hypersecretion, is associated with an increased risk of premature death. Cardiac complications are known to be major determinants of the shortened life expectancy. Treatment of acromegaly accounts for a substantial decrease in morbidity and mortality. Surgery, radiation therapy and bromocriptine have only been able to reduce GH levels to normal levels in 10-30% of patients. The synthesis of somatostatin analogs has provided a new approach to acromegaly treatment. These drugs reduce GH and IGF-I levels in 80% of cases and normalize them in 40-60% of cases. Finally, GH/IGF-I system improves left ventricular systolic function and has also indirect effects on the cardiovascular system, mainly as a consequence of the peripheral vasodilatation. These effects are important in the understanding of the potential role of GH on improving ventricular systolic dysfunction and point to the use of GH as a potential therapy for chronic heart failure. The aim of the present review is to provide an update overview describing the role of GH on acromegaly, adult GH deficiency and heart failure, as well as the influence of GH-based therapy on heart structure and function.

Cardiovascular disease remains the most common cause of death worldwide, yet there is a wide variation in disease prevalence between different ethnic groups. One's individual risk is not entirely explained by ‘traditional’ risk factors and this, along with the observation that endogenous and lifestyle risk factors appear to cluster in the same individuals has led to the idea that there may be a common mechanism underlying this disease. It has been postulated that inflammatory pathways may be important. Results from our own and other studies have demonstrated that there may be ethnic differences in the level of circulating inflammatory markers which may be partially related to demographic, lifestyle or genetic factors. Before it is possible to add inflammatory markers to global risk scores it is imperative that a clear understanding of their function, normal range and major determinants in different ethnic groups is established. To date the ethnic research in this area has been very sparse and further work is urgently required. The usefulness of these inflammatory markers in the diagnosis and prognosis of disease in these different populations also needs to be investigated before therapeutic strategies can be fully developed.

The field of diagnostic cardiac biomarkers has grown exponentially since the development of an assay for aspartate transaminase activity to diagnose myocardial infarction in 1954. The clinician now has a vast array of clinical tools, which include biomarkers of inflammation, ischaemia and necrosis as well as sensitive imaging technology and coronary anatomy intervention at their disposal when evaluating acute coronary syndromes. Previously the World Health Organisation (1979) defined a myocardial infarction (MI) in the presence of two of the following triad: History of chest pain, electrocardiographic (ECG) changes and a rise in cardiac enzymes to twice the upper limit of normal. At this time, creatine kinase and its MB isoenzyme were the preferred biochemical markers. The clinical requirements of early diagnosis, risk stratification and effective treatment have stimulated the development of numerous new and cardiac specific biomarkers (e.g. cardiac troponins). Cardiac troponins are now integral to the diagnosis of MI and have led to the reclassification of MI into either ST elevated MI (STEMI) or non-ST elevated MI (NSTEMI). Subsequent to the release of each new cardiac specific assay there typically follows an array of studies supporting or refuting its efficacy. Many cardiac biomarkers originally proposed with high sensitivity and specificity for ACS are now of questionable clinical value or require the addition of significant caveats once they have been fully evaluated. Indeed, acute exercise often stimulates perturbations in cardiac biomarkers; such as elevations in creatine kinase, cardiac troponins or reductions in Ischemia Modified Albumin (IMA®). Such an influence of exercise upon commercially available cardiac biomarkers may hamper or distort the viability of such assays in the clinical arena. The purpose of this review is to examine the influence of exercise upon a number of established and novel cardiac biomarkers, including markers of necrosis, inflammation, cardiac function and ischemia. We will also address the clinical relevance of such exercise-induced perturbations.

Calcium-activated potassium channels modulate calcium signaling cascades and membrane potential in both excitable and non-excitable cells. In this article we will review the physiological properties, the structure activity relationships of the existing peptide and small molecule modulators and the therapeutic importance of the three small-conductance channels KCa2.1- KCa2.3 (a.k.a. SK1-SK3) and the intermediate-conductance channel KCa3.1 (a.k.a. IKCa1). The apamin-sensitive KCa2 channels contribute to the medium afterhyperpolarization and are crucial regulators of neuronal excitability. Based on behavioral studies with apamin and on observations made in several transgenic mouse models, KCa2 channels have been proposed as targets for the treatment of ataxia, epilepsy, memory disorders and possibly schizophrenia and Parkinson's disease. In contrast, KCa3.1 channels are found in lymphocytes, erythrocytes, fibroblasts, proliferating vascular smooth muscle cells, vascular endothelium and intestinal and airway epithelia and are therefore regarded as targets for various diseases involving these tissues. Since two classes of potent and selective small molecule KCa3.1 blocker, triarylmethanes and cyclohexadienes, have been identified, several of these postulates have already been validated in animal models. The triarylmethane ICA-17043 is currently in phase III clinical trials for sickle cell anemia while another triarylmethane, TRAM-34, has been shown to prevent vascular restenosis in rats and experimental autoimmune encephalomyelitis in mice. Experiments showing that a cyclohexadiene KCa3.1 blocker reduces infarct volume in a rat subdural hematoma model further suggest KCa3.1 as a target for the treatment of traumatic and possibly ischemic brain injury. Taken together KCa2 and KCa3.1 channels constitute attractive new targets for several diseases that currently have no effective therapies.

This review collates and analyses recent work done on dual action approaches to tackling the mounting health problem of resistance by human pathogenic bacteria to antibacterial agents. In particular the areas reviewed include the use of two drugs in combination, dual action prodrugs, and dual action drugs (or hybrid drugs)

On undergoing an operation under general anesthesia, we tend to lose consciousness, and on recovering from the anesthetic effect, we realize a memory loss during the operation, but do remember the happenings before the operation. It implies that the anesthesia deprivers us of short-term memory without affecting long-term memory. Drosophila melanogaster is known to be an excellent model for genetic studies related to general anesthesia and memory. The various mutants in the genes related to general anesthesia and memory have been found to influence these mechanisms at the molecular level. In Drosophila, learning and memory are classified into four distinct phases: (1) short-term memory (STM), (2) middle-term memory (MTM), (3) longer-lasting anesthesia-resistant memory (ARM), and (4) long-term memory (LTM). On the other hand, based on the genetic studies of the putative target molecules of general anesthetics in model animals, the anesthetic action is classified into five pathways: (1) presynaptic pathway including action potential production, its transmission, and neurotransmitter release; (2) postsynaptic pathway including inhibitory receptors for sleep and pain; (3) memory pathway coupled with cAMP/PKA signaling; (4) adhesion pathway in neuron; and (5) energy production pathway. Memory and adhesion pathways of the anesthetic action are developed in the Drosophila melanogaster model. Many mutants of general anesthesia and those of memory are overlapped suggesting that common molecules and signal pathways are involved in both phenomena. In this review, we will describe the relation between anesthesia and memory, especially highlighting the interaction between the general anesthetics and STM and MTM processes in Drosophila, especially concentrating on the cAMP/PKA signaling and molecular adhesion pathways.