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Cardiovascular (CV) morbidity and mortality is high in patients with chronic kidney disease (CKD). Most patients reveal a high prevalence of CV risk factors such as diabetes or arterial hypertension and many have manifest cardiovascular disease (CVD), such as coronary artery disease and chronic heart failure with an increased risk of clinical events including sudden cardiac death. Diabetes mellitus and hypertension contribute to the development of CKD and the prevalence of CKD is in the range of 20–65% in diabetic and 30–50% in hypertensive patients. Therefore, prevention and optimal treatment of CV risk factors and comorbidities are key strategies to reduce CV risk and improve survival in CKD. Beyond common CV risk factors, patients with CKD are often physically inactive and have low physical function leading to subsequent frailty with muscle fatigue and weakness, sarcopenia and increased risk of falling. Consequently, the economic health burden of CKD is high, requiring feasible strategies to counteract this vicious cycle. Regular physical activity and exercise training (ET) have been shown to be effective in improving risk factors, reducing CVD and reducing frailty and falls. Nonetheless, combining ET and a healthy lifestyle with pharmacological treatment is not frequently applied in clinical practice. For that reason, this Clinical Consensus Statement reviews the current literature and provides evidence-based data regarding the role of ET in reducing CV and overall burden in patients with CKD. The aim is to increase awareness among cardiologists, nephrologists, and healthcare professionals of the potential of exercise therapy in order to encourage implementation of ET in clinical practice, eventually reducing CV risk and disease, as well as reducing frailty in patients with CKD G3–G5D.

An increasing number of economic evaluations are published annually investigating the economic effectiveness of pharmacogenomic (PGx) testing. This work was designed to provide a comprehensive summary of the available utility methods used in cost–effectiveness/cost–utility analysis studies of PGx interventions. A comprehensive review was conducted to identify economic analysis studies using a utility valuation method for PGx testing. A total of 82 studies met the inclusion criteria. A majority of studies were from the USA and used the EuroQol-5D questionnaire, as the utility valuation method. Cardiovascular disorders was the most studied therapeutic area while discrete-choice studies mainly focused on patients' willingness to undergo PGx testing. Future research in applying other methodologies in PGx economic evaluation studies would improve the current research environment and provide better results.

Remote digital health interventions to enhance physical activity provide a potential solution to improve the sedentary behaviour, physical inactivity, and poor health-related quality of life that are typical of chronic conditions, particularly for people with chronic kidney disease. However, there is a need for high-quality evidence to support implementation in clinical practice. The Kidney BEAM trial evaluated the clinical effect of a 12-week physical activity digital health intervention on health-related quality of life.

Background: Pharmacogenomics (PGx) constitutes an important part of personalized medicine and has several clinical applications. PGx role in clinical practice is known, however, it has not been widely adopted yet. In this study, we aim to investigate the perspectives of Greek physicians regarding the implementation of PGx testing in clinical practice and the key issues associated with it. Methods: Fourteen interviews were conducted with physicians of various specialties for which PGx applications are available. A semi-structured interview guide was utilized based on the Consolidated Framework for Implementation Research (CFIR) context and the Diffusion of Innovation model. Transcripts were coded independently and compared by two members of the research team. Descriptive statistics were generated using Microsoft Excel. Results: Six main themes emerged: awareness and use of PGx testing; source of information; key stakeholders of the PGx supply chain, their interactions and change agents; clinical benefit and significance of PGx testing; barriers and lack of reimbursement; and recommendations to boost the PGx adoption rate. Most respondents were aware of PGx applications, but only three had already recommended PGx testing. Peer-reviewed journals along with clinical guidelines were regarded as the most used source of information while stakeholders of the PGx supply chain were discussed. PGx was considered that promote patient-centered care, enhance medication clinical effectiveness, decrease the risk of side effects, and reduce healthcare costs. Lack of reimbursement, scarcity of resources, and high PGx cost were the foremost barriers affecting PGx adoption. Conclusions: It was concluded that if case PGx testing is reimbursed and physicians’ training is reinforced, PGx implementation will be boosted and improved shortly.

Chronic kidney disease (CKD) is a global health issue. Kidney failure patients may undergo a kidney transplantation (KTX) and prescribed an immunosuppressant medication i.e., tacrolimus. Tacrolimus’ efficacy and toxicity varies among patients. This study investigates the cost-utility of pharmacogenomics (PGx) guided tacrolimus treatment compared to the conventional approach in Austrian patients undergone KTX, participating in the PREPARE UPGx study. Treatment’s effectiveness was determined by mean survival, and utility values were based on a Visual Analog Scale score. Incremental Cost-Effectiveness Ratio was also calculated. PGx-guided treatment arm was found to be cost-effective, resulting in reduced cost (3902 euros less), 6% less hospitalization days and lower risk of adverse drug events compared to the control arm. The PGx-guided arm showed a mean 0.900 QALYs (95% CI: 0.862–0.936) versus 0.851 QALYs (95% CI: 0.814–0.885) in the other arm. In conclusion, PGx-guided tacrolimus treatment represents a cost-saving option in the Austrian healthcare setting.

Background: Cardiovascular diseases and especially Acute Coronary Syndrome (ACS) constitute a major health issue impacting millions of patients worldwide. Being a leading cause of death and hospital admissions in many European countries including Spain, it accounts for enormous amounts of healthcare expenditures for its management. Clopidogrel is one of the oldest antiplatelet medications used as standard of care in ACS. Methods: In this study, we performed an economic evaluation study to estimate whether a genome-guided clopidogrel treatment is cost-effective compared to conventional one in a large cohort of 243 individuals of Spanish origin suffering from ACS and treated with clopidogrel. Data were derived from the U-PGx PREPARE clinical trial. Effectiveness was measured as survival of individuals while study data on safety and efficacy, as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups. Results: Based on our findings, PGx-guided treatment group is cost-effective. PGx-guided treatment demonstrated to have 50% less hospital admissions, reduced emergency visits and almost 13% less ADRs compared to the non-PGx approach with mean QALY 1.07 (95% CI, 1.04–1.10) versus 1.06 (95% CI, 1.03–1.09) for the control group, while life years for both groups were 1.24 (95% CI, 1.20–1.26) and 1.23 (95% CI, 1.19–1.26), respectively. The mean total cost of PGx-guided treatment was 50% less expensive than conventional therapy with clopidogrel [€883 (95% UI, €316–€1582), compared to €1,755 (95% UI, €765–€2949)]. Conclusion: These findings suggest that PGx-guided clopidogrel treatment represents a cost-effective option for patients suffering from ACS in the Spanish healthcare setting.

Background: Pharmacists’ contribution to pharmacogenomics (PGx) implementation in clinical practice is vital, but a great proportion of them are not aware of PGx and its applications. This highlights the university education’s crucial role to prepare pharmacists to face future challenges in such a constantly evolving and demanding environment. Objectives: Our study aims to examine pharmacy students’ training satisfaction, knowledge, self-confidence and attitudes towards PGx on their intentions for postgraduate training in PGx and personalised medicine (PM). Methods: An initial model on students’ intention to pursue postgraduate training in PGx and PM and its predicting factors, based on the Theory of Planned Behaviour (TPB), was proposed. Based on it, a questionnaire was developed and distributed to 346 pharmacy students of all study years, capturing the selected factors influencing students’ intentions to postgraduate training in PGx and PM, as well as their demographics. Structural equation modelling (SEM) analysis was employed to determine the effects of both the examined factors and demographics on students’ intentions. Results: Students did not consider themselves adequately prepared for using PGx in clinical practice. Their attitudes towards PGx implementation were the most important factor influencing their intentions to pursue postgraduate training in PGx and PM. Other factors such as self-confidence and training satisfaction also affected students’ intentions, but to a lower extent. Students of the last two study years (40% of the whole sample) and male (36%) students stated to be less willing to pursue PGx-related studies in the future. Only 10% of the participants claimed to have undergone a recent PGx or genetic test, but this did not affect their intentions. Conclusion: There is an important gap in pharmacy school curriculum regarding PGx and PM training which coupled with the slow rate of PGx and PM implementation into clinical practice seems to restrain students’ aspiration to further expand their knowledge and horizons in terms of PGx and PM.

Background: There is an increasing interest worldwide in investigating healthcare stakeholders’ perceptions and intentions to adopt pharmacogenomics (PGx) into clinical practice. However, the existing inquiries based on well-established theories and models that interpret their intentions to implement PGx are scarce. This study is the first that examines the impact of selected factors on health science students’ intention to adopt genetic testing applications using the technology acceptance model while it compares two different cultural groups: Greeks (Europe; Christian) and Malays (Asia; Muslim). Results: Malay students were more persuaded about benefits of genomics for drug management compared to their Greek counterparts. However, participants from both countries appear to be particularly convinced about the benefits of genomics on disease management. Moreover, students from both countries considered the potential misuse of genetic information by corporate or government bodies as their most important concern; Greek students appeared to be considerably less worried than Malay about other probable hazards such as the deficient protection of privacy and confidentiality, which could be attributed to their religious background. Participants from both samples expressed very positive attitudes towards genetic research and testing and their favourable intentions to adopt genetic testing for personal use. Exploratory factors analysis and path analysis yielded quite similar results for both samples. Path analysis revealed that the factors of attitudes, concerns, drug management benefits and disease management benefits significantly influenced students’ intentions to adopt genetic testing for personal use, with attitudes being the most inspirational factor with rather high impact, while training did not seem to affect participant’s intentions. The squared multiple correlation of both models was quite satisfactory reaching to 0.55 for the Malaysian sample. Conclusion: Similarities in the results of the two groups along with the relevant validity and reliability tests indicate that the proposed model is a good fit for future studies to interpret stakeholders’ intentions to adopt genetic testing. Therefore, it can provide a promising and reliable basis for future model development to explain the relationships between intentions to adopt genetic testing and its predictors.

Cardiovascular disease remains the leading cause of death in kidney transplant recipients. This pilot study examined the potential effect of aerobic training or resistance training on vascular health and indexes of cardiovascular risk in kidney transplant recipients.

Exercise capacity, which is predictive of all-cause mortality and cardiovascular disease risk, is reduced significantly in patients with non–dialysis-dependent chronic kidney disease. This pilot study examined the effect of moderate-intensity exercise training on kidney function and indexes of cardiovascular risk in patients with progressive chronic kidney disease stages 3 to 4.

AbstractBackground:Patients with chronic kidney disease (CKD) have elevated cardiovascular disease (CVD) risk. Physical activity (PA) is a strong and independent CVD risk factor, and despite the fact that current clinical practice guidelines recommend simultaneous treatment of multiple risk factors for optimum management of CKD, PA is rarely addressed by renal care teams. The aim of this observational cross-sectional survey was to document current exercise/PA practices across renal units in the UK, and capture views and experiences regarding the provision of PA/exercise options for patients with CKD. Methods:An 18-item online survey questionnaire regarding exercise counselling practice patterns was administered to 565 multidisciplinary renal care professionals. Results:142 individuals (25 response rate) completed the questionnaire. Overall, 42 of respondents discussed and encouraged PA, but only 18 and 11 facilitated implementation of PA for their patients. Nephrologists (p < 0.003) were more likely to prescribe or recommend PA compared to professionals with a nursing background and believed that specific renal rehabilitation services, including an active PA/exercise component, should be available to all patients (p < 0.01). The most commonly reported barriers for the development and implementation of PA/exercise options included lack of funding, time, and knowledgeable personnel, such as physiotherapists or other exercise professionals. Conclusion:Beliefs and attitudes towards PA amongst members of the renal multidisciplinary team are encouraging. However there is a big gap between believing in the benefits of PA and promoting/implementing PA for patient benefit. This gap needs to be minimised by at least trying to address some of the reported barriers.© 2014 S. Karger AG, Basel

Introduction:Lipoic acid (LA), a naturally occurring 1,2-dithiolane analog that plays an essential role in mitochondrial bioenergetic reactions, has gained unprecedented attention as nutritional supplement and as therapeutic agent. Moreover, LA conjugates with other pharmacophores represent a promising approach toward the development of multifunctional drugs.Areas covered:The reviewed patent applications from January 2011 to April 2014 include combinations of LA with other bioactive compounds as well as LA conjugates for the treatment of a wide range of clinical conditions. Additionally, some patents disclose methods to overcome the stability problems of LA.Expert opinion:LA is currently in clinical use for the treatment of diabetic neuropathy, while small clinical trials using combinations of LA with known bioactive agents have been undertaken. The use of the LA is hampered by its instability and its rapid metabolism. Thus, formulations containing LA, in a form ensuring its stability and improving its bioavailability, can have important applications as medicines, nutritional supplements or cosmeceuticals. LA hybrids with other pharmacophores endowed with various activities, possess an enormous potential to promote human health and have been the subject of numerous publications and patent applications. Nevertheless, reliable in vivodata and clinical trials are necessary to prove these beneficial effects.

Several hundreds of studies published the last decade have reported that -lipoic acid (LA) possesses the potential to intervene in various therapeutically interesting pathways. However, it should be noted that LA reportedly exerts most of its effects at high micromolar concentrations; that amides of LA exhibit higher biological activity than the parent compound; and that molecular combinations (hybrids) obtained by coupling LA with an amino-substituted bioactive moiety, possess multifunctional activity. The design and synthesis of hybrid molecules encompassing two pharmacophores in one molecular scaffold is a well established approach to the synthesis of more potent drugs with dual activity. Using this approach, various research groups have recently designed and synthesized LA containing hybrid compounds with antioxidant activity hyphenated with a wide variety of other activities such as neuroprotective, cardioprotective, anti-inflammatory, antidiabetic and anticancer activity as well as enzyme inhibition. Moreover, LA represents an ideal chemical entity for the development of biologically interesting functionalized nanoparticles. Many recent publications describe the use of LA: i) as component of nanospheres and nanoprodrugs, ii) as a linker for the attachment of lipids, carbohydrates, proteins and oligonucleotides on gold nanoparticles to form Self Assembled Monolayers (SAMs) and iii) as surface ligand for cap exchange reactions to prepare water-soluble semiconducting nanocrystal Quantum Dots (QDs). This review is focused on the growing field of the design and synthesis of LA conjugates, for the development of novel molecules with a dual mode of action and the construction of nanosized antioxidants, Self Assembled Monolayers and Quantum Dots.

Although low and deteriorating physical function are increasingly recognized as key characteristics of CKD, assessment of physical function does not yet form part of the routine clinical monitoring of this patient group. This is somewhat surprising as measures of physical function, from across the entire functional measurement spectrum, have been shown to be related to clinically important outcomes (morbidity, quality of life and increasingly survival) in patients being treated for CKD. In order to promote a standardized approach to assessment of people with CKD, it is recommended that renal professionals adopt the physical function and measurement classification systems of the International Classification Framework of Functioning, Disability and Health. Selection of physical function assessment “tool(s)” is influenced by the intended goal of the assessment (e.g., clinical assessment, tracking of progress with physical activity, research purposes, diagnostic purposes), the personal characteristics of the patient, and also by the prevailing information quality requirements and potential operational constraints (e.g., measurement burden, patient inclusiveness/sample size, cost). As exercise tolerance, functional capacity, and functional status assessments have been shown to be safe, feasible, and clinically useful, it is recommended that their implementation be incorporated within clinical management protocols for the patient with CKD.

Indium−tin−oxynitride (ITON) films have been fabricated by rf sputtering from an indium−tin−oxide target in nitrogen plasma. The influence of postdeposition annealing up to 800 °C is analyzed by electrical, optical, and surface characterization of the films in comparison to indium−tin−oxide (ITO) films fabricated in argon plasma. High-temperature annealing resulted in ITO(N) films with similar carrier concentrations. However, the resistivity and optical transmittance of the ITON films were higher than those of the ITO films. Photoelectron spectroscopy revealed that nitrogen is incorporated into the ITON structure in an unbound state as well as through the formation of metal−nitrogen and oxynitride bonds that decorate oxygen vacancies. When the core level electron spectra of ITO and ITON films are compared, a correlation between carrier concentration and the incorporated nitrogen is found. Changes in ITON electrical properties are mainly induced by the release of nitrogen at temperatures above 550 °C. In this context, ohmic contact behavior was achieved for ITON on p-type GaN after annealing at 600 °C, while no ohmic contact could be realized using ITO.

Despite current optimal treatment, the morbidity and mortality of coronary heart disease remain significant worldwide and open the way for the development of novel cardioprotective therapies. In the last two decades, a remarkable scientific effort has focused on the limitation of infarct size. Important input from experimental studies has led the way in this direction. However, clinical and preclinical results using various cardioprotective strategies to attenuate reperfusion injury have generally not been applicable for every day clinical practice. Protection of the ischemic myocardium is known to occur as a result of ischemic preconditioning (PC), in which repetitive brief periods of ischemia protect the heart from a subsequent prolong ischemic insult. Although PC is a powerful form of protection, it is of limited clinical application for obvious ethical and practical reasons. Another endogenous form of cardioprotection, similar to PC but applicable at the time of reperfusion, termed postconditioning (PostC), has been recently described. Short series of repetitive cycles of brief reperfusion and re-occlusion of the coronary artery applied at the onset of reperfusion, reduce the infarct size and coronary artery endothelial dysfunction. At present, pharmacological PC and PostC are possible alternative methods that may substitute pharmaceutical treatments the short ischemic insults. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. We summarize the recent research efforts on novel therapeutic strategies and on the design of new compounds, based on the accumulated knowledge of the ligands, receptors and intracellular signaling pathways of PC and PostC.

Ischemic preconditioning (PC) and postconditioning (PostC) are endogenous mechanisms of protection of the ischemic heart. In brief, short cycles of sublethal ischemia separated by brief periods of reperfusion render the heart resistant to infarction from a subsequent lethal episode of prolonged ischemia. Although PC is a powerful form of protection, its clinical application is limited because of ethical and practical reasons. It is of interest that multiple very short periods of ischemia and reperfusion applied at the onset of reperfusion are also capable in limiting the infarct size. In fact, the short ischemic insults in PC have to be applied before the onset of sustained period of ischemia which cannot be precisely anticipated. On The contrary, the very brief insults in postconditioning (PostC) have to be applied immediately after the end of the long ischemia thus making the intervention more easily applicable. Both mechanisms reduce the infarct size by limiting the reperfusion injury. Pharmacological PC and PostC represent ideal alternatives that may substitute the short ischemic insults for pharmaceuticals means. The components of PC share two pathways, one that involves the mitochondrial KATP channels- free radicals and PKC and another one that involves adenosine and PKC. Reperfusion injury salvage kinases (RISK) prevent the mitochondrial permeability transition pores (mPTP) which destroy the mitochondria and cause cell death. PC via PKC and PostC via gradual restoration of pH at reperfusion up-regulate RISK and preserve viable part of the ischemic region of the heart. In order to confer pharmacological protection, novel therapeutic strategies, based on the knowledge of the ligands, of the receptors and of the intracellular signaling pathways have emerged. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. Furthermore, agents that increase RISK or directly prevent mPTP are also under investigation as PostC analogues. We summarize recent studies focused on the pharmacological interventions and on the discovery of novel agents that may reduce the infarct size.

Three series of chromans substituted at positions 2 or 5 by catechol derivatives were synthesized, and their activity against oxidative stress induced cellular damage was studied. Specifically, the ability of the new molecules to protect cultured cells from H2O2-induced DNA damage was evaluated using single cell gel electrophoresis (comet assay), while the neuroprotective activity of the new compounds against oxidative stress induced programmed cell death was studied using glutamate-challanged hippocampal HT22 cells. The majority of the new compounds are stronger neuroprotectants than quercetin. 5-Substituted chroman analogues such as the caffeic acid amides 12 and 16 and the dihydrostilbene analogue 24 were the most potent against both H2O2- and glutamate-induced damage in Jurkat T cells and HT22 cells, respectively.

The morphology of gastrocnemius muscles was examined in RFPs (renal failure patients) being treated using HD (haemodialysis) and CAPD (continuous ambulatory peritoneal dialysis). RFPs (n=24) volunteered to participate in the present study. Twelve RFPs (five women and seven men; mean age, 55 years) were undergoing CAPD treatment and 12 RFPs (two women and ten men; mean age, 62 years) were undergoing HD treatment. Muscle biopsies from gastrocnemius muscles were found not to differ (P>0.05) in fibre type distribution, MyHC (myosin heavy chain) expression or fibre CSA (cross-sectional area) between the two groups. There were, however, significant differences (P<0.05) in CC/F (capillary contact/fibre), C/F (capillary to fibre ratio) and cytochrome c oxidase activity. The HD group had 33% more CC/F, with a 19% higher C/F and 33% greater cytochrome c activity in glycolytic fibres (II) than the CAPD group. There were no apparent differences in age, gender, co-morbidity, self-reported physical activity or physical functioning between the two groups, which could account for the difference in muscle capillarity between the groups. The HD patients were, however, administered heparin as a routine part of the dialysis therapy. The possibility is discussed that heparin in combination with mild anaemia and acidosis may have augmented angiogenesis in the HD patients.

Control of AIDS requires development of special therapeutic strategies in order to reduce the level of monocyte / macrophage HIV infection, to prevent spread of HIV within the monocyte / macrophage reservoir, to maintain a therapeutically effective drug concentration in sanctuaries such as the brain and to overcome the problem of cellular resistance mechanisms. A popular approach towards this end has been the development of prodrugs of anti-HIV drugs. This review covers the different strategies devised for the design of prodrugs of anti-HIV agents with emphasis on the recent findings in this field of research. Thus, prodrugs of nucleoside reverse transcriptase inhibitors (NRTIs) including, 5-O carboxylic ester derivatives, 5-O- monophosphate analogues, macromolecular derivatives, prodrugs of purine nucleosides, prodrugs of acyclic nucleosides, homo and hetero dinucleotides, prodrugs of non-classical nucleoside analogues, boranophosphate triesters of NRTIs, and prodrugs of protease inhibitors including acyl-substituted prodrugs, prodrugs with increased water solubility, monophosphate prodrugs, and conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor through spontaneously cleavable linkers, constitute the subject of this review.

In the present study we investigated the effect of a 6-month aerobic exercise programme on the morphology of the gastrocnemius muscle of end-stage renal disease (ESRD) patients.

Three series of ring-substituted ether phospholipids were synthesized carrying N,N,N-trimethylammonium, N-methylpiperidino, or N-methylmorpholino headgroups. The first series is substituted by 2-cyclohexyloxyethyl or 2-(4-alkylidenecyclohexyloxy)ethyl groups, the second series by cyclohexylidenealkyl or adamantylidenealkyl moieties, and the third series by 2-aryloxyethyl or 6-aryloxyhexyl groups in the alkyl portion of the molecule. The antileishmanial activity of the new compounds was evaluated in vitro against the promastigote forms of L. donovani and L. infantum using an MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide)-based microassay as a marker of cell viability. Analogues 12, 15, 24, 30, 32, 41, 43, and 45 were more potent than the control compound miltefosine (hexadecylphosphocholine) against both L. donovani and L. infantum while, derivatives 13 and 42 were equipotent to miltefosine. Analogues 16, 17, 19, 20 were more potent than miltefosine against L. infantum and compounds 27, 31, 44 were more active than miltefosine against L. donovani. Differential scanning calorimetry (DSC) was used to probe the role of individual ether phospholipids on the physicochemical properties of model membranes. The DSC scans showed that the active compounds have a more profound effect on the thermotropic properties of model membrane bilayers than the less active ones.

KOUFAKI, P., P. F. NASH, and T. H. MERCER. Assessing the efficacy of exercise training in patients with chronic disease. Med. Sci. Sports Exerc., Vol. 34, No. 8, pp. 1234–1241, 2002.

A series of new compounds that contain lipoic acid and trolox connected through spacers were synthesized and examined for their antioxidant activity and their protective effects against reperfusion arrhythmias in isolated heart preparations. All compounds tested are strong inhibitors of lipid peroxidation in rat liver microsomal membranes induced by ferrous ions and ascorbate. N-(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carbonyl)-N‘-(1,2-dithiolane-3-pentanoyl)-1,2-phenylenediamine (13) exhibits anti-lipid peroxidation activity at the nanomolar range. N-(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carbonyl)-N‘-(1,2-dithiolane-3-pentanoyl)ethylenediamine (10) and 13 totally suppressed reperfusion arrhythmias.

Various radiotracers based on uracil nucleosides (e.g. [124I]2'-fluoro-2'-deoxy-5-iodo-1-β-D-arabinofuranosyluracil, [124I]FIAU) and acycloguanosine derivatives (e.g. [18F]9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine, [18F]FHPG) have been proposed for the non-invasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene expression. However, these radiotracers have been evaluated in different in vitro and in vivo models, precluding a direct comparison. Therefore, we directly compared [18F]FHPG and radioiodinated FIAU to assess their potential for PET imaging of transgene expression. The uptake of [125I]FIAU, [18F]FHPG and [3H]acyclovir was determined in vitro using four different HSV1-tkexpressing cell lines and their respective negative controls. The in vitro tracer uptake was generally low in non-transduced parental cell lines. In HSV1-tkexpressing cells, [3H]acyclovir showed approximately a twofold higher tracer accumulation, the [18F]FHPG uptake increased by about sixfold and the [125I]FIAU accumulation increased by about 28-fold after 120-min incubation of T1115 human glioblastoma cells. Similar results were found in the other cell lines. In addition, biodistribution and positron emission tomography (PET) studies with [18F]FHPG and [124/125I]FIAU were carried out in tumour-bearing BALB/c mice. Significantly higher specific accumulation of radioactivity was found for [125I]FIAU compared with [18F]FHPG. The ratio of specific tracer accumulation between [125I]FIAU and [18F]FHPG increased from 21 (30 min p.i.) to 119 (4 h p.i.). PET imaging, using [124I]FIAU, clearly visualised and delineated HSV1-tkexpressing tumours, whereas only a negligible uptake of [18F]FHPG was observed. This study demonstrated that in vitro and in vivo, the radioiodinated uracil nucleoside FIAU has a significantly higher specific accumulation than the acycloguanosine derivative [18F]FHPG. This suggests that [124I]FIAU should be the preferred reporter probe for PET imaging of HSV1-tkgene expression. Thus, further attempts to develop suitable PET tracers for the assessment of HSV1-tkgene expression should also focus on 18F-labelled uracil derivatives.

The 1-O-hexadecyl-2-O-methyl-sn-glyceryl phosphodiester AZT 4 and hexadecyl-phosphodiester AZT 5 derivatives were synthesized and found to be active against HIV-1, HIV-2, and tumor cell proliferation. Compared to AZT, compound 4 possessed ca. 10-fold lower anti-HIV activity and ca. 10-fold higher anti-tumor cell activity. Compound 5 was 10-fold less potent than compound 4 in both biological tests. In an attempt to correlate biological activity of compounds 4 and 5 with structure, their conformational and thermal effects on membrane bilayers were compared using a combination of NMR spectroscopy, computational analysis, and Differential Scanning Calorimetry. The obtained results showed that compound 4 adopts a compact conformation in which the alkyl chain, the 2-methoxyglyceryl functionality, and the methyl group of thymine are in spatial proximity, while analogue 5 possesses a less compact conformation of the nucleoside base and the alkyl chain. The presence of the 2-methoxyglyceryl group in compound 4 may augment its potency by inducing a turn of the alkyl chain stabilized by hydrophobic interactions. The DSC scans show that conjugate 4 affects less effectively the thermotropic properties of model membrane bilayers than compound 5. This may be attributed to the fact that compound 4 is incorporated in a compact conformation and does not perturb significantly the trans:gauche isomerization of the membrane phospholipids. In contrast, conjugate 5 may enter with a less compact conformation and perturb more the membrane bilayers.

Abstract: Because of the accomplishments in biotechnical research in the past few decades our knowledge about the molecular mechanisms of carcinogenesis has grown rapidly. Colorectal cancer has been one of the most intensively investigated tumor entities, and it seems to be well established that colorectal tumor growth is associated with an accumulation of acquired somatic mutational events in tumor suppressor genes and oncogenes. Recent progress in our understanding of the molecular basis of the most prevalent colorectal cancer syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), is reflected by modifications in diagnosis and therapy. Identification and characterization of the causative genes for these colorectal cancer syndromes have enabled precise presymptomatic detection of mutations in individuals who bear an a priori risk of about 50% of developing colorectal cancer. Genotype-phenotype correlations might further increase the clinical management of hereditary colorectal cancer. Even though developments in cancer research are restricted to the minority of individuals with hereditary cancer syndromes, growing knowledge about the effect of low penetrance variations in tumor suppressor genes may affect the diagnosis and therapy of sporadic colorectal cancer.

A series of new AZT conjugates with alkyl and oxyalkyl ether phospholipids was synthesized and evaluated for inhibitory activities against HIV-1 and HIV-2. The alkoxyethyl derivatives 6a-c proved 3- to 5-fold more active against HIV-1 and HIV-2 than the alkyl analogues 6d-f. A trend for higher activity with longer alkyl side-chains was observed. However, the analogues with the shortest chain possessed the most favourable therapeutic index.

A series of new ether lipid−3‘-azido-3‘-deoxythymidine (AZT) conjugates (11a−g) were synthesized and evaluated for anti-HIV activity. The effect of chirality on the antiviral activity was examined through the synthesis of AZT conjugates bearing alkoxypropanols in the lipid portion of the molecule (11a−d). In addition, the long alkyl chain of alkoxyethyl ether lipid−AZT analogs was replaced with aromatic groups (11e−g), and the effect of this structural modification on activity is reported. The results of the biological tests indicate that analogs with a methyl group α to the phosphate moiety (11c,d) exhibit a marked degree of stereoselectivity with regard to their anti-HIV activity. Also, replacement of the long alkyl chain with aromatic groups in the oxyalkyl ether phospholipid−AZT conjugates leads to substantially more potent compounds (11e−g) with an anti-HIV activity comparable to that of AZT.

Two series of phosphodiester ether lipid analogs with (N-methylmorpholino)ethyl or (N-methylpiperidino)ethyl polar head groups and long aliphatic or alkoxyethyl chains in the nonpolar portion of the molecule were synthesized as potential antineoplastic agents. The cytotoxic activity of these compounds (9−19) was evaluated in vitro against a panel of six human tumor xenografts and in two biochemical, mechanism-based screens (cdc2 kinase and cdc25 phosphatase). Analogs 13, 14, 17, and 19 showed activity in the in vitro tests. Specifically, 14 and 17 were more active than the reference compound hexadecylphosphocholine (Miltefosine, He-PC) while 13 and 19 possessed activity similar to that of the control. Of the analogs tested the one with the highest potency and least toxicity (17) has an N-methylpiperidino head group and a C16 alkyl chain. In the mechanism-based tests 11 showed weak inhibitory activity in the cdc25 phosphatase screen.

The article offers information on the statement from the British Association of Sport and Exercise Sciences (BASES) expert regarding the exercise therapy as treatment for people with chronic kidney disease (CKD). Topics include the risk factor of the physical inactivity for the progression of CKD, the effectiveness of exercise therapy as treatment for CKD such as no adverse effects and the benefits of regular physical activity to people with cardiovascular disease and diabetes.

The acquired immunodeficiency syndrome (AIDS) epidemic has led to an unprecedented scientific and clinical effort to understand the pathogenesis and develop strategies to combat this lethal disease. The causal agent of AIDS is a retrovirus, the human immunodeficiency virus (HIV), which was identified in 1983. Drug therapy for HIV / AIDS was initially focused on treating opportunistic infections and malignancies that often accompany HIV and increase mortality. Since then, a significant body of information about the HIV-1 life cycle was rapidly accumulated, resulting in the development of drugs that interfere with different steps of the HIV replication. The process of clinical evaluation has changed dramatically by compressing phase I, II and III studies and using laboratory markers, such as CD4 cell counts, as surrogate end points for disease progression and death. This was due to the large number of agents available for study as well as to the pressure placed by HIV epidemic on investigators, patients, regulators and pharmaceutical companies. A decrease in morbidity and mortality was observed after 1996, particularly as a result of combination therapy, comprising at least three anti-HIV drugs. However, poor and variable absorption, side effects and resistance, limit the effectiveness of these agents. Moreover recent studies show that the CNS and lymphatic tissue act as a sanctuary for HIV, rendering the virus less vulnerable to current antiviral treatment. Therefore, efforts are still necessary to develop novel effective therapeutic agents or prodrugs of known anti-HIV agents, as well as vaccines in order to achieve viral eradication. This issue of the Current Topics in Medicinal Chemistry, present the current state of knowledge of therapeutic strategies against HIV. Combating AIDS, involves concerted efforts from chemists, biologists and clinicians. The first review of this issue, by Jozsef Tozser (Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen Hungary), deals with HIV replicative cycle, beginning with the attachment of the virus to the host cell and finishing with the release of virions from the cell, identifying the potential targets for chemotherapeutic intervention. These targets include several events of the viral replication: attachment / penetration, reverse transcription and formation of preintegration complex, integration, transcription (transactivation), assembly of virus, budding and maturation. Brian Gazzard, Simon Portsmouth and Justin Stebbing (Department of HIV Medicine, Chelsea and Westminster Hospital, London, UK) describe the compounds that have been licensed for clinical use and are inhibitors of the viral reverse transcriptase (RT) or protease (PR), as well as the management of treatment failure with these drugs. Moreover, drug candidates that are under clinical trial and they are targeted also to other steps of HIV replicative cycle, are addressed. The review by Theodora Calogeropoulou, Anastasia Detsi, Maria Koufaki and Eleni Lekkas (Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Athens, Greece) highlights recent efforts towards the development of prodrugs of anti-HIV drugs, as a promising strategy to overcome problems associated with toxicity, lack of specificity, limited (oral) bioavailability and cellular resistance mechanisms. HIV-RT remains a primary target for the treatment of HIV infection. Nucleoside RT inhibitors (NRTIs) are very potent anti-HIV agents, thus research efforts have been focused on prodrugs of this class of compounds, to reduce the level of monocyte / macrophage HIV infection, to maintain a therapeutically effective drug concentration in sanctuaries such as the brain and to bypass the first phosphorylation step necessary for their activity. Furthermore, in this article, present knowledge related to prodrugs of PI inhibitors is also reviewed. The recognition of HIV-reverse transcriptase 3D structure, allowed a thorough understanding of the mode of action of nucleoside and non- nucleoside RT inhibitors (NRTIs and NNRTIs), thus leading to computer-aided drug design and modeling. Recent studies based on molecular dynamics, detailed analysis of the interaction of NNRTIs with RT, the recent awareness of the important role of the RT initiation complex RTIC, as well as the incidence of cases of non classical biological behavior, suggest novel mechanisms of action. Jean M. J. Tronchet (Department of Pharmaceutical Chemistry, University of Geneva, Switzerland) and Michel Seman (Laboratory of Immunodifferentiation, University Denis- Diderot, Paris, France) review the current state of the art in this field which will expedite the development of successful drug candidates. Besides the advances in computer - assisted drug design, efforts in a continual search for natural products with anti-HIV activity should not be undermined. Natural products derived from numerous marine species have been found to exhibit significant activity against HIV and for many of them the target of interaction has been identified. This field of increasing importance is reviewed by Vassilios Roussis, Leto-A. Tziveleka, Constantinos Vagias (Division of Pharmacognosy & Chemistry of Natural Products, School of Pharmacy, University of Athens, Greece). Their article is focused on extracts of marine organisms (algae, invertebrates, microbes) and isolated metabolites with anti-HIV activities. The rapid and devastating spread of the AIDS epidemic in the developing countries, as well as the limited durability, significant toxicities, resistance and cost of the current antiretroviral therapies, results to urgent need for the development of a safe and effective AIDS vaccine. Robert Redfield and Bruce L. Gilliam (Institute of Human Virology, University of Maryland, USA) thoroughly review this immunomodulatory appr oach. They discuss the rationale for therapeutic H IV -1 vaccines and the results of the clinical trials using recombinant envelope glycopr oteins, inactivated envelope depleted virus , regulatory pr oteins such as Tat, cytokines such as I FN- , DN A vaccines and live vir al vectors , as well as the future aspects of therapeutic HIV vaccines. I would like to thank all the authors for their outstanding contributions. It is hoped that scientists who would like to be involved in the field of HIV infections, will find this issue a useful source of concise and comprehensive information.

The acquired immunodeficiency syndrome (AIDS) epidemic has led to an unprecedented scientific and clinical effort to understand the pathogenesis and develop strategies to combat this lethal disease. The causal agent of AIDS is a retrovirus, the human immunodeficiency virus (HIV), which was identified in 1983. Drug therapy for HIV / AIDS was initially focused on treating opportunistic infections and malignancies that often accompany HIV and increase mortality. Since then, a significant body of information about the HIV-1 life cycle was rapidly accumulated, resulting in the development of drugs that interfere with different steps of the HIV replication. The process of clinical evaluation has changed dramatically by compressing phase I, II and III studies and using laboratory markers, such as CD4 cell counts, as surrogate end points for disease progression and death. This was due to the large number of agents available for study as well as to the pressure placed by HIV epidemic on investigators, patients, regulators and pharmaceutical companies. A decrease in morbidity and mortality was observed after 1996, particularly as a result of combination therapy, comprising at least three anti-HIV drugs. However, poor and variable absorption, side effects and resistance, limit the effectiveness of these agents. Moreover recent studies show that the CNS and lymphatic tissue act as a sanctuary for HIV, rendering the virus less vulnerable to current antiviral treatment. Therefore, efforts are still necessary to develop novel effective therapeutic agents or prodrugs of known anti-HIV agents, as well as vaccines in order to achieve viral eradication. This issue of the Current Topics in Medicinal Chemistry, present the current state of knowledge of therapeutic strategies against HIV. Combating AIDS, involves concerted efforts from chemists, biologists and clinicians. The first review of this issue, by Jozsef Tozser (Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen Hungary), deals with HIV replicative cycle, beginning with the attachment of the virus to the host cell and finishing with the release of virions from the cell, identifying the potential targets for chemotherapeutic intervention. These targets include several events of the viral replication: attachment / penetration, reverse transcription and formation of preintegration complex, integration, transcription (transactivation), assembly of virus, budding and maturation. Brian Gazzard, Simon Portsmouth and Justin Stebbing (Department of HIV Medicine, Chelsea and Westminster Hospital, London, UK) describe the compounds that have been licensed for clinical use and are inhibitors of the viral reverse transcriptase (RT) or protease (PR), as well as the management of treatment failure with these drugs. Moreover, drug candidates that are under clinical trial and they are targeted also to other steps of HIV replicative cycle, are addressed. The review by Theodora Calogeropoulou, Anastasia Detsi, Maria Koufaki and Eleni Lekkas (Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Athens, Greece) highlights recent efforts towards the development of prodrugs of anti-HIV drugs, as a promising strategy to overcome problems associated with toxicity, lack of specificity, limited (oral) bioavailability and cellular resistance mechanisms. HIV-RT remains a primary target for the treatment of HIV infection. Nucleoside RT inhibitors (NRTIs) are very potent anti-HIV agents, thus research efforts have been focused on prodrugs of this class of compounds, to reduce the level of monocyte / macrophage HIV infection, to maintain a therapeutically effective drug concentration in sanctuaries such as the brain and to bypass the first phosphorylation step necessary for their activity. Furthermore, in this article, present knowledge related to prodrugs of PI inhibitors is also reviewed. The recognition of HIV-reverse transcriptase 3D structure, allowed a thorough understanding of the mode of action of nucleoside and non- nucleoside RT inhibitors (NRTIs and NNRTIs), thus leading to computer-aided drug design and modeling. Recent studies based on molecular dynamics, detailed analysis of the interaction of NNRTIs with RT, the recent awareness of the important role of the RT initiation complex RTIC, as well as the incidence of cases of non classical biological behavior, suggest novel mechanisms of action. Jean M. J. Tronchet (Department of Pharmaceutical Chemistry, University of Geneva, Switzerland) and Michel Seman (Laboratory of Immunodifferentiation, University Denis- Diderot, Paris, France) review the current state of the art in this field which will expedite the development of successful drug candidates. Besides the advances in computer - assisted drug design, efforts in a continual search for natural products with anti-HIV activity should not be undermined. Natural products derived from numerous marine species have been found to exhibit significant activity against HIV and for many of them the target of interaction has been identified. This field of increasing importance is reviewed by Vassilios Roussis, Leto-A. Tziveleka, Constantinos Vagias (Division of Pharmacognosy & Chemistry of Natural Products, School of Pharmacy, University of Athens, Greece). Their article is focused on extracts of marine organisms (algae, invertebrates, microbes) and isolated metabolites with anti-HIV activities. The rapid and devastating spread of the AIDS epidemic in the developing countries, as well as the limited durability, significant toxicities, resistance and cost of the current antiretroviral therapies, results to urgent need for the development of a safe and effective AIDS vaccine. Robert Redfield and Bruce L. Gilliam (Institute of Human Virology, University of Maryland, USA) thoroughly review this immunomodulatory appr oach. They discuss the rationale for therapeutic H IV -1 vaccines and the results of the clinical trials using recombinant envelope glycopr oteins, inactivated envelope depleted virus , regulatory pr oteins such as Tat, cytokines such as I FN- α, DN A vaccines and live vir al vectors , as well as the future aspects of therapeutic HIV vaccines. I would like to thank all the authors for their outstanding contributions. It is hoped that scientists who would like to be involved in the field of HIV infections, will find this issue a useful source of concise and comprehensive information.