Do we achieve LDL-cholesterol targets in routine clinical practice? Evidence from a tertiary care hospital in Sri Lanka

Background: Statins are widely used for primary and secondary prevention of cardiovascular disease (CVD). European Society of Cardiology / European Atherosclerosis Society (ESC/EAS) guidelines recommend LDL-cholesterol targets based on CVD risk.Objectives: This study aimed to determine whether LDL-cholesterol targets recommended by2016 ESC/EASare achieved in routine clinical practice.Methods: This paper is based on baseline data of patients recruited to a controlled clinical trial conducted at a tertiary care hospital. Participants have been on atorvastatin for >2 months. Demographic and clinical data were obtained using clinic records and interviewer administered questionnaires. LDL-cholesterol was assessed using Friedewald equation (when triglyceride was <400mg/dL) or by direct measurement (when triglyceride was ≥400mg/dL). Each participant’s CVD risk level and appropriate LDL-cholesterol target (very-high CVD risk:<70mg/dL; high CVD risk:<100mg/dL; low to moderate CVD risk:<115mg/dL) was determined according to 2016 ESC/EAS Guideline.Results: 101 patients were studied. (Women: 76.2%; mean-age: 61.2:±9.3years). Prevalence of coronary heart disease, ischaemic stroke, diabetes, hypertension and smoking was 30.7%, 4%, 77.2%, 80.2% and 4%, respectively. According to CVD risk level 80.2%, 15.8% and 4% were in very-high, high and moderate risk categories, respectively. Most were on atorvastatin 10mg (45.5%) followed by 20mg (43.6%), 40mg (8.9%), 30mg (1%) and 5mg (1%). Median duration of treatment was 41-months. Overall, only 12.9% had achieved target LDL-cholesterol (very-high risk: 7.4%; high risk: 37.5%, moderate risk: 25%; p=0.003). Men did better than women in achieving target LDL-cholesterol (men: 29.2%, women: 7.8%; p=006). There was no difference based on age, comorbidities or atorvastatin dose.Conclusions: In the study population majority has failed to achieve LDL-cholesterol targets recommended by 2016 ESC/EAS. Failure to achieve targets was more common among women and those having very-high CVD risk. Reason for suboptimal target achievement has to be studied further.Acknowledgement: Funded by University of Sri Jayewardenepura Research Grant (ASP/01/RE/MED/2015/54) and Ceylon College of Physicians Research Grant (2014)

Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites

Histone deacetylase (HDAC) enzymes work together with histone acetyltransferases (HATs) to reversibly acetylate both histone and non-histone proteins. As a result, these enzymes are involved in regulating chromatin structure and gene expression as well as other important cellular processes. HDACs are validated drug targets for some types of cancer, with four HDAC inhibitors clinically approved. However, they are also showing promise as novel drug targets for other indications, including malaria and other parasitic diseases. In this study the in vitro activity of four anti-cancer HDAC inhibitors was examined against parasites that cause malaria and trypanosomiasis. Three of these inhibitors, suberoylanilide hydroxamic acid (SAHA; vorinostat (R)), romidepsin (Istodax (R)) and belinostat (Beleodaq (R)), are clinically approved for the treatment of T-cell lymphoma, while the fourth, panobinostat, has recently been approved for combination therapy use in certain patients with multiple myeloma. All HDAC inhibitors were found to inhibit the growth of asexual-stage Plasmodium falciparum malaria parasites in the nanomolar range (IC50 10-200 nM), while only romidepsin was active at sub-mu M concentrations against bloodstream form Trypanosoma brucei brucei parasites (IC50 35 nM). The compounds were found to have some selectivity for malaria parasites compared with mammalian cells, but were not selective for trypanosome parasites versus mammalian cells. All compounds caused hyperacetylation of histone and non-histone proteins in P. falciparum asexual stage parasites and inhibited deacetylase activity in P. falciparum nuclear extracts in addition to recombinant PfHDAC1 activity. P. falciparum histone hyperacetylation data indicate that HDAC inhibitors may differentially affect the acetylation profiles of histone H3 and H4. (C) 2015 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology

A framework to enhance email based business processes

Despite the consensus that email is an important tool to handle a business process(BP), this prevailing tool poorly supports the tasks it needs to accomplish in a BP. A collection of interrelated business activities which solve a particular issue is commonly known as a BP. The performance of BP is vital for the growth and development of a business. The ineffective performance of BP is a major, yet avoidable, obstacle to the business productivity. Diverse technologies bear weight in enhancing the performance of BP. The technology involved in BP plays a dominant role in BP streamlining. Over the last decade, email has been embraced, not only by the organizations of every shape and form, but also by individuals as a very popular communication technology. The ubiquitous and simple nature of email makes it a suitable candidate to be used as a technology to support BP related communication However, email poorly supports the task of handling BPes, due to its ad-hoc and heavi y distributed nature. In addition, the primary messaging metaphor of most email clients is not optimized for the activities of a BP. But they only address the problem of anaging the volume of email. Therefore this paper provides a solution to enhance the use of email for performing BP related activities efficiently and effectively, without changing email's fundamental technical infrastructure. The proposed solution is expected to achieve its objectives by means of a cognitive approach reducing huma intervention to the BP. In the proposed framework, when an email receives a BP activity, it is sent to the central server. The central server takes care of resolving the required next action based on the specified ordering of actions for that particular BP. Such a coordination via a central server, attempts to eliminate the ad-hoc and highly distributed nature of email that prevents it to be effectively used for BP related activities

Defining the targets of antiparasitic compounds

The treatment of major human parasitic infections is dependent on drugs that are plagued by issues of drug resistance. New chemotherapeutics with novel mechanisms of action (MOA) are desperately needed to combat multi-drug-resistant parasites. Although widespread screening strategies are identifying potential new hits for development against most major human parasitic diseases, in many cases such efforts are hindered by limited MOA data. Although MOA data are not essential for drug development, they can facilitate compound triage and provide a mechanism to combat drug resistance. Here we describe and discuss methods currently used to identify the targets of antiparasitic compounds, which could circumvent this bottleneck and facilitate the development of new antiparasitic drugs

Erratum to “Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites” [Int. J. Parasitol. Drugs Drug Res. 5 (2015) 117–126]

The publisher regrets that there was an error in the name of the seventh author in the published article. The correct name is as above. The publisher would like to apologise for any inconvenience caused

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity; however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in Plasmodium falciparum gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in P. falciparum gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology. Copyrigh

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity; however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in Plasmodium falciparum gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in P. falciparum gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology. Copyrigh