Cytotoxicity and potential antiviral evaluation of violacein produced by Chromobacterium violaceum

Natural products are an inexhaustible source of compounds with promising pharmacological activities including antiviral action. Violacein, the major pigment produced by Chromobacterium violaceum, has been shown to have antibiotic, antitumoral and anti-Trypanosoma cruzi activities. The goal of the present work was to evaluate the cytotoxicity of violacein and also its potential antiviral properties.The cytotoxicity of violacein was investigated by three methods: cell morphology evaluation by inverted light microscopy and cell viability tests using the Trypan blue dye exclusion method and the MTT assay. The cytotoxic concentration values which cause destruction in 50% of the monolayer cells (CC50) were different depending on the sensitivity of the method. CC50 values were > 2.07 ± 0.08 µM for FRhK-4 cells: > 2.23 ± 0.11 µM for Vero cells; > 2.54 ± 0.18 µM for MA104 cells; and > 2.70 ± 0.20 µM for HEp-2 cells. Violacein showed no cytopathic inhibition of the following viruses: herpes simplex virus type 1 (HSV-1) strain 29-R/acyclovir resistant, hepatitis A virus (strains HM175 and HAF-203) and adenovirus type 5 nor did it show any antiviral activity in the MTT assay. However violacein did show a weak inhibition of viral replication: 1.42 ± 0.68%, 14.48 ± 5.06% and 21.47 ± 3.74% for HSV-1 (strain KOS); 5.96 ± 2.51%, 8.75 ± 3.08% and 17.75 ± 5.19% for HSV-1 (strain ATCC/VR-733); 5.13 ± 2.38 %, 8.18 ± 1.11% and 8.51 ± 1.94% for poliovirus type 2; 8.30 ± 4.24%; 13.33 ± 4.66% and 24.27 ± 2.18% for simian rotavirus SA11, at 0.312, 0.625 and 1.250 mM, respectively, when measured by the MTT assay.

Ampakine CX546 bolsters energetic response of astrocytes: a novel target for cognitive-enhancing drugs acting as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators.

Glutamate was previously shown to enhance aerobic glycolysis i.e. increase glucose utilization and lactate production with no change in oxygen levels, in mouse cortical astrocytes by a mechanism involving glutamate uptake. It is reported here that a similar response is produced in both hippocampal and cerebellar astrocytes. Application of the cognitive-enhancing drug CX546 promoted further enhancement of glucose utilization by astrocytes from each brain area following glutamate exposure. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors represent the purported molecular target of cognitive-enhancing drugs such as CX546, and the presence of AMPA receptor subunits GluR1-4 was evidenced in astrocytes from all three regions by immunocytochemistry. AMPA itself did not stimulate aerobic glycolysis, but in the presence of CX546, a strong enhancement of glucose utilization and lactate production was obtained in cortical, hippocampal and cerebellar astrocytes. The effect of CX546 was concentration-dependent, with an EC(50) of 93.2 microm in cortical astrocytes. AMPA-induced glucose utilization in the presence of CX546 was prevented by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the negative modulator GYKI 52466. In addition, the metabolic effect of CX546 in the presence of AMPA was mimicked by the AMPA receptor modulator cyclothiazide. Our data suggest that astrocyte energetics represents a novel target for cognitive-enhancing drugs acting as AMPA receptor modulators.

Drugs and solvents: a guide for parents

This booklet provides information on why young people try drugs, the risks of taking illegal drugs, the signs of drug taking and information about individual drugs.

Talking about drugs: a guide for parents

This leaflet explains why and at what age parents should talk to their children about drugs and also provides advice and tips on how to do this.

What do you know about drugs? Your body, your life, your choice

This booklet provides information about the appearance, street names and effects of various drugs including: cannabis, LSD, magic mushrooms, Ecstasy, solvents, poppers, speed, cocaine, crack, heroin, alcohol and tobacco.

Hypertension artérielle réfractaire au traitement due au syndrome d'apnées du sommeil et à la prise de médicaments [Obstructive sleep apnea and drugs as causes of treatment-resistant hypertension].

Treatment-resistant hypertension is still common despite the availability of several types of antihypertensive agents acting by different mechanisms. The existence of refractory hypertension should lead to rule out "white-coat hypertension", poor adherence to prescribed drugs as well as classical causes of secondary hypertension such as renal artery stenosis, primary aldosteronism, pheochromocytoma and renal disease. It is also important to consider the possible existence of obstructive sleep apnea or the regular intake of vasopressive drugs or substances.

Effects of immunosuppressive drugs on T helper cells subsets and potential to promote tolerance in a stringent experimental transplantation model.

To achieve the goal of sustained donor-specifi c transplantation (Tx) tolerance, research efforts are now focusing on therapies based on specifi c cell subsets with regulatory properties. We and others have previously highlighted the therapeutic potential of naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTreg) in promoting long-term graft acceptance. Using more stringent experimental Tx models, we were however confronted to limitations. Indeed, while the transfer of antigenspecifi c nTreg promoted long-term MHC-mismatched skin allograft acceptance in lymphopenic mice in the absence of any immunosuppressive drug, allograft survival was only slightly prolonged when nTreg were transferred alone into non-lymphopenic mice. This suggested that in more stringent conditions, adjuvant therapies may be needed to effectively control alloreactive T cells (Teff). Whether and how the expansion of the Treg pool could be best combined with current immunosuppressive regimens in clinical settings remains to be defi ned. In this study, we have used in vitro assays and an in vivo skin Tx model to investigate the effects of various immunosuppressive drugs on the survival, proliferation and effector function of Teff and nTreg in response to alloantigens. Teff proliferation was inhibited in a dose-dependent manner by rapamycin and cyclosporine A, while anti-CD154 mAb only marginally affected Teff survival, proliferation and effector fucntion in vitro. Rapamycin promoted apoptosis of Teff as compared to nTreg that were more resistant in the presence of IL-2. In vivo, the transfer and/or expansion of Treg could be advantageously combined with rapamycin and anti-CD154 mAb treatment to signifi cantly prolong MHC-mismatched skin allografts survival in non-lymphopenic recipients. Taken together our data indicate that immunosuppressive drugs differentially target T-cell subsets and that some regimens could promote Treg expansion while controlling the Teff pool in response to alloantigens.

Trypanosoma cruzi: establishment of permeable cells for RNA processing analysis with drugs

Pre-mRNA maturation in trypanosomatids occurs through a process called trans-splicing which involves excision of introns and union of exons in two independent transcripts. For the first time, we present the standardization of Trypanosoma cruzi permeable cells (Y strain) as a model for trans-splicing study of mRNAs in trypanosomes, following by RNase protection reaction, which localizes the SL exon and intron. This trans-splicing reaction in vitro was also used to analyze the influence of NFOH-121, a nitrofurazone-derivative, on this mechanism. The results suggested that the prodrug affects the RNA processing in these parasites, but the trans-splicing reaction still occurred.

Action plan against Drugs and Drug Addiction: Horizons 2008

Portugese action plan against drugs.This resource was contributed by The National Documentation Centre on Drug Use.

Report Against Drugs- an action plan to combat substance abuse in Longford.

The Forum for Longford was started in 1997 to provide a co-ordinated inter-agency approach to identify and help tackle social problems in Longford. A survey was carried out with 1,331 post-primary students to ascertain attitudes and behaviours towards alcohol, smoking and drug use. Of the pupils interviewed, 64% had taken an alcoholic drink at age 15 or younger; of these 73% had their first drink between the ages of 12 to 15. Of those that had experience of alcohol, 51% drank several times a week or daily. For smoking, 67% had smoked a cigarette; of these 8% smoked 5 or more daily. Of those that smoked, 47% began between the ages of 11 to 14. With regard to illegal drugs 27% had used cannabis, 20% had used inhalants, 10% hallucinogens, 9% amphetamines and 7.4% had used ecstasy. Following on form these findings, the report makes several recommendations, including the formation of a community task force, Garda/ neighbourhood watch response, schools prevention and information. Also among these key areas are the role of parents, the needs of young people and facilities for young people.This resource was contributed by The National Documentation Centre on Drug Use.

2006 Drugs estimate refuels debate on governance, Issue 17, Spring 2006

In November 2005 €34.027 million was voted for the Drugs Initiative, which funds the local and regional drugs task forces, and the Young People’s Facilities and Services Fund (YPFSF), in 2006 – an 8 per cent increase on the allocation for 2005 and ‘well in excess of inflation’ according to the government. The community sector strongly criticised this estimate, calling for an additional €8 million to €15 million, to fund the projects identified following the creation of the Emerging Needs Fund in January 2005. In February 2006, the government revised its drugs estimate upwards by a further €8.979 million. As well as criticising the 2006 drugs estimate, the community sector raised a series of concerns with regard to governance – the rules, processes and behaviour that affect the way in which powers are exercised4 – or, in short, decision-making with regard to drugs policy in Ireland.This resource was contributed by The National Documentation Centre on Drug Use.

A re-focused and re-energised National Drugs Strategy, Issue 14, Summer 2005

The Mid-Term Review1 of the National Drugs Strategy 2001–2008, published on 2 June 2005, recommends a number of additions and amendments to the existing Strategy, including making rehabilitation a new, ‘fifth’ pillar of the Strategy. The Steering Group that oversaw the Review, and the extensive consultation process on which it is based, found that the aims and objectives of the Strategy are fundamentally sound. While what has been achieved varies from action to action, progress has been made across the four pillars of supply reduction, prevention, treatment and research, and in the co-ordination of the institutional structures of the Strategy. The Review recommends the addition of eight new actions, the replacement of nine of the existing actions and amendments to a further eight. It also recommends revisions to the Strategy’s key performance indicators, reflecting new developments and data availability. The recommendations serve to ‘re-focus and re-energise’ the Strategy in the remaining period up to 2008.This resource was contributed by The National Documentation Centre on Drug Use.

Vulnerable young people and drugs: opportunities to tackle inequalities.

This document presents executive summaries of pieces of research carried out under the auspices of a Department of Health funded research programme. The aim of the programme was to provide research based evidence that would underpin the development of high quality and effective interventions with groups of young people thought to be vulnerable to developing drug misuse problems. The focus of the initiative was to inform primary and secondary drug prevention strategies and other opportunities to intervene. The background to each project, methodology used and findings are presented.This resource was contributed by The National Documentation Centre on Drug Use.

The prevalence of erectile dysfunction and its association with antiretroviral therapy in HIV-infected men: the Swiss HIV Cohort Study.

BACKGROUND: Here, we aimed to determine the prevalence of erectile dysfunction (ED) among HIV-infected men and its association with components of antiretroviral therapy. METHODS: Cross-sectional data on sexual dysfunction were collected in the Swiss HIV Cohort Study (SHCS) between December 2009 and November 2010. Multilevel logistic regression models were used to estimate the association between ED and exposure to 24 different antiretroviral drugs from four drug classes. RESULTS: During the study period, 5,194 of 5,539 eligible men in the SHCS had a follow-up visit; 4,064 men answered a question on ED for the first time. Among these men, ED was experienced often by 459 (11%), sometimes by 543 (13%), rarely by 389 (10%), never by 2,526 (62%) and 147 (4%) did not know. ED was associated with older age, an earlier HIV diagnosis and depression. No association was found with any drug class; however, ED was associated with cumulative exposure to either zalcitabine (OR 1.29 per year of use; 95% CI 1.07, 1.55) or enfuvirtide (OR 1.28; 95% CI 1.08, 1.52). CONCLUSIONS: Around 1 in 10 men in the SHCS reported often experiencing ED. We found no association between ED and any drug class, but those exposed to zalcitabine or enfurvitide (drugs no longer or rarely used) were more likely to report ED; this second association was probably not causal.

Local and regional drugs task forces: handbook.

This handbook has been developed within the context of the institutional structures recommended under the National Drugs Strategy 2009-2016 and within the overall framework of the National Social Inclusion Plan 2007-2016. It sets out the role of the Drugs Task Forces within the national and local framework required to address the existing and emerging problems associated with drug use for individuals, families and communities in the context of the long term development of the work of the Drugs Task Forces.This resource was contributed by The National Documentation Centre on Drug Use.