Can the biology of VEGF and haem oxygenases help solve pre-eclampsia?

Pre-eclampsia, a pregnancy-specific multi-organ syndrome characterized by widespread endothelial damage, is a new risk factor for cardiovascular disease. No therapies exist to prevent or treat this condition, even to achieve a modest improvement in pregnancy length or birth weight. Co-administration of soluble VEGFR-1 [VEGF (vascular endothelial growth factor) receptor-1; more commonly known as sFlt-1 (soluble Fms-like tyrosine kinase-1)] and sEng (soluble endoglin) to pregnant rats elicits severe pre-eclampsia-like symptoms. These two anti-angiogenic factors are increased dramatically prior to the clinical onset of pre-eclampsia and are quite possibly the 'final common pathway' responsible for the accompanying signs of hypertension and proteinuria as they can be reversed by VEGF administration in animal models. HO-1 (haem oxygenase-1), an anti-inflammatory enzyme, and its metabolite, CO (carbon monoxide), exert protective effects in several organs against oxidative stimuli. In a landmark publication, we showed that the HO-1 pathway inhibits sFlt-1 and sEng in cultured cells and human placental tissue explants. Both CO and NO (nitric oxide) promote vascular homoeostasis and vasodilatation, and activation of VEGFR-1 or VEGFR-2 induced eNOS (endothelial nitric oxide synthase) phosphorylation, NO release and HO-1 expression. Our studies established the HO-1/CO pathway as a negative regulator of cytokine-induced sFlt-1 and sEng release and eNOS as a positive regulator of VEGF-mediated vascular morphogenesis. These findings provide compelling evidence for a protective role of HO-1 in pregnancy and identify it as a target for the treatment of pre-eclampsia. Any agent that is known to up-regulate HO-1, such as statins, may have potential as a therapy. Any intervention achieving even a modest prolongation of pregnancy or amelioration of the condition could have a significant beneficial health impact worldwide.

New insights into the etiology of preeclampsia:identification of key elusive factors for the vascular complications

The incidence of preeclampsia is reduced by a third in smokers, but not in snuff users. Soluble Flt-1 (sFlt-1) and soluble endoglin (sEng) are increased prior to the clinical onset of preeclampsia. Animals exposed to high circulating levels of sFlt-1 and sEng elicit severe preeclampsia-like symptoms. Smokers have reduced circulating sFlt-1 and cigarette smoke extract decreases sFlt-1 release from placental villous explants. An anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO), inhibit sFlt-1 and sEng release. Women with preeclampsia exhale less CO than women with normal pregnancies and HO expression decreases as the severity of preeclampsia increases. In contrast, sFlt-1 levels increase with increasing severity. More importantly, chorionic villous sampling from women at eleven weeks gestation shows that HO-1 mRNA expression is decreased in women who go on to develop preeclampsia. Collectively, these facts provide compelling evidence to support the proposition that the pathogenesis of preeclampsia is largely due to loss of HO activity. This results in an increase in inflammation and excessive elevation of the two key anti-angiogenic factors responsible for the clinical signs of preeclampsia. These findings provide strong evidence for a protective role of HO-1 in pregnancy and identify HO as a target for the treatment of preeclampsia. The cardiovascular drugs, statins, stimulate HO-1 expression and inhibit sFlt-1 release in vivo and in vitro, thus, they have the potential to ameliorate early onset preeclampsia. The StAmP trial is underway to address this and if positive, its outcome will lead to the very first therapeutic intervention to prolong affected pregnancies.

Use of general practice prescribing data as a surrogate estimate of statin compliance

Background and Objective: To maximise the benefit from statin therapy, patients must maintain regular therapy indefinitely. Non-compliance is thought to be common in those taking medication at regular intervals over long periods of time, especially where they may perceive no immediate benefit (News editorial, 2002). This study extends previous work in which commonly held prescribing data is used as a surrogate marker of compliance and was designed to examine compliance in those stabilised on statins in a large General Practice. Design: Following ethical approval, details of all patients who had a single statin for 12 consecutive months with no changes in drug, frequency or dose, between December 1999 and March 2003, were obtained. Setting: An Eastern Birmingham Primary Care Trust GP surgery. Main Outcome Measures: A compliance ratio was calculated by dividing the number of days treatment by the number of doses prescribed. For a once daily regimen the ratio for full compliance_1. Results: 324 patients were identified. The average compliance ratio for the first six months of the study was 1.06 ± 0.01 (range 0.46 – 2.13) and for the full twelve months was 1.05 ± 0.01 (range 0.58 – 2.08). Conclusions: The data shown here indicates that as a group, long-term, stabilised statin users appear compliant. However, the range of values obtained show that there are identifiable subsets of patients who are not taking their therapy as prescribed. Although the apparent use of more doses than prescribed in some patients may result from medication hording, this cannot be the case in the patients who apparently take less. It has been demonstrated here that the compliance ratio can be used as an early indicator of problems allowing targeted compliance advice can be given where it will have the most benefit. References: News Editorial. Pharmacy records could be used to enhance statin compliance in elderly. Pharm. J. 2002; 269: 121.

Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis

Objective: The recent withdrawal of a targeted sepsis therapy has diminished pharmaceutical enthusiasm for developing novel drugs for the treatment of sepsis. Angiopoietin-2 is an endothelial-derived protein that potentiates vascular inflammation and leakage and may be involved in sepsis pathogenesis. We screened approved compounds for putative inhibitors of angiopoietin-2 production and investigated underlying molecular mechanisms. Design: Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897). Setting: Research laboratories of Hannover Medical School and Harvard Medical School. Patients: Septic patients/C57Bl/6 mice and human endothelial cells. Interventions: Food and Drug Administration-approved library screening. Measurements and Main Results: In a cell-based screen of more than 650 Food and Drug Administration-approved compounds, we identified multiple members of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor drug class (referred to as statins) that suppressed angiopoietin-2. Simvastatin inhibited 3-hydroxy-3-methyl-glutaryl-CoA reductase, which in turn activated PI3K-kinase. Downstream of this signaling, PI3K-dependent phosphorylation of the transcription factor Foxo1 at key amino acids inhibited its ability to shuttle to the nucleus and bind cis-elements in the angiopoietin-2 promoter. In septic mice, transient inhibition of angiopoietin-2 expression by liposomal siRNA in vivo improved absolute survival by 50%. Simvastatin had a similar effect, but the combination of angiopoietin-2 siRNA and simvastatin showed no additive benefit. To verify the link between statins and angiopoietin-2 in humans, we performed a pilot matched case-control study and a small randomized placebo-controlled trial demonstrating beneficial effects on angiopoietin-2. Conclusions: 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors may operate through a novel Foxo1-angiopoietin-2 mechanism to suppress de novo production of angiopoietin-2 and thereby ameliorate manifestations of sepsis. Given angiopoietin-2's dual role as a biomarker and candidate disease mediator, early serum angiopoietin-2 measurement may serve as a stratification tool for future trials of drugs targeting vascular leakage.

LDL-Lipids from patients with hypercholesterolaemia and Alzheimer's disease are inflammatory to microvascular endothelial cells:mitigation by statin intervention

Elevated LDL concentration in mid-life increases the risk of developing Alzheimer's disease (AD) in later life. Increased oxidative modification (oxLDL) and nitration is observed during dementia and hypercholesterolemia. We investigated the hypothesis that statin intervention in mid-life mitigates the inflammatory effects of oxLDL on the microvasculature. Human microvascular endothelial cells (HMVEC) were maintained on transwells to mimic the microvasculature and exposed to patient and control LDL. Blood was obtained from statin-naïve, normo- and hyperlipidaemic subjects, AD with vascular dementia (AD-plus) and AD subjects (n=10/group) at baseline. Only hyperlipidaemic subjects with normal cognitive function received 40mg simvastatin intervention/day for three months. Blood was re-analysed from normo- and hyper-lipidaemic subjects after three months. LDL isolated from statin-naïve hyperlipidaemic, AD and AD-plus subjects was more oxidised (agarose gel electrophoretic mobility, protein carbonyl content and 8-isoprostane F2α) compared to control subjects. Statin intervention decreased protein carbonyls (2.5±0.4 Vs 3.95±0.2nmol/mg; P<0.001) and 8-isoprostane F2α (30.4±4.0 pg/ml Vs 43.5±8.42 pg/ml; P<0.05). HMVEC treatment with LDL-lipids from hyperlipidaemic, AD and AD-plus subjects impaired endothelial tight junction expression and decreased total glutathione levels (AD; 18.61±1.3, AD-plus; 16.5±0.7nmol/mg protein) compared to untreated cells (23.8±1.2 vs nmol/mg protein). Basolateral IL-6 secretion was increased by LDL-lipids from hyperlipidaemic (78.4±1.9 pg/ml), AD (63.2±5.9 pg/ml) and AD-plus (80.8±0.9 pg/ml) groups compared to healthy subject lipids (18.6±3.6 pg/ml). LDL-Lipids isolated after statin intervention did not affect endothelial function. In summary, LDL-lipids from hypercholesterolaemic, AD and AD-plus patients are inflammatory to HMVEC. In vivo intervention with statins reduces the damaging effects of LDL-lipids on HMVEC.

Paradoxical decrease in HDL-cholesterol and apolipoprotein A1 with simvastatin and atorvastatin in a patient with type 2 diabetes

Statins are agents widely used to lower LDL-cholesterol (LDL-C) in primary and secondary prevention of coronary heart disease. The five statins available in the UK (simvastatin, pravastatin, fluvastatin, atorvastatin and rosuvastatin) differ in many of their pharmacologic properties. In addition to lowering LDL-C, statins also increase HDL-cholesterol (HDL-C) moderately. There have been rare reports of significant HDL-C decreases in patients commenced on fibrates and when thiazolidinediones are added to fibrates. This is known as a 'paradoxical HDL-C decrease' as both groups of agents usually increase HDL-C. This phenomenon has never been clearly documented following statin therapy. We now describe a patient with type 2 diabetes who showed this paradoxical fall in HDL-C (baseline HDL-C: 1.8 mmol/L; on simvastatin 40 mg HDL-C 0.6 mmol/L; on atorvastatin 20 mg HDL-C 0.9 mmol/L) with a similar decrease in apolipoprotein A1. No similar decrease was observed with pravastatin and rosuvastatin therapy. This phenomenon appeared to be associated with statin treatment and not a statin/fibrate combination. Our patient clearly demonstrated a paradoxical HDL-C fall with simvastatin and atorvastatin, but not pravastatin or rosuvastatin. Simvastatin and atorvastatin share many pharmacokinetic properties such as lipophilicity while pravastatin and rosuvastatin are relatively hydrophilic and are not metabolized by cytochrome P450 3A4. However, these characteristics do not explain the dramatic reductions in HDL-C observed.

Preeclampsia : an accelerator–brake defect disorder

Life's perfect partnership starts with the placenta. If we get this right, we have the best chance of healthy life. In preeclampsia, we have a failing placenta. Preeclampsia kills one pregnant woman every minute and the life expectancy of those who survive is greatly reduced. Preeclampsia is treated roughly the same way it was when Thomas Edison was making the first silent movie. Globally, millions of women risk death to give birth each year and almost 300,000 lose their lives in this process. Over half a million babies around the world die each year as a consequence of preeclampsia. Despite decades of research, we lack pharmacological agents to treat it. Maternal endothelial dysfunction is a central phenomenon responsible for the clinical signs of preeclampsia. In the late nineties, we discovered that vascular endothelial growth factor (VEGF) stimulated nitric oxide release. This led us to suggest that preeclampsia arises due to the loss of VEGF activity, possibly due to a rise in soluble Flt-1 (sFlt-1), the natural antagonist of VEGF. Researchers have shown that high sFlt-1 elicits preeclampsia-like signs in pregnant rats and sFlt-1 increases before the clinical signs of preeclampsia in pregnant women. We demonstrated that removing or reducing this culprit protein from preeclamptic placenta restored the angiogenic balance. Heme oxygenase-1 (HO-1 or Hmox1) that generates carbon monoxide (CO), biliverdin (rapidly converted to bilirubin) and iron is cytoprotective. We showed that the Hmox1/CO pathway prevents human placental injury caused by pro-inflammatory cytokines and suppresses sFlt-1 and soluble endoglin release, factors responsible for preeclampsia phenotypes. The other key enzyme we identified is the hydrogen sulfide generating cystathionine-gamma-lyase (CSE or Cth). These are the only two enzyme systems shown to suppress sFlt-1 and to act as protective pathways against preeclampsia phenotypes in animal models. We also showed that when hydrogen sulfide restores placental vasculature, it also improves lagging fetal growth. These molecules act as the inhibitor systems in pregnancy and when they fail, this triggers preeclampsia. Discovering that statins induce these enzymes led us to an RCT to develop a low-cost therapy (StAmP Trial) to prevent or treat preeclampsia. If you think of pregnancy as a car then preeclampsia is an accelerator–brake defect disorder. Inflammation, oxidative stress and an imbalance in the angiogenic milieu fuel the ‘accelerator’. It is the failure in the braking systems (the endogenous protective pathway) that results in the ‘accelerator’ going out of control until the system crashes, manifesting itself as preeclampsia.

The impact of statin use on fetal development:a meta-analysis

INTRODUCTION: Statin use inadvertently during pregnancy and proposed use of statins for the treatment of preeclampsia, led us to question the evidence behind their current contraindicated status. Several studies have evaluated the relationship between statin use in pregnancy with fetal outcome but their results have not been quantitatively assessed by meta-analysis. Our objective was to undertake a systematic review of all published clinical evidence to assess the effects of statin use in pregnancy on subsequent fetal wellbeing. METHODS: A comprehensive search strategy was performed of all electronic databases and the Merck reporting database for studies published from 1966 to 2014. Two reviewers independently screened citations and undertook study quality assessment and data extraction. We obtained summary estimates of adverse fetal events that were classified as potentially fatal, clinically significant morbidity or minor adverse event. We identified 602 titles and reviewed 30 articles for inclusion and exclusion criteria. Meta-analysis was performed on seven studies (3 cohort, 3 case-series and 1 case-control). RESULTS: Of the 922 cases of statin exposure in pregnancy, 27 exposures were associated with lethal or clinically significant fetal morbidity and 10 with minor adverse events. Statin exposure was limited to the first trimester in all but two cases. The pooled rate of lethal or clinically significant fetal abnormalities in pregnant women exposed to statins was 0.01 (95% CI 0.00-0.04), less than the European rate of 0.026 (95% CI 2.54- 2.57)EUROCAT. The rate of fetal abnormality for simvastatin was 0.03 (95% CI 0.00-0.08), atorvostatin 0.11 (95% CI 0.00-0.52), pravastatin 0.01 (95% CI 0.00-0.2) and lovastatin use 0.04 (95% CI 0.00-0.28). Systems based anomalies were also calculated, congenital heart disease was 0.8 (95% CI 0.02-0.12) compared with the background rate of 0.79 (95% CI 0.78- 0.80). CONCLUSIONS: The published data suggests that statins may not be teratogenic when given inadvertently during pregnancy and prospective studies such as The StAmP Trial may provide more data

Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy

Background: Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials. Methods and Findings: Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93-1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93-1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82-1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (<2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76-1.10]). Conclusions: In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).

Drug prescribing patterns in the General Medical Services Scheme in Ireland and projected costs to 2026

The primary objective is to investigate the main factors contributing to GMS expenditure on pharmaceutical prescribing and projecting this expenditure to 2026. This study is located in the area of pharmacoeconomic cost containment and projections literature. The thesis has five main aims: 1. To determine the main factors contributing to GMS expenditure on pharmaceutical prescribing. 2. To develop a model to project GMS prescribing expenditure in five year intervals to 2026, using 2006 Central Statistics Office (CSO) Census data and 2007 Health Service Executive{Primary Care Reimbursement Service (HSE{PCRS) sample data. 3. To develop a model to project GMS prescribing expenditure in five year intervals to 2026, using 2012 HSE{PCRS population data, incorporating cost containment measures, and 2011 CSO Census data. 4. To investigate the impact of demographic factors and the pharmacology of drugs (Anatomical Therapeutic Chemical (ATC)) on GMS expenditure. 5. To explore the consequences of GMS policy changes on prescribing expenditure and behaviour between 2008 and 2014. The thesis is centered around three published articles and is located between the end of a booming Irish economy in 2007, a recession from 2008{2013, to the beginning of a recovery in 2014. The literature identified a number of factors influencing pharmaceutical expenditure, including population growth, population aging, changes in drug utilisation and drug therapies, age, gender and location. The literature identified the methods previously used in predictive modelling and consequently, the Monte Carlo Simulation (MCS) model was used to simulate projected expenditures to 2026. Also, the literature guided the use of Ordinary Least Squares (OLS) regression in determining demographic and pharmacology factors influencing prescribing expenditure. The study commences against a backdrop of growing GMS prescribing costs, which has risen from e250 million in 1998 to over e1 billion by 2007. Using a sample 2007 HSE{PCRS prescribing data (n=192,000) and CSO population data from 2008, (Conway et al., 2014) estimated GMS prescribing expenditure could rise to e2 billion by2026. The cogency of these findings was impacted by the global economic crisis of 2008, which resulted in a sharp contraction in the Irish economy, mounting fiscal deficits resulting in Ireland's entry to a bailout programme. The sustainability of funding community drug schemes, such as the GMS, came under the spotlight of the EU, IMF, ECB (Trioka), who set stringent targets for reducing drug costs, as conditions of the bailout programme. Cost containment measures included: the introduction of income eligibility limits for GP visit cards and medical cards for those aged 70 and over, introduction of co{payments for prescription items, reductions in wholesale mark{up and pharmacy dispensing fees. Projections for GMS expenditure were reevaluated using 2012 HSE{PCRS prescribing population data and CSO population data based on Census 2011. Taking into account both cost containment measures and revised population predictions, GMS expenditure is estimated to increase by 64%, from e1.1 billion in 2016 to e1.8 billion by 2026, (ConwayLenihan and Woods, 2015). In the final paper, a cross{sectional study was carried out on HSE{PCRS population prescribing database (n=1.63 million claimants) to investigate the impact of demographic factors, and the pharmacology of the drugs, on GMS prescribing expenditure. Those aged over 75 (ẞ = 1:195) and cardiovascular prescribing (ẞ = 1:193) were the greatest contributors to annual GMS prescribing costs. Respiratory drugs (Montelukast) recorded the highest proportion and expenditure for GMS claimants under the age of 15. Drugs prescribed for the nervous system (Escitalopram, Olanzapine and Pregabalin) were highest for those between 16 and 64 years with cardiovascular drugs (Statins) were highest for those aged over 65. Females are more expensive than males and are prescribed more items across the four ATC groups, except among children under 11, (ConwayLenihan et al., 2016). This research indicates that growth in the proportion of the elderly claimants and associated levels of cardiovascular prescribing, particularly for statins, will present difficulties for Ireland in terms of cost containment. Whilst policies aimed at cost containment (co{payment charges, generic substitution, reference pricing, adjustments to GMS eligibility) can be used to curtail expenditure, health promotional programs and educational interventions should be given equal emphasis. Also policies intended to affect physicians prescribing behaviour include guidelines, information (about price and less expensive alternatives) and feedback, and the use of budgetary restrictions could yield savings.

Statin prescription initiation and lifestyle behaviour: a primary care cohort study

BACKGROUND: Statin prescribing and healthy lifestyles contribute to declining cardiovascular disease mortality. Recent guidelines emphasise the importance of giving lifestyle advice in association with prescribing statins but adherence to healthy lifestyle recommendations is sub-optimal. However, little is known about any change in patients' lifestyle behaviours when starting statins or of their recall of receiving advice. This study aimed to examine patients' diet and physical activity (PA) behaviours and their recall of lifestyle advice following initiation of statin prescribing in primary care.

METHOD: In 12 general practices, patients with a recent initial prescription of statin therapy, were invited to participate. Those who agreed received a food diary by post, to record food consumed over 4 consecutive days and return to the researcher. We also telephoned participants to administer brief validated questionnaires to assess typical daily diet (DINE) and PA level (Godin). Using the same methods, food diaries and questionnaires were repeated 3 months later. At both times participants were asked if they had changed their behaviour or received advice about their diet or PA.

RESULTS: Of 384 invited, 122 (32 %) participated; 109 (89.3 %) completed paired datasets; 50 (45.9 %) were male; their mean age was 64 years. 53.2 % (58/109) recalled receiving lifestyle advice. Of those who did, 69.0 % (40/58) reported having changed their diet or PA, compared to 31.4 % (16/51) of those who did not recall receiving advice. Initial mean daily saturated fat intake (12.9 % (SD3.5) of total energy) was higher than recommended; mean fibre intake (13.8 g/day (SD5.5)), fruit/vegetable consumption (2.7 portions/day (SD1.3)) and PA levels (Godin score 7.1 (SD13.9)) were low. Overall, although some individuals showed evidence of behaviour change, there were no significant changes in the proportions who reported high or medium fat intake (42.2 % v 49.5 %), low fibre (51.4 % v 55.0 %), or insufficient PA (80.7 % v 83.5 %) at 3-month follow-up.

CONCLUSION: Whilst approximately half of our cohort recalled receiving lifestyle advice associated with statin prescribing this did not translate into significant changes in diet or PA. Further research is needed to explore gaps between people's knowledge and behaviours and determine how best to provide advice that supports behaviour change.

Statin use and breast cancer survival: a nationwide cohort study in Scotland

Background: Preclinical evidence suggests that statins could delay cancer progression. Previous epidemiological findings have been inconsistent and some have been limited by small sample sizes, as well as certain time-related biases. This study aimed to investigate whether breast cancer patients who were exposed to statins had reduced breast cancer-specific mortality. Methods: We conducted a retrospective cohort study of 15,140 newly diagnosed invasive breast cancer patients diagnosed from 2009 to 2012 within the Scottish Cancer Registry. Dispensed medication usage was obtained from linkages to the Scottish Prescribing Information System and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Using time-dependent Cox regression models, hazard ratios (HR) and 95 % confidence intervals (CI) were calculated for the association between post-diagnostic exposure to statins (including simvastatin) and breast cancer-specific mortality. Adjustments were made for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of aspirin. Results: A total of 1,190 breast cancer-specific deaths occurred up to January 2015. Overall, after adjustment for potential confounders, there was no evidence of an association between statin use and breast cancer-specific death (adjusted HR 0.93, 95 % CI 0.77, 1.12). No significant associations were observed in dose–response analyses or in analysis of all-cause mortality. For simvastatin use specifically, a weak non-significant reduction in breast cancer-specific mortality was observed compared to non-users (adjusted HR 0.89, 95 % CI 0.73, 1.08). Statin use before diagnosis was weakly associated with a reduction in breast cancer-specific mortality (adjusted HR 0.85, 95 % CI 0.74, 0.98). Conclusion: Overall, we found little evidence of a protective association between post-diagnostic statin use and cancer-specific mortality in a large nation-wide cohort of breast cancer patients. These findings will help inform the decision whether to conduct randomised controlled trials of statins as an adjuvant treatment in breast cancer.

Statin withdrawal in people with dementia

Background: There are approximately 24 million people worldwide with dementia; this is likely to increase to 81 million by 2040. Dementia is a progressive condition, and usually leads to death eight to ten years after first symptoms. End-of-life care should emphasise treatments that optimise quality of life and physicians should minimise unnecessary or non-beneficial interventions. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors; they have become the cornerstone of pharmacotherapy for the management of hypercholesterolaemia but their ability to provide benefit is unclear in the last weeks or months of life. Withdrawal of statins may improve quality of life in people with advanced dementia, as they will not be subjected to unnecessary polypharmacy or side effects. However, they may help to prevent further vascular events in people of advanced age who are at high risk of such events.

Objectives: To evaluate the effects of withdrawal or continuation of statins in people with dementia on: cognitive outcomes, adverse events, behavioural and functional outcomes, mortality, quality of life, vascular morbidity, and healthcare costs.

Search methods: We searched ALOIS (medicine.ox.ac.uk/alois/), the Cochrane Dementia and Cognitive Improvement Group Specialised Register on 11 February 2016. We also ran additional searches in MEDLINE, EMBASE, PsycINFO, CINAHL, Clinical.Trials.gov and the WHO Portal/ICTRP on 11 February 2016, to ensure that the searches were as comprehensive and as up-to-date as possible.

Selection criteria: We included all randomised, controlled clinical trials with either a placebo or 'no treatment' control group. We applied no language restrictions.

Data collection and analysis: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, using standard methodological procedures expected by Cochrane. We found no studies suitable for inclusion therefore analysed no data.

Main results: The search strategy identified 28 unique references, all of which were excluded.

Authors' conclusions: We found no evidence to enable us to make an informed decision about statin withdrawal in dementia. Randomised controlled studies need to be conducted to assess cognitive and other effects of statins in participants with dementia, especially when the disease is advanced.

Simvastatin improves the healing of infected skin wounds of rats

This study explores the potential of the simvastatin to ameliorate inflammation and infection in open infected skin wounds of rats. Methods: Fourteen Wistar rats weighing 285±12g were used. The study was done in a group whose open infected skin wounds were treated with topical application of sinvastatina microemulsion (SIM, n=7) and a second group with wounds treated with saline 0.9 % (SAL, n=7). A bacteriological exam of the wounds fluid for gram positive and gram negative bacteria, the tecidual expression of TNFá and IL-1â by imunohistochemical technique, and histological analysis by HE stain were performed. Results: The expression of TNFa could be clearly demonstrated in lower degree in skin wounds treated with simvastatin (668.6 ± 74.7 ìm2) than in saline (2120.0 ± 327.1 ìm2). In comparison, wound tissue from SIM group displayed leukocyte infiltration significantly lower than that observed in SAL group (p<0.05). Culture results of the samples taken from wound fluid on fourth post treatment day revealed wound infection in only one rat of group simvastatin (SIM), where Proteus mirabilis, Escherchia coli and Enterobacter sp were isolated. In the rats whose wounds were treated with saline (SAL), polymicrobial infection with more than 100,000 CFU/g was detected in all the wounds. Conclusion: In addition to its antiinflammatory properties, the protective effects of simvastatin in infected open skin wounds is able to reduce infection and probably has antibacterial action. The potential to treat these wounds with statins to ameliorate inflammation and infection is promising

Effects of simvastatin in abdominal sepsis in rats

Statins are widely recognized as hypolipemic drugs, but some studies have observed anti-inflammatory and immunomodulatory effects, known as pleiotropic. The aims of this work was to study possible anti-inflammatory effects of simvastatin in abdominal sepsis. Serum pro-inflammatory cytokines and leukocytes count were determined in an experimental model of abdominal sepsis, using cecal ligation and puncture (CLP) in rats. Methods: Twenty eigth Wistar rats weighing 285±12g were randomly divided in: CLP/Sinvastatin rats (n=7), treated with 10 mg/Kg of oral simvastatin 18 and 2 hs berofe CLP; CLP/Saline group rats (n=7), treated with oral saline; group Sham/Simvastatin (n=7), treated with simvastatin, and group Sham/Saline (n=7), treated with saline. Serum TNF-α, IL-1β and IL-6 by ELISA and total leukocytes, neutrophils, lymphocytes, and eosinophils were determined 24 hs after CLP. ANOVA and Tukey test were used considering significant p<0.05. Results: It was demonstrated that serum TNF-α, IL-1β and IL-6 were respectively 364,8±42pg/mL; 46,3±18pg/mL and 28,4±13pg/mL in CLP/Sinvastatin rats, significantly lower (p<0.05) than in group CLP/Saline (778,5±86pg/ml; 176,9±46pg/ ml; 133,6±21 pg/ml, respectively). The same results were observed in total leukocytes and neutrophils counts. Conclusion: These results clearly demonstrate that simvastatin is an effective agent that reduces cytokines levels and leukocyte count in sepsis, independently of its well-known lipid-lowering effects. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects in abdominal sepsis in rats