A Review of Perindopril in the Reduction of Cardiovascular Events

Duncan J CampbellSt. Vincent’s Institute of Medical Research and the Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, AustraliaBackground: Angiotensin-converting enzyme inhibitors (ACEI) have a well-established role in the prevention of cardiovascular events in hypertension, left ventricular dysfunction, and heart failure. More recently, ACEI have been shown to prevent cardiovascular events in individuals with increased cardiovascular risk, where hypertension, left ventricular dysfunction, or heart failure was not the primary indication for ACEI therapy.Objective: To review studies of the effects of the ACEI perindopril on cardiovascular events.Method: The EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease Study), PROGRESS (Perindopril Protection Against Recurrent Stroke Study), and ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm) trials are reviewed.Results: Perindopril alone reduced cardiovascular events in subjects with stable coronary heart disease. Perindopril in combination with indapamide reduced cardiovascular events in subjects with cerebrovascular disease. Perindopril in combination with amlodipine reduced cardiovascular events in subjects with hypertension.Conclusion: Perindopril reduced cardiovascular events. The reduction of cardiovascular events by perindopril was in large part associated with reduction of blood pressure, and greater reduction in cardiovascular events was associated with greater reduction of blood pressure. Perindopril may need to be combined with other antihypertensive agents to maximize reduction of cardiovascular events.Keywords: Angiotensin-converting enzyme inhibitor, hypertension, coronary heart disease, stroke, myocardial infarction, heart failur

Neprilysin Inhibitors and Bradykinin

Bradykinin has important physiological actions related to the regulation of blood vessel tone and renal function, and protection from ischemia reperfusion injury. However, bradykinin also contributes to pathological states such as angioedema and inflammation. Bradykinin is metabolized by many different peptidases that play a major role in the control of bradykinin levels. Peptidase inhibitor therapies such as angiotensin converting enzyme (ACE) and neprilysin inhibitors increase bradykinin levels, and the challenge for such therapies is to achieve the beneficial cardiovascular and renal effects without the adverse consequences such as angioedema that may result from increased bradykinin levels. Neprilysin also metabolizes natriuretic peptides. However, despite the potential therapeutic benefit of increased natriuretic peptide and bradykinin levels, neprilysin inhibitor therapy has only modest efficacy in essential hypertension and heart failure. Initial attempts to combine neprilysin inhibition with inhibition of the renin angiotensin system led to the development of omapatrilat, a drug that combines ACE and neprilysin inhibition. However, omapatrilat produced an unacceptably high incidence of angioedema in patients with hypertension (2.17%) in comparison with the ACE inhibitor enalapril (0.68%), although angioedema incidence was less in patients with heart failure with reduced ejection fraction (HFrEF) treated with omapatrilat (0.8%), and not different from that for enalapril therapy (0.5%). More recently, LCZ696, a drug that combines angiotensin receptor blockade and neprilysin inhibition, was approved for the treatment of HFrEF. The approval of LCZ696 therapy for HFrEF represents the first approval of long-term neprilysin inhibitor administration. While angioedema incidence was acceptably low in HFrEF patients receiving LCZ696 therapy (0.45%), it remains to be seen whether LCZ696 therapy for other conditions such as hypertension is also accompanied by an acceptable incidence of angioedema

A phase 1 trial of nebulised heparin in acute lung injury

INTRODUCTION: Animal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. No human studies have been undertaken to date. We assessed the feasibility, safety and potential anticoagulant effects of administration of nebulised heparin to patients with ALI. METHODS: An open label phase 1 trial of four escalating doses of nebulised heparin was performed. A total of 16 ventilated patients with ALI were studied. The first group was administered a total of 50,000 U/day, the second group 100,000 U/day, the third group 200,000 U/day and the fourth group 400,000 U/day. Assessments of lung function included the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction. Monitoring of anticoagulation included the activated partial thromboplastin time (APTT) and the thrombin clotting time. Bronchoalveolar lavage fluid was collected and the prothrombin fragment and tissue plasminogen activator levels were assessed. Analysis of variance was used to compare the effects of dose. RESULTS: No serious adverse events occurred for any dose. The changes over time for the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction levels were similar for all doses. A trend to increased APTT and thrombin clotting time levels was present with higher doses (P = 0.09 and P = 0.1, respectively). For the highest dose, the APTT reached 64 seconds; following cessation of nebulised heparin, the APTT fell to 39 seconds (P = 0.06). In bronchoalveolar lavage samples a trend to reduced prothrombin fragment levels was present with higher doses (P = 0.1), while tissue plasminogen activator levels were similar for all doses. CONCLUSION: Administration of nebulised heparin to mechanically ventilated patients with ALI is feasible. Nebulised heparin was not associated with any serious adverse events, and at higher doses it increased APTT levels. Larger trials are required to further investigate the safety and efficacy of nebulised heparin. In these trials due consideration must be given to systemic anticoagulant effects. TRIAL REGISTRATION: Australian Clinical trials registry ACTRN12606000388516

Mood Management Intervention for College Smokers with Elevated Depressive Symptoms: A Pilot Study

Objective This pilot study examined smoking reduction and cessation among college smokers with elevated depressive symptomatology participating in a group-based behavioral counseling, mood management, and motivational enhancement combined intervention (CBT). Participants & Methods Fifty-eight smokers (smoked ≥ 6 days in the past 30) were randomized to six sessions of CBT (n=29) or a nutrition-focused attention-matched control group (CG, n=29). Results Relative to CG participants, significantly more CBT participants reduced smoking intensity by 50% (χ2(1, N=58)=4.86, p=.028) at end of treatment. Although CBT participants maintained smoking reductions at 3- and 6-month follow-up, group differences were no longer significant. No group differences in cessation emerged. Finally, participants in both groups evidenced increased motivation to reduce smoking at end of treatment (F(1, 44)=11.717, p=.001, ηp2=.207). Conclusions Findings demonstrate the utility of this intervention for smoking reduction and maintenance of reductions over time among a population of college students with elevated depressive symptomatology

Barriers and enablers to the effective implementation of robotic assisted surgery

Acknowledgements We thank the participants - specialty leads, surgeons, scrub nurses, the anaesthetist, policy makers/commissioners and industry representatives - for their time, energy and invaluable insight to assist this research. We also thank Jared Torkington, Arul Immanuel, and Richard Kerr for providing a clinical review of the work prior to submission. Funding: MKC and DB were funded via an unrestricted grant (https://www.intuitive.com/en-gb) awarded by Intuitive Surgical (European Research Board). The funder had no role in the conception, design, conduct, analysis, or interpretation of the study.Peer reviewedPublisher PD

Q Fever Update, Maritime Canada

Since the 1990s, reports of Q fever in Nova Scotia, Canada, have declined. Passive surveillance for Q fever in Nova Scotia and its neighboring provinces in eastern Canada indicates that the clinical manifestation of Q fever in the Maritime provinces is pneumonia and that incidence of the disease may fluctuate

Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial

INTRODUCTION: Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulised heparin improved lung function in patients expected to require prolonged mechanical ventilation. METHODS: Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomised placebo-controlled trial of nebulised heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomisation. RESULTS: Nebulised heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point ventilator free days amongst survivors at day 28 (22.6 4.0 versus 18.0 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events. CONCLUSIONS: Nebulised heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings. Trial registration: The Australian Clinical Trials Registry (ACTR-12608000121369

Measuring the effects of fractionated radiation therapy in a 3D prostate cancer model system using SERS nanosensors.

Multicellular tumour spheroids (MTS) are three-dimensional cell cultures that possess their own microenvironments and provide a more meaningful model of tumour biology than monolayer cultures. As a result, MTS are becoming increasingly used as tumor models when measuring the efficiency of therapies. Monitoring the viability of live MTS is complicated by their 3D nature and conventional approaches such as fluorescence often require fixation and sectioning. In this paper we detail the use of Surface Enhanced Raman Spectroscopy (SERS) to measure the viability of MTS grown from prostate cancer (PC3) cells. Our results show that we can monitor loss of viability by measuring pH and redox potential in MTS and furthermore we demonstrate that SERS can be used to measure the effects of fractionation of a dose of radiotherapy in a way that has potential to inform treatment planning.EaStCHEM, NHS Lothian, Jamie King Cancer Research FundThis is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C6AN01032