Donald R. J. Singer

Management of Hypertension in Peripheral Arterial Disease: Does the Choice of Drugs Matter?

Cardiovascular disease and death are major life-threatening problems in patients with atheromatous peripheral arterial disease (PAD). This review focuses on management of hypertension in the context of cardiovascular risk in patients with PAD. PAD is underdiagnosed and hypertension in PAD is often poorly managed. Current evidence supports a low threshold for blood pressure treatment in PAD and intensive blood pressure control to reduce the high risk of cardiovascular disease and death in patients with PAD. Optimal treatment targets should be <140/85 mmHg, with the lower target of <130/80 mmHg in the presence of diabetes mellitus or chronic renal disease. Class-specific selection of anti-hypertensive treatments in PAD should be based on caution in relation to co-existing renovascular disease and indications and contraindications based on other significant co-morbidity. There is a pressing need for primary end-point studies targeted specifically at patients with PAD. In particular, prospective studies in PAD are needed to obtain evidence for benefits from specific blood pressure classes of treatment as well as the optimal blood pressure treatment target level. These studies should consider impact in PAD of different demographic, risk factor, and co-morbidity profiles.

Effects of cyclic strain on endothelial cell apoptosis and tubulogenesis are dependent on ROS production via NAD(P)H subunit p22phox

OBJECTIVEnVascular endothelial cells (ECs) are constantly exposed to blood flow associated forces such as cyclic strain due to blood pressure, which affects ECs survival and angiogenesis by producing ROS via NAD(P)H oxidase. NAD(P)H oxidase subunit p22phox is reported to be related to the development of atherosclerosis and increased levels of p22phox mRNA are correlated to ECs proliferation. However, the importance and signaling mechanism of p22phox on ECs survival and angiogenesis under cyclic strain are unclear.nnnMETHODSn5%-20% cyclic strain were applied by the Flexercell system to simulate in vivo environment of human ECs; the effect of p22phox on mechanical ECs survival mechanism and tubulogenesis was determined by western blot and 3-D tissue culture by knocking down p22phox expression via shRNA plasmid.nnnRESULTSnKnockdown of p22phox induced expression of cleaved caspase-3 and decreased cell viability ratio (CVR). 5% strain increased and 20% strain decreased CVR of shp22phox cells. There were complex biphasic effects of cyclic strain on ECs survival signaling. 5% strain continuously increased Akt phosphorylation; 20% strain increased after 10min stimulation and decreased Akt phosphorylation lately. 5% strain increased and 20% strain decreased eNOS phosphorylation. Knockdown of p22phox decreased Akt and eNOS phosphorylation with or without cyclic strain. ROS production was increasingly stimulated progressively by strain via the p22phox pathway. 5% strain increased and 20% strain decreased total NO production and vascular tubulogenesis via p22phox pathway.nnnCONCLUSIONnROS production is pivotal to responses to physiological or pathological strain. Physiological strain increases but pathological strain decreases ECs survival and tubulogenesis, and these effects occur via the NAD(P)H subunit p22phox pathway.

The impact of interventions by pharmacists in community pharmacies on control of hypertension: a systematic review and meta-analysis of randomized controlled trials.

AIMSnTo undertake a systematic review and meta-analysis of randomized controlled trials concerned with the impact of community pharmacist-led interventions on blood pressure control in patients with hypertension.nnnMETHODSnEight electronic databases were searched up to 30 November 2013, with no start date (Web of Science, Embase, The Cochrane Library, Medline Ovid, Biomed Central, Biosis Citation Index, CINAHL, PsycINFO). All studies included were randomized controlled trials involving patients with hypertension, with or without cardiovascular-related co-morbidities, with difference in blood pressure as an outcome. Data collected included the study design, baseline characteristics of study populations, types of interventions and outcomes. The Cochrane tool was used to assess risk of bias.nnnRESULTSnFrom 340 articles identified on initial searching, 16 randomized controlled trials (3032 patients) were included. Pharmacist-led interventions were patient education on hypertension, management of prescribing and safety problems associated with medication, and advice on lifestyle. These interventions were associated with significant reductions in systolic [11 studies (2240 patients); -6.1u2009mmHg (95% confidence interval, -3.8 to -8.4u2009mmHg); P < 0.00001] and diastolic blood pressure [11 studies (2246 patients); -2.5u2009mmHg (95% confidence interval, -1.5 to -3.4u2009mmHg); P < 0.00001].nnnCONCLUSIONSnCommunity pharmacist-led interventions can significantly reduce systolic and diastolic blood pressure. These interventions could be useful for improving clinical management of hypertension.

Abnormal Vasoconstrictor Responses to Angiotensin II and Noradrenaline in Isolated Small Arteries From Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Background and Purpose— Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by ultrastructural abnormalities in small cerebral and systemic vessels. We assessed vasomotor function in systemic small arteries in CADASIL. Methods— We studied 10 CADASIL patients and 10 control subjects. Resistance arteries isolated from gluteal biopsies were mounted on small-vessel myographs, and concentration responses were determined for vasoconstrictors (noradrenaline, angiotensin II, and endothelin-I) and vasodilators (acetylcholine, bradykinin, spermine-NONOate, and nifedipine). Maximum data are shown as percent potassium contraction. Results— There was reduced potency for noradrenaline in CADASIL (CADASIL [38 arteries]: EC50, 240 nmol/L; control subjects [27 arteries]: EC50, 100 nmol/L; 2-way analysis of variance, F=9.76, P =0.002). Maximum response to angiotensin II was greater in CADASIL (120±8% versus 97±5% in control subjects; F=4.28, P =0.043). Tachyphylaxis to angiotensin II occurred in all control subjects studied but in only 3 of 9 CADASIL subjects (P =0.011, Fisher’s exact test). Vasodilation was similar in CADASIL patients compared with control subjects for endothelium-dependent dilators (acetylcholine and bradykinin) and endothelium-independent dilators (spermine-NONOate and nifedipine). Conclusions— These results suggest a selective systemic microvascular vasoconstrictor abnormality in CADASIL in noradrenaline and angiotensin II pathways that is not explained by vasodilator impairment in endothelium or vascular smooth muscle. This could have important implications for prophylaxis and treatment of CADASIL.

Adverse drug reactions: current issues and strategies for prevention and management

Adverse drug reactions (ADRs) are common, frequently serious and cause considerable morbidity and mortality. In addition to human costs, ADRs place considerable economic burden on society and already-stretched healthcare systems. Much work has been done to determine potential causes, commonly responsible drugs and susceptible patient groups. To this end, various national pharmacovigilance schemes exist to collate information about ADRs. Despite this, levels of ADR reporting are universally poor, with ADRs remaining a significant clinical problem. Therefore, more effective dissemination and implementation of available knowledge is needed, together with better use of the systems already in place. Local ADR centres and teams, in close liaison with national centres, appear to be an important part of this process and need to be developed within healthcare systems. In addition, there is now evidence to suggest that better use of informatics will help to facilitate this, together with wider availability of electronic notes and greater use of computer-prescribing. Although advancing technology may help to make the use of medicines safer, more effective and more specific in the future, investment to develop informatics infrastructure and local ADR teams is now needed in our healthcare systems.

Xanthine oxidase interaction with vascular endothelial growth factor in human endothelial cell angiogenesis.

Objectives: Reduced capillary density occurs early in cardiovascular diseases. Oxidant stress is implicated in endothelial apoptosis. We investigated the effects of xanthine oxidase (XO) on endothelial survival signaling: protein kinase B/Akt, its cross‐talk with p38 MAPK and apoptosis pathways, and its effect on vascular tube formation in vascular endothelial growth factor (VEGF)‐simulated human umbilical vein cells.

Registry Report on Kinetics of Rescue Antiplatelet Treatment to Abolish Cerebral Microemboli After Carotid Endarterectomy

Background and Purpose— Cerebral microemboli signals (MES) are associated with increased risk of acute stroke syndromes. We compared the effects on cerebral microemboli after carotid endarterectomy of tirofiban with dextran-40. Methods— We used transcranial Doppler ultrasound to study transient MES acutely after carotid endarterectomy between August 2000 and December 2010 in 128 subjects refractory to preoperative antiplatelet treatment. Antithrombotic treatment was given for MES ≥50 hour−1 (tirofiban: 40 patients [age 74 ± 1 {SEM}, males 27, and white 38]; dextran-40: 34 patients [age 69 ± 2, males 22, white 30]). In 54 patients with MES <50 hour−1 (age 71 ± 1, male 36, white 52), MES were monitored during their spontaneous resolution (controls). Data are median (interquartile range). Results— The time to 50% reduction in MES (tirofiban 23 minutes [15–28]; dextran-56 [43–83]; controls 30 [22–38]; P<0.001, Kruskal-Wallis analysis) and for complete MES resolution (tirofiban 68 minutes [53–94]; dextran-113 [79–146]; controls 53 [49–68]; P<0.001, Kruskal-Wallis analysis) were shorter with tirofiban. The early cardiovascular event rate was similar with tirofiban compared with controls but increased in patients who received dextran. Conclusions— These findings suggest that transcranial Doppler-directed tirofiban therapy is more effective than dextran-40 in suppression of cerebral microemboli after carotid endarterectomy.

Using companion and coupled diagnostics within strategy to personalize targeted medicines

Regulatory authorities expect the pharmaceutical and biotechnology industries to accelerate their development of companion diagnostics and companion therapeutics towards the goal of personalized medicine, and expect health services to fund, prescribers to adopt and patients to accept these new therapeutic technologies. Expected benefits from more systematic development of combination products (companion diagnostic and its companion therapeutic) are expected to include safer and improved clinical and cost-effective use of medicines, more efficient patient selection for clinical trials, more cost-effective treatment pathways for health services, and a more profitable approach for drug developers. This review discusses challenges to timely development of companion diagnostics and provides case studies of single and multiple protein and genetic biomarkers of clinical response and risk of adverse drug effects.

Prospective validation study of transorbital Doppler ultrasound imaging for the detection of transient cerebral microemboli.

Transient cerebral microemboli are independent biomarkers of early risk of ischaemic stroke in acute carotid syndromes. Transcranial Doppler imaging (TCD) through the temporal bone is the standard method for detection of cerebral microemboli, but an acoustic temporal bone window for TCD is not available in around one in seven patients. Transorbital Doppler imaging (TOD) has been used when TCD is not possible. The aim of this study was to validate the use of TOD against TCD for detecting cerebral microemboli.

International Hippocrates prize for poetry and medicine

Poetry and medicine may appear an unnatural partnership and it is thought by some that poetry on medical subjects is a modern development. However there is a tradition linking poetry and medicine at least as old as the ancient Greeks. Their God Apollo was associated with medicine and healing, poetry, music and dance. Formal discussion of medical themes in poetry dates at least to the Roman poet Lucretius, writing in the first century BC. The scientific and philosophical subjects he covered in his 6 book treatise on the nature of things, De rerum natura,1 include discussion of biological processes such as digestion and sleep (Book 4), and a harrowing account of plague (Book 6).nnIn the two thousand years since Lucretius, poetry has included medical subjects of every description, from Robert Burnss ‘Address to the Tooth-Ache’, to the Australian poet A. D. Hopes 1967 ‘On an Engraving by Casserius’, to Philip Larkins observation of ambulances going about their daily missions in the streets where we all live. Burnss curse must have been echoed by many toothache sufferers down the years:nn> My curse on your envenomd stang …n> n> Wi gnawing vengeance;n> n> Tearing my …