Dvojni lijekovi primakina i nesteroidnih protuupalnih lijekova: Sinteza, hvatanje slobodnih radikala, antioksidativno djelovanje i keliranje Fe2+ iona

Novel primaquine conjugates with non-steroidal anti-inflammatory drugs (PQ-NSAIDs, 4a-h) were prepared, fully chemically characterized and screened for radical scavenging and antioxidant activities. The synthetic procedure leading to twin drugs 4a-h involved two steps: i) preparation of NSAID benzotriazolides 3a-h from the corresponding NSAID (ibuprofen, ketoprofen, fenoprofen, ketoprofen hydroxy and methylene analogues, diclofenac or indomethacin) and benzotriazole carboxylic acid chloride (BtCOCl, 1), ii) reaction of intermediates 3a-h with PQ. The prepared PQ-NSAIDs exerted moderate activities in the DPPH free radical test and -carotene-linoleic acid assay. Moreover, ketoprofen derivatives 4d and 4b demonstrated a notable Fe2+ chelating ability as well. On the other hand, negligible antiproliferative and antituberculotic effects of conjugates 4a-h were observed.U radu je opisana sinteza novih konjugata primakina s nesteroidnim protuupalnim lijekovima (PQ-NSAIDs, 4a-h), njihova potpuna karakterizacija te testiranje sposobnosti hvatanja slobodnih radikala i antioksidativnog djelovanja. Sintetski postupak za pripravu dvojnih lijekova 4a-h uključuje dva koraka: i) pripravu NSAID-benzotriazolida 3a-h iz odgovarajućih nesteroidnih protuupalnih lijekova (ibuprofena, ketoprofena, fenoprofena, hidroksi i metilenskih analoga ketoprofena, diklofenaka i indometacina) i klorida 1-benzotriazol karboksilne kiseline (BtCOCl, 1), ii) reakciju intermedijera 3a-h s primakinom. Novi PQ-NSAID konjugati pokazuju umjerenu sposobnost hvatanja slobodnih radikala u DPPH testu te umjereno antioksidativno djelovanje u pokusu s -karotenom i linoleinskom kiselinom. Osim toga, derivati ketoprofena 4d i 4b imaju primjetnu sposobnost keliranja Fe2+ iona. Svi konjugati 4a-h pokazuju vrlo slabo antiproliferativno i antituberkulotsko djelovanje

Left atrial function in heart failure with mid-range ejection fraction differs from that of heart failure with preserved ejection fraction: a 2D speckle-tracking echocardiographic study

Aims: Heart failure (HF) with mid-range ejection fraction (HFmrEF) shares similar diagnostic criteria to HF with preserved ejection fraction (HFpEF). Whether left atrial (LA) function differs between HFmrEF and HFpEF is unknown. We, therefore, used 2D-speckle-tracking echocardiography (2D-STE) to assess LA phasic function in patients with HFpEF and HFmrEF. Methods and results: Consecutive outpatients diagnosed with HF according to current European recommendations were prospectively enrolled. There were 110 HFpEF and 61 HFmrEF patients with sinus rhythm, and 37 controls matched by age. LA phasic function was analysed using 2D-STE. Peak-atrial longitudinal strain (PALS), peak-atrial contraction strain (PACS), and PALS-PACS were measured reflecting LA reservoir, pump, and conduit function, respectively. Among HF groups, most of left ventricular (LV) diastolic function measures, and LA volume were similar. Both HF groups had abnormal LA phasic function compared with controls. HFmrEF patients had worse LA phasic function than HFpEF patients even among patients with LA enlargement. Among patients with normal LA size, LA reservoir, and pump function remained worse in HFmrEF. Differences in LA phasic function between HF groups remained significant after adjustment for confounders. Global PALS and PACS were inversely correlated with brain natriuretic peptide, LA volume, E/A, E/e', pulmonary artery systolic pressure, and diastolic dysfunction grade in both HF groups. Conclusion: LA phasic function was worse in HFmrEF patients compared with those with HFpEF regardless of LA size, and independent of potential confounders. These differences could be attributed to intrinsic LA myocardial dysfunction perhaps in relation to altered LV function

Hepatoprotective and nephroprotective activities of Juniperus sabina L. aerial parts

Context: Previous studies indicated that Juniperus species exhibited promising hepatoprotective activity. Aims: To evaluate the hepatoprotective and nephroprotective activity of the total alcohol extract of the aerial parts of Juniperus sabina against carbon tetrachloride (CCl4) induced toxicity using male Wistar rats as experimental animals. Methods: Daily oral administration of two doses (200 and 400 mg/kg) of the total extract of the aerial parts of J. sabina for seven days followed by one dose of CCl4 (1.25 mL/kg) at day 6. Liver and kidney functions were monitored via measuring serum and tissue parameters as well as histopathological study. Normal rats, rats treated only with CCl4 and rats treated with CCl4 and silymarin were used as controls. Results: The higher dose showed 47, 50, 38, 17 and 42% decrease in the levels of AST, ALT, GGT, ALP, and bilirubin respectively. Animals received the total extract of J. sabina showed a significant dose-dependent recovery of the NP-SH contents, total proteins, and reduction the level of MDA in both liver and kidney tissues. Histopathological study revealed improvement in the architecture of hepatocytes and kidney cells. Conclusions: The hepatoprotective effect offered by J. sabina crude extract at the two used doses was found to be significant in all serum parameters. Histopathological study revealed moderate improvement in the architecture of the liver cells that add another indication of protection. Improvement of kidney function was less than liver function

Study Protocol – Insight 46 Cardiovascular: A Sub-study of the MRC National Survey of Health and Development

The commonest causes of dementia are Alzheimer's disease and vascular cognitive impairment. Although these conditions have been viewed as distinct entities, there is increasing evidence that neurodegenerative and vascular pathologies interact or overlap to cause cognitive decline, and that at least in some cases individuals at risk of cognitive decline exhibit abnormal cardiovascular physiology long before emergence of disease. However, the mechanisms linking haemodynamic disturbances with cognitive impairment and the various pathologies that cause dementia are poorly understood. A sub-sample of 502 participants from the Medical Research Council National Survey of Health and Development (NSHD) have participated in the first visit of a neuroscience sub-study referred to as Insight 46, where clinical, cognitive, imaging, and lifestyle data have been collected for the purpose of elucidating the pathological changes preceding dementia. This paper outlines the cardiovascular phenotyping performed in the follow-up visit of Insight 46, with the study participants now aged 74. In addition to standard cardiovascular assessments such as blood pressure measurements, echocardiography, and electrocardiography (ECG), functional Near Infrared Spectroscopy (fNIRS) has been included to provide an assessment of cerebrovascular function. A detailed description of the fNIRS protocol along with preliminary results from pilot data is presented. The combination of lifestyle data, brain structure/function, cognitive performance, and cardiovascular health obtained not only from Insight 46, but also from the whole NSHD provides an exciting opportunity to advance our understanding of the cardiovascular mechanisms underlying dementia and cognitive decline, and identify novel targets for intervention

Imaging Protocol, Feasibility, and Reproducibility of Cardiovascular Phenotyping in a Large Tri-Ethnic Population-Based Study of Older People: The Southall and Brent Revisited (SABRE) Study

Background: People of South Asian and African Caribbean ethnicities living in UK have a high risk of cardiometabolic disease. Limited data exist regarding detailed cardiometabolic phenotyping in this population. Methods enabling this are widely available, but the practical aspects of undertaking such studies in large and diverse samples are seldom reported. / Methods: The Southall and Brent Revisited (SABRE) study is the UK's largest tri-ethnic longitudinal cohort. Over 1,400 surviving participants (58–85 years) attended the 2nd study visit (2008–2011); during which, comprehensive cardiovascular phenotyping, including 3D-echocardiography [3D-speckle-tracking (3D-STE)], computed tomography, coronary artery calcium scoring, pulse wave velocity, central blood pressure, carotid artery ultrasound, and retinal imaging, were performed. We describe the methods used with the aim of providing a guide to their feasibility and reproducibility in a large tri-ethnic population-based study of older people. / Results: Conventional echocardiography and all vascular measurements showed high feasibility (>90% analyzable of clinic attendees), but 3D-echocardiography (3DE) and 3D-STE were less feasible (76% 3DE acquisition feasibility and 38% 3D-STE feasibility of clinic attendees). 3D-STE feasibility differed by ethnicity, being lowest in South Asian participants and highest in African Caribbean participants (p < 0.0001). Similar trends were observed in men (P < 0.0001) and women (P = 0.005); however, in South Asians, there were more women with unreadable 3D-images compared to men (67 vs. 58%). Intra- and inter-observer variabilities were excellent for most of conventional and advanced echocardiographic measures. The test-retest reproducibility was good-excellent and fair-good for conventional and advanced echocardiographic measures, respectively, but lower than when re-reading the same images. All vascular measures demonstrated excellent or fair-good reproducibility. / Conclusions: We describe the feasibility and reproducibility of detailed cardiovascular phenotyping in an ethnically diverse population. The data collected will lead to a better understanding of why people of South Asian and African Caribbean ancestry are at elevated risk of cardiometabolic diseases

Association between carotid atherosclerosis and brain activation patterns during the Stroop task in older adults: An fNIRS investigation

There is an increasing body of evidence suggesting that vascular disease could contribute to cognitive decline and overt dementia. Of particular interest is atherosclerosis, as it is not only associated with dementia, but could be a potential mechanism through which cardiovascular disease directly impacts brain health. In this work, we evaluated the differences in functional near infrared spectroscopy (fNIRS)-based measures of brain activation, task performance, and the change in central hemodynamics (mean arterial pressure (MAP) and heart rate (HR)) during a Stroop color-word task in individuals with atherosclerosis, defined as bilateral carotid plaques (n = 33) and healthy age-matched controls (n = 33). In the healthy control group, the left prefrontal cortex (LPFC) was the only region showing evidence of activation when comparing the incongruous with the nominal Stroop test. A smaller extent of brain activation was observed in the Plaque group compared with the healthy controls (1) globally, as measured by oxygenated hemoglobin (p = 0.036) and (2) in the LPFC (p = 0.02) and left sensorimotor cortices (LMC)(p = 0.008) as measured by deoxygenated hemoglobin. There were no significant differences in HR, MAP, or task performance (both in terms of the time required to complete the task and number of errors made) between Plaque and control groups. These results suggest that carotid atherosclerosis is associated with altered functional brain activation patterns despite no evidence of impaired performance of the Stroop task or central hemodynamic changes