A pilot study on reparixin, a CXCR1/2 antagonist, to assess safety and efficacy in attenuating ischaemia-reperfusion injury and inflammation after on-pump coronary artery bypass graft surgery.

Reparixin, a CXCR 1/2 antagonist, has been shown to mitigate ischaemia-reperfusion injury (IRI) in various organ systems in animals, but data in humans are scarce. The aim of this double-blinded, placebo-controlled pilot study was to evaluate the safety and efficacy of reparixin to suppress IRI and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG). Patients received either reparixin or placebo (n = 16 in each group) after induction of anaesthesia until 8 h after cardiopulmonary bypass (CPB). We compared markers of systemic and pulmonary inflammation, surrogates of myocardial IRI and clinical outcomes using Mann-Whitney U- and Fisher's exact tests. Thirty- and 90-day mortality was 0% in both groups. No side effects were observed in the treatment group. Surgical revision, pleural and pericardial effusion, infection and atrial fibrillation rates were not different between groups. Reparixin significantly reduced the proportion of neutrophil granulocytes in blood at the beginning [49%, interquartile range (IQR) = 45-57 versus 58%, IQR = 53-66, P = 0·035], end (71%, IQR = 67-76 versus 79%, IQR = 71-83, P = 0·023) and 1 h after CPB (73%, IQR = 71-75 versus 77%, IQR = 72-80, P = 0·035). Reparixin patients required a lesser positive fluid balance during surgery (2575 ml, IQR = 2027-3080 versus 3200 ml, IQR = 2928-3778, P = 0·029) and during ICU stay (2603 ml, IQR = 1023-4288 versus 4200 ml, IQR = 2313-8160, P = 0·021). Numerically, more control patients required noradrenaline ≥ 0·11 µg/kg/min (50 versus 19%, P = 0·063) and dobutamine (50 versus 25%, P = 0·14). Therefore, administration of reparixin in CABG patients appears to be feasible and safe. It concurrently attenuated postoperative granulocytosis in peripheral blood.

Decreased renal function in hypertensive emergencies.

Data about acute renal function in hypertensive crises are scarce. We hypothesised that acute kidney damage could result from hypertensive emergency (HE), as indicated by the earliest biomarker of kidney injury, neutrophil gelatinase-associated lipocalin (NGAL). Thus, we compared renal function between patients with HE, patients with urgencies and normotensive controls. Sixty emergency department patients were enroled in a prospective, cross-sectional study. Creatinine, blood urea nitrogen (BUN), NGAL and cystatin C were measured and estimated glomerular filtration rate was calculated (eGFR). Creatinine and BUN were significantly higher and eGFR was significantly lower in HE as compared with urgencies or controls (P < 0.01). Similarly, cystatin C and NGAL levels were significantly higher in emergencies compared with the other groups (P < 0.001). All renal function parameters were similar between urgencies and controls. Among HE, NGAL was significantly higher (61%) in patients with pulmonary oedema than in those with cerebral events (P = 0.008), whereas the other parameters were not significantly different. In conclusion, this cross-sectional investigation showed that markers of acute and chronic kidney injury were higher in patients with HE than in urgencies or controls. These results should encourage further studies to better characterise the role of acute kidney damage in hypertensive pulmonary oedema, and HE in general.

Establishment of a low dose canine endotoxemia model to test anti-inflammatory drugs: effects of prednisolone.

Infusion of low doses of lipopolysaccharide (LPS) in human volunteers provides a standardised model to study novel anti-inflammatory drugs. However, low dose endotoxemia is not well characterised in animals larger than rodents and trials with immunomodulating substances are scarce. We conducted a dose-finding study to establish a canine endotoxemia model combining optimal cytokine response with minimal burden for the animals. We thereafter evaluated the pharmacodynamics and pharmacokinetics (PK) of prednisolone. For dose-finding, dogs randomly received a single bolus of 0.03, 0.1 or 1.0 microg/kg BW LPS i.v. The second part was a randomised, placebo controlled trial with 4 parallel groups. Either 0.25, 0.5 or 5mg/kgBW prednisolone or placebo were given for 3 days. On day 3, all animals received 0.1microg/kg BW LPS i.v. Blood was sampled to measure interleukin 6 (IL-6) and tumor necrosis factor-alpha, C-reactive protein, prednisolone and cortisol concentrations. In accordance with human endotoxemia, LPS substantially and dose-dependently increased IL-6 and TNF-alpha several 1000-fold. Prednisolone significantly attenuated the LPS-induced IL-6 and TNF-alpha responses by a maximum of 96 percent (p less than 0.03 for all treatment groups) and significantly reduced peak cortisol concentrations in a dose-dependent way (p less than 0.004 for all treatment groups). PK showed a non-linear kinetic. In conclusion, this dog model could provide a reliable setting to test experimental drugs for canine or human use.

Hypertensive emergencies are associated with elevated markers of inflammation, coagulation, platelet activation and fibrinolysis.

Data from in vitro and animal experiments suggest that progressive endothelial damage with subsequent activation of coagulation and inflammation have a key role in hypertensive crisis. However, clinical investigations are scarce. We hypothesized that hypertensive emergencies are associated with enhanced inflammation, endothelial- and coagulation activation. Thus, we enrolled 60 patients admitted to an emergency department in a prospective, cross-sectional study. We compared markers of coagulation, fibrinolysis (prothrombin fragment F(1+2), plasmin-antiplasmin complexes, plasmin-activator inhibitor, tissue plasminogen activator), platelet- and endothelial activation and inflammation (P-selectin, C-reactive protein, leukocyte counts, fibrinogen, soluble vascular adhesion molecule-1, intercellular adhesion molecule-1, myeloperoxidase and asymmetric dimethylarginine) between hypertensive emergencies, urgencies and normotensive patients. In hypertensive emergencies, markers of inflammation and endothelial activation were significantly higher as compared with urgencies and controls (P<0.05). Likewise, plasmin-antiplasmin complexes were 75% higher in emergencies as compared with urgencies (P<0.001), as were tissue plasminogen-activator levels (∼30%; P<0.05) and sP-selectin (∼40%; P<0.05). In contrast, similar levels of all parameters were found between urgencies and controls. We consistently observed elevated markers of thrombogenesis, fibrinolysis and inflammation in hypertensive emergencies as compared with urgencies. Further studies will be needed to clarify if these alterations are cause or consequence of target organ damage.

[Effects of terazosine and atenolol on serum lipids in essential hypertension]. / Effekte von Terazosin und Atenolol auf die Serumlipide bei essentieller Hypertonie.

BACKGROUND: Only a few studies have evaluated the efficacy of alpha-blocking agents in combination with other classes of antihypertensive agents, especially in patients not adequately controlled by monotherapy. As alpha-blockers have an additional beneficial effect on serum lipids, it seems reasonable to use them instead of beta-blockers or diuretics in insufficiently treated hypertensive patients with hyperlipidemia. MATERIALS AND METHODS: All patients with insufficient blood pressure control with either a calcium channel blocker or an ACE inhibitor and evidence of hyperlipidemia (total serum cholesterol > 5.69 mmol/L) were included into an open, randomized and prospective study to evaluate the effects of terazosin and atenolol on lipid profile in hypertensive patients. The patients received either terazosin (n = 26; dose 1 to 10 mg) or atenolol (n = 28; dose 25 to 100 mg). Blood pressure was assessed by 24-hour ambulatory blood pressure measurement and serum lipids were evaluated at the time of inclusion and 12 weeks later. RESULTS: Blood pressure was similar after 12 weeks of treatment (atenolol: 129 (9)/75 (7) mm Hg; terazosin: 128 (11)/75 (9) mm Hg) and total cholesterol was significantly reduced after 12 weeks of treatment (atenolol: Diff 0-12 weeks: 7.29 (1.32) versus 6.62 (1.14 mmol/L, p = 0.006; terazosin: 7.34 (0.93) versus 6.67 (0.85) mmol/L, p = 0.002). In the terazosin group, HDL-cholesterol increased and triglycerides decreased significantly (Diff 0-12 weeks: HDL-chol: 1.55 (0.31) versus 1.63 (0.44) mmol/L, p = 0.04; TG: 1.93 (1.17) versus 1.34 (0.64) mmol/L, p = 0.03). Comparing both groups a significant difference was found with regard to HDL-cholesterol and triglycerides (atenolol versus terazosin: HDL-chol: -0.05 (0.12) versus +0.08 (0.1) mmol/L, p = 0.04; TG: -0.18 (0.61) versus--0.59 (0.6), p = 0.03). CONCLUSIONS: The alpha-blocker terazosin is as effective as atenolol when combined with either an ACE inhibitor or a calcium-channel blocker as a part of a multidrug regimen to achieve sufficient blood pressure control. In addition, terazosin is superior to atenolol with regard to the effect on the lipid profile of hypertensive and hyperlipidemic patients and seems therefore a reasonable alternative to beta-blockers in hypertensive patients with hyperlipidemia.

Recalibration of the point-of-care test for CARDIAC T Quantitative with Elecsys Troponin T 3rd generation.

The rapid troponin T assay CARDIAC T Quantitative was recalibrated using Elecsys Troponin T 3rd Generation as a new reference method. This paper presents the method comparisons at six centres using the new reference method. Method comparison between CARDIAC T Quantitative versus Elecsys Troponin T 3rd Generation were performed using 319 samples from patients with acute coronary syndromes. The quality of the CARDIAC T Quantitative was controlled by a daily single determination of CARDIAC Control Troponin T, and for the Elecsys Troponin T 3rd Generation, the Elecsys controls were included in each run. The results for the control materials for the CARDIAC T Quantitative were between 93% and 107% of the target values. The CV ranged from 7% to 16%. From the regression analysis, according to Bablok and Passing (y=1.07x) and the Bland and Altman plot, the bias between CARDIAC T Quantitative and Elecsys Troponin T 3rd Generation is from +6% to +7%. The correlation coefficient is 0.93, and a 3x3 comparison of the clinical efficiency yielded 92% clinical concordance between CARDIAC T Quantitative and Elecsys Troponin T 3rd Generation. In conclusion, CARDIAC T Quantitative was in good agreement with the reference and calibration method Elecsys Troponin T 3rd Generation.