[Show abstract][Hide abstract] ABSTRACT: Dyslipidaemic effects of antiretrovirals (ARVs) may contribute to increased cardiovascular risk (CR) in HIV-1-infected patients. The ARTEN (atazanavir/ritonavir on a background of tenofovir and emtricitabine vs. nevirapine on the same background, in naïve HIV-1-infected patients) study compared prospectively ritonavir-boosted atazanavir (ATZ/r) 300 mg/100 mg once daily (qd) with immediate release nevirapine (NVP) 200 mg twice daily or 400 mg qd, each combined with fixed-dose tenofovir 300 mg/emtricitabine 200 mg qd in 569 ARV-naïve HIV-1-infected patients. Lipid profiles and CR from baseline to week 48 are reported.
Changes from baseline to week 48 in fasting plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), TC:HDL-c ratio, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and total triglycerides (TG) were determined. The Framingham algorithm was used to estimate CR. Analysis was by intention-to-treat (ITT) with last observation carried forward (LOCF) for missing data.
At week 48, NVP treatment resulted in significantly greater mean increases from baseline in TC (24.4 vs. 19.6 mg/dL; P=0.038), HDL-c (9.7 vs. 3.9 mg/dL; P<0.0001), LDL-c (15.0 vs. 10.4 mg/dL; P=0.011) and ApoA1 (0.18 vs. 0.08 g/L; P<0.0001) but not ApoB (0.02 vs. 0.02 g/L) compared with ATZ/r treatment. ATZ/r use was associated with higher mean TG increases (27.80 vs. 0.02 mg/dL; P=0.0001). Significantly greater mean decreases in TC:HDL-c and ApoB/ApoA ratios were observed with NVP vs. ATZ/r (P=0.0001 and P=0.008, respectively). Framingham CR scores were low and comparable between the arms, with only a slight mean increase from baseline to week 48 of 0.70 for NVP and 0.80 for ATZ/r [difference -0.069; 95% confidence interval (CI) -0.61 to 0.46; P=0.80].
In ARV-naïve patients with low CR at the outset, NVP showed a potentially less atherogenic lipid profile compared with ATZ/r.
[Show abstract][Hide abstract] ABSTRACT: Selection of first-line antiretroviral therapy requires consideration of efficacy as well as effects on lipids given the increased concern about cardiovascular risk in HIV-1 patients.
ARTEN is a randomized, open-label, non-inferiority trial that compares nevirapine (NVP) 200 mg twice daily or 400 mg once daily to atazanavir/ritonavir (ATZ/r) 300 mg/100 mg once daily, each combined with fixed-dose tenofovir disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg once daily, in antiretroviral-naive HIV-1 patients with CD4(+) T-cell counts <400 (men) and <250 cells/mm(3) (women). The primary end point was plasma HIV RNA<50 copies/ml at two consecutive visits prior to week 48.
A total of 569 patients were randomized and treated. Overall, 66.8% of NVP and 65.3% of ATZ/r patients achieved the primary end point (difference 1.9%, 95% CI -5.9-9.8%). Similar rates of serious adverse events were observed (9.6% on NVP versus 8.8% on ATZ/r), although discontinuations due to adverse events were more frequent with NVP than ATZ/r (13.6% versus 3.6%, respectively). None of the 28 patients virologically failing ATZ/r selected resistance mutations, while they were selected in 29/44 patients virologically failing NVP. NVP induced a significantly greater increase in high-density lipoprotein cholesterol (HDL-c) and apolipoprotein A1 from baseline than ATZ/r, whereas triglycerides increased significantly more with ATZ/r than NVP. Mean change from baseline in TC:HDL-c ratio was -0.24 for NVP and 0.13 for ATZ/r (P=0.0001).
NVP demonstrated at week 48 non-inferior antiviral efficacy compared with ATZ/r when given along with TDF/FTC, despite more drug-related discontinuations with NVP than ATZ/r. NVP was associated with a lower atherogenic lipid profile than ATZ/r although resistance mutations were more frequently selected with NVP than ATZ/r.
Full-text · Article · Jan 2011 · Antiviral therapy
[Show abstract][Hide abstract] ABSTRACT: BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120. Patients and Methods: Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients.
Most frequent BIBF 1120-related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (t(max) = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients.
BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile, and first efficacy signals were observed. Twice daily dosing permitted increased drug exposure without additional toxicity. Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies.
Full-text · Article · Dec 2009 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: The indication for the use of the pulmonary artery catheter (PAC) in high-risk patients is still a matter of discussion. Observational studies suggested that the use of the PAC did not result in decreased mortality but may even lead to increased mortality and morbidity. Therefore, a number of randomized controlled trials have been performed throughout recent years in patients suffering from sepsis/ARDS, congestive heart failure, multi-organ failure and those undergoing high-risk non-cardiac surgery. The majority of recent randomized studies failed to demonstrate any benefit of the PAC with respect to mortality and morbidity. However, the use of the PAC was also regularly not associated with an increase in morbidity and/or mortality. This review gives an overview of measurement parameters obtained by the current generation of PACs, alternatives to the PAC and recent studies on the use of the PAC in clinical practice.
No preview · Article · Jul 2006 · Der Anaesthesist
[Show abstract][Hide abstract] ABSTRACT: Der Einsatz des Pulmonalarterienkatheters (PAK) zur erweiterten hämodynamischen Überwachung wird in der konservativen und operativen Medizin in den letzten Jahren zunehmend kritisch hinterfragt. Seit Mitte der 90er-Jahre zeigte sich, dass der Einsatz des Pulmonalarterienkatheters die Letalität und Morbidität schwerstkranker Patienten nicht positiv beeinflusst. In einigen Untersuchungen fand sich sogar eine höhere Letalität bei Patienten, die mit dem PAK überwacht wurden. Daher wurden in den letzten Jahren randomisierte Untersuchungen mit adäquater Fallzahl bei Patienten mit ARDS, Herzinsuffizienz, Multiorganversagen und Hochrisikochirurgie durchgeführt. In der Mehrzahl der aktuellen Untersuchungen zeigte sich kein positiver Einfluss des Monitorings mit dem PAK auf das Überleben und die Komplikationsrate. Der vorliegende Beitrag gibt eine Übersicht über Messparameter der aktuellen PAK-Generation, mögliche Alternativen und die aktuelle Studienlage zum Einsatz des PAK in der Anästhesie und Intensivmedizin
[Show abstract][Hide abstract] ABSTRACT: The use of miniaturized cardiopulmonary bypass (CPB) circuits and avoidance of cardioplegic arrest are attempts to reduce the inflammatory response to cardiac surgery. We studied the effects of beating heart surgery (BHS) with assistance of simplified bypass systems (SBS) on global hemodynamics, myocardial function and the inflammatory response to CPB. We hypothesized that the use of SBS was associated with less hemodynamic instability after CPB resulting from attenuation of the inflammatory response when compared with surgery performed with a conventional CPB (cCPB) circuit. Forty-five patients undergoing coronary artery bypass grafting were prospectively studied. Fifteen patients were randomized to the use of a cCPB circuit, cold crystalloid cardioplegia, and moderate hypothermia. Two groups of 15 patients underwent BHS during normothermia with assistance of two different SBS consisting of only blood pump and oxygenator. Hemodynamic variables were assessed with transpulmonary thermodilution and transesophageal echocardiography. Plasma levels of proinflammatory and antiinflammatory mediators were measured perioperatively. After CPB, variables of global hemodynamics and systolic ventricular function did not differ among groups. Left ventricular diastolic function was impaired after CPB equally in all groups (P < 0.01 versus pre-CPB). At the end of surgery, there was more need for vasopressor (norepinephrine) support in both SBS groups than in the cCPB group (P < 0.01). After CPB, the release of interleukin (IL)-6 did not differ significantly among groups, whereas plasma levels of IL-10 were higher in the cCPB group (P < 0.01 versus SBS). The extent of myocardial necrosis (Troponin T) was comparable in all groups. We conclude that in our study, miniaturizing bypass systems and avoidance of cardioplegic arrest were not effective in improving hemodynamic performance and in attenuating the proinflammatory immune response after CPB.
Full-text · Article · Mar 2006 · Anesthesia and analgesia
[Show abstract][Hide abstract] ABSTRACT: A large number of patients undergoing elective surgical procedures already take routine medication preoperatively. The majority of these patients use drugs for therapy of preexisting cardiovascular, pulmonary or endocrinological diseases which are independent of the planned surgical procedure. The number and type of preoperative drug therapy are correlated to age, gender and co-morbidity of the patients. Furthermore, patients with higher ASA-classes usually take more drugs, as they suffer from several medical diseases. Information about the perioperative handling of routine drug therapy is important for the planning of anaesthesia and surgery. A close cooperation of all medical specialities involved is necessary, in particular when patients take anticoagulants or other substances which should be withdrawn or replaced. This review focuses on the handling of routine preoperative medication by the anaesthesiologist in the light of available literature.
No preview · Article · Oct 2005 · Der Anaesthesist
[Show abstract][Hide abstract] ABSTRACT: Zusammenfassung Ein Großteil der Patienten, die sich chirurgischen Eingriffen unterziehen, nimmt bereits präoperativ Medikamente ein. Nur bei einem Teil der Patienten steht die Medikamenteneinnahme in direkter Beziehung zum geplanten chirurgischen Eingriff. Der überwiegende Teil erhält eine Dauermedikation aufgrund vorbestehender Erkrankungen. Im Vordergrund stehen dabei behandlungspflichtige Erkrankungen des kardiovaskulären, pulmonalen und endokrinologischen Systems. Die Anzahl und die Art der präoperativen Pharmakotherapie ist mit dem Alter des Patienten, der Komorbidität und dem Geschlecht korreliert. Darüber hinaus erhalten Patienten höherer ASA-Klassen mehr Medikamente, da sie häufiger unter Erkrankungen des kardiovaskulären, pulmonalen, neurologischen und endokrinologischen Formenkreises leiden. Der Umgang mit der präoperativen Dauertherapie ist für die Planung des anästhesiologischen und auch des chirurgischen Vorgehens von praktischer Bedeutung. Insbesondere auf dem Gebiet der gerinnungsaktiven Substanzen und anderer Medikamente, die abgesetzt oder umgestellt werden sollten, ist eine enge Kooperation der beteiligten Disziplinen erforderlich. In dieser Übersicht wird der Umgang mit der präoperativen Medikation für die wichtigsten Krankheitsbilder und Organsysteme besprochen und anhand der zur Verfügung stehenden Literatur kritisch diskutiert.
No preview · Article · Sep 2005 · Der Anaesthesist
[Show abstract][Hide abstract] ABSTRACT: Several lines of evidence have implicated activated protein C (APC) to be an endogenous inhibitor of the inflammatory septic cascade. APC may exhibit direct anti-inflammatory properties, independent of its antithrombotic effects. Chemokines influence the interaction of monocytes at the endothelium during infection and sepsis and are involved in the molecular events leading to an adverse and lethal outcome of sepsis. Defining regulatory mechanisms on the monocytic release profile of the proinflammatory C-C chemokines macrophage inflammatory protein-1-alpha (MIP-1-alpha) and monocyte chemoattractant protein-1 (MCP-1) might have therapeutic implications for the treatment of sepsis. We established a monocytic cell model of inflammation by the addition of lipopolysaccharide (LPS) and examined the effect of human APC on LPS-stimulated chemokine release from the monocytic cell line THP-1. We found that human APC in supra-physiological concentrations of 2.5-10 microg/ml inhibited the LPS-induced release of the chemokines MIP-1-alpha and MCP-1, as measured by enzyme-linked immunosorbent assays (ELISA) at 6 up to 24 h. In addition to experiments on THP-1 cells, recombinant human APC in concentrations of 50 ng/ml was found to have an inhibiting effect on the release of MIP-1-alpha from freshly isolated mononuclear cells of septic patients. The ability of APC to decrease the release of the C-C chemokine MIP-1-alpha from the monocytic cell line THP-1 and from human monocytes may identify a novel immunomodulatory pathway by which APC exerts its anti-inflammatory action and may contribute to control the inflammatory response in sepsis.
[Show abstract][Hide abstract] ABSTRACT: Anesthetics are known to interfere with the production of inflammatory cytokines. In this study, we investigated the effect of xenon and isoflurane on the lipopolysaccharide (LPS)-induced activation of the nuclear transcription factor (NF)-kappaB and production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in vitro. Whole blood was incubated with LPS in the absence or presence of the either xenon (30 and 60 Vol%) and isoflurane (1 and 2 minimum alveolar anesthetic concentration [MAC]). After 4 h, TNF-alpha and IL-6 were assayed in the supernatant. Involvement of NF-kappaB was investigated using isolated monocytes from the blood samples. Whole-cell lysates were prepared, and binding of the NF-kappaB p50 and p65 subunit to its target DNA were measured with an enzyme-linked immunosorbent assay-based NF-kappaB kit. LPS-induced production of TNF-alpha and IL-6 as well as activation of NF-kappaB were significantly increased in the presence of xenon compared with controls. In contrast, isoflurane inhibited the activation of NF-kappaB, which was associated with a decreased production of TNF-alpha and IL-6. Our results demonstrate that xenon and isoflurane have opposite effects on the LPS-induced production of TNF-alpha and IL-6. Furthermore, xenon increases, whereas isoflurane inhibits the activation of NF-kappaB, providing a possible molecular mechanism for the different effects on monocyte TNF-alpha and IL-6 production. IMPLICATIONS: This study has shown that monocytes respond to lipopolysaccharide (LPS) in the presence of xenon with an increased activation of nuclear transcription factor (NF)-kappaB, whereas isoflurane inhibits LPS-induced activation of NF-kappaB. These findings suggest a possible molecular mechanism for the different effects of both anesthetics on monocyte tumor necrosis factor-alpha and interleukin-6 production.
No preview · Article · May 2004 · Anesthesia & Analgesia
[Show abstract][Hide abstract] ABSTRACT: Anesthetics are known to interfere with the production of inflammatory cytokines. In this study, we investi- gated the effect of xenon and isoflurane on the lipopoly- saccharide (LPS)-induced activation of the nuclear tran- scription factor (NF)-B and production of tumor necrosis factor (TNF)- and interleukin (IL)-6 in vitro. Whole blood was incubated with LPS in the absence or presence of the either xenon (30 and 60 Vol%) and isoflurane (1 and 2 minimum alveolar anesthetic con- centration (MAC)). After 4 h, TNF- and IL-6 were as- sayed in the supernatant. Involvement of NF-B was investigated using isolated monocytes from the blood samples. Whole-cell lysates were prepared, and bind- ing of the NF-B p50 and p65 subunit to its target DNA were measured with an enzyme-linked immunosor- bent assay-based NF-B kit. LPS-induced production of TNF- and IL-6 as well as activation of NF-B were sig- nificantly increased in the presence of xenon compared with controls. In contrast, isoflurane inhibited the acti- vation of NF-B, which was associated with a de- creased production of TNF- and IL-6. Our results demonstrate that xenon and isoflurane have opposite effects on the LPS-induced production of TNF- and IL-6. Furthermore, xenon increases, whereas isoflurane inhibits the activation of NF-B, providing a possible molecular mechanism for the different effects on mono- cyte TNF- and IL-6 production. (Anesth Analg 2004;98:1007-12)
[Show abstract][Hide abstract] ABSTRACT: Xenon reduces the infarct size after regional ischaemia in the rabbit heart in vivo, but the underlying mechanisms are unknown. Since adhesion molecules on neutrophils are closely involved in the pathophysiology of ischaemia/reperfusion injury and modulation of neutrophil function, we investigated the effect of xenon on neutrophil adhesion molecule expression in vitro.
Freshly isolated neutrophils were incubated with 30% or 60% xenon for 60 min. In unstimulated and after stimulation with either N-formyl-methionyl-leucyl-phenylalanine or phorbol-12-myristate-13-acetate neutrophil surface expression of PSGL-1, L-selectin, CD11a and CD11b were measured by flow cytometry.
At both concentrations, xenon reduced the surface expression of PSGL-1 by 10% (P < 0.05), and of L-selectin by 15% (P < 0.05) in the 60% xenon group. Furthermore, N-formyl-methionyl-leucyl-phenylalanine activated neutrophils showed an increased removal of L-selectin from the neutrophil surface following incubation with xenon (30% compared to controls, P < 0.05). Neutrophil beta2-integrin expression was not altered by xenon.
Xenon increases the removal of the selectins PSGL-1 and L-selectin from the neutrophil surface in vitro. Since both selectins are involved in the initial contact between neutrophils and endothelial cells, xenon may affect neutrophil adhesion to endothelium during ischaemia/reperfusion injury. However, because the beta2-integrin expression was unaffected by xenon, further investigations are required to clarify whether xenon may modulate neutrophil transmigration through endothelial cells in vivo.
No preview · Article · Feb 2004 · European Journal of Anaesthesiology
[Show abstract][Hide abstract] ABSTRACT: To investigate the effect of propofol and its solvent Intralipid on the adhesion of activated platelets to leukocytes in vitro.
Prospective study in an experimental laboratory.
Sixteen healthy volunteers.
Whole blood was incubated for 60 min with propofol (4, 40 micro g/ml), an equal volume of Intralipid 10% or phosphate-buffered saline (PBS). After stimulation with adenosine-5-diphosphate (ADP) platelet-leukocyte adhesion and platelet surface expression of P-selectin, GPIb and fibrinogen-binding to platelets were evaluated by flow cytometry.
The 4 micro g/ml concentration of propofol did not alter binding of platelets to leukocytes, expression of P-selectin, GPIb and fibrinogen binding to platelets. The 40 micro g/ml concentration of propofol reduced spontaneous and ADP-induced formation of platelet-neutrophil conjugates compared with PBS and the equal volume of Intralipid. In addition, binding of ADP-activated platelets to monocytes were also inhibited by 40 micro g/ml propofol. Following incubation with propofol, platelets showed reduced binding of fibrinogen in the unstimulated and ADP-stimulated blood samples as well as a lower percentage of platelets with bound fibrinogen. Effects dependent on the solvent Intralipid were enhanced adhesion of platelets to monocytes in comparison with propofol (40 micro g/ml) and PBS.
In clinically used concentrations, propofol does not alter the adhesion of platelets to leukocytes in vitro. At ten-fold anesthetic concentration propofol reduced the formation of platelet-neutrophil and platelet-monocyte conjugates. We suggest that this effect is due to an inhibition of fibrinogen-binding to platelets by propofol. These effects were all independent of the propofol carrier Intralipid.
No preview · Article · Aug 2003 · Intensive Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Recruitment of monocytes to inflamed tissue is a crucial step in the acute inflammatory reaction. Adherence of monocytes to endothelial cells followed by transmigration depends on monocyte surface adhesion molecules, inflammatory cytokines and chemoattractant chemokines. In the present study, we determined the effect of isoflurane on monocyte adhesion receptor expression in vitro.
Citrated whole blood was incubated for 60 min with either 0.5 or 1 MAC isoflurane. In unstimulated blood samples and after stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP) monocyte cell-surface expression of the selectins PSGL-1 and L-selectin, and the beta2-integrins CD11a and CD11b were evaluated by flow cytometry.
Isoflurane reduced significantly the expression of PSGL-1 on unstimulated monocytes, whereas the remaining selectins and beta2-integrins were not affected. At both concentrations, the FMLP-induced removal of PSGL-1 from the monocyte surface was increased. Furthermore, at 1 MAC isoflurane the FMLP-induced increase in CD11a expression was significantly inhibited. The surface expression of L-selectin and CD11b was not affected following exposure to isoflurane.
Isoflurane increases the removal of the selectin PSGL-1 from the monocyte surface. Since PSGL-1 is important during the initial step of monocyte adhesion to endothelial P-selectin, the decrease in monocyte surface PSGL-1 may have profound effects on monocyte-endothelial interactions. Furthermore, the effects of isoflurane on monocyte adhesion molecule expression are different from those reported for neutrophils.
No preview · Article · Jun 2003 · Acta Anaesthesiologica Scandinavica
[Show abstract][Hide abstract] ABSTRACT: The interaction between platelets and leukocytes plays an important role in inflammatory and thrombotic processes. We investigated whether the volatile anaesthetics sevoflurane and desflurane alter the formation of platelet-leukocyte aggregates and the expression of P-selectin on platelets. Whole blood was incubated with 1 and 2 minimum alveolar concentration (MAC) sevoflurane or desflurane. Unstimulated and adenosine diphosphate, or thrombin receptor agonist peptide-6-stimulated samples were stained with fluorochrome-conjugated antibodies. The formation of platelet-leukocyte conjugates and the expression of P-selectin on platelets were measured using flow cytometry. Sevoflurane was found to enhance the binding of platelets to lymphocytes, neutrophils and monocytes, it also increased the expression of P-selectin on platelets especially in the stimulated samples. Desflurane decreased the percentage of lymphocyte-platelet, neutrophil-platelet and monocyte-platelet conjugates principally in unstimulated samples. The results show that these two volatile anaesthetics have differing effects on the formation of platelet-leukocyte conjugates in vitro. Sevoflurane also enhanced the expression of P-selectin on platelets.
[Show abstract][Hide abstract] ABSTRACT: Sepsis and septic shock are among the leading causes of deaths of critically ill patients in intensive care units. Mortality is influenced by severity of illness (systemic inflammatory response syndrome (SIRS) - sepsis - severe sepsis - septic shock), age, comorbidities and primary site of infection. Despite great efforts in understanding the underlying pathophysiology to improve diagnostic procedures and therapeutic concepts, mortality of sepsis remains high with 30 to 50% dying from the disease; 2 - 3% of ward patients and 10 - 15% ICU patients develop severe sepsis or septic shock. In the USA, estimated 750,000 patients per year suffer from this systemic inflamatory response to infection with 200,000 dying. In Germany, there are no national epidemiologic data. Therefore, in 2003, a nationwide analysis of the prevalence of sepsis and septic shock in intensive care units will be undertaken, sponsored by a national grant. Due to the incidence and the expensive effort of intensive care therapy of such patients, sepsis consumes considerable health care resources. Under the pressure of cost containment and the recent implementation of a DRG-based reimbursement system, this might gain further importance for German hospitals. There is an urgent need for cost and incidence studies on sepsis, especially when innovative and expensive therapies are introduced. Besides therapeutical efficiency of these therapies, cost-effectiveness will play a major role in future. This review aims on epidemiology and costs of sepsis.
No preview · Article · Mar 2003 · Intensiv- und Notfallbehandlung