Joint recommendations on cost calculation and estimation in paediatric clinical trials.

The conduct of clinical trials in paediatrics is essential to improve drug therapy in children. In Europe, paediatric clinical trials have been supported by the European Paediatric Regulation since 2007, but there is still a great need for high-quality clinical trials. The personnel and time required to conduct clinical trials in accordance with EU Regulations 536/2014 and 745/2017 is considerably higher compared to other studies, such as observational studies. It is important that this additional workload for the trial centre is fully compensated, also taking into account EU state aid rules. In paediatric trials, it is necessary to take into account the special requirements of paediatric and adolescent medicine when calculating the additional costs. Within the framework of the pan-European paediatric study network c4c/GermanNetPaeT, a working group dealt with specific aspects of cost calculation in order to support paediatric study centres in internal cost calculation as well as in the subsequent preparation of financing requirements for industrial sponsors or public funders. In several workshops the working group developed a cost calculation template with the content derived from the "Joint recommendations for a total services account as a factor in simplifying contracts" of the Deutsche Hochschulmedizin (DHM, German University Medicine), the Netzwerk der Koordinierungszentren für Klinische Studien (KKS Network, Network of Coordinating Centres for Clinical Trials) and the Verband Forschender Arzneimittelhersteller (vfa, German Association of Research-Based Pharmaceutical Companies). By estimating the specific time required for measures and investigations as part of a sample study, the background to the increased time required was discussed and a list with aspects to be considered for cost calculation was compiled together with the study centres. The paediatrics-specific aspects mentioned in detail are intended to increase understanding of the particular problem of higher costs for clinical trials involving children and adolescents and the need for correspondingly appropriate remuneration. This transparent and comprehensible presentation of the higher financial requirements for both the study centres and the financial supporters is intended to promote the high-quality conduct of clinical trials in paediatric study centres in the long term.

Exploring Albumin Functionality Assays: A Pilot Study on Sepsis Evaluation in Intensive Care Medicine.

Human serum albumin (HSA) as the most abundant plasma protein carries multifunctional properties. A major determinant of the efficacy of albumin relies on its potent binding capacity for toxins and pharmaceutical agents. Albumin binding is impaired in pathological conditions, affecting its function as a molecular scavenger. Limited knowledge is available on the functional properties of albumin in critically ill patients with sepsis or septic shock. A prospective, non-interventional clinical trial assessed blood samples from 26 intensive care patients. Albumin-binding capacity (ABiC) was determined by quantifying the unbound fraction of the fluorescent marker, dansyl sarcosine. Electron paramagnetic resonance fatty acid spin-probe evaluated albumin's binding and detoxification efficiencies. Binding efficiency (BE) reflects the strength and amount of bound fatty acids, and detoxification efficiency (DTE) indicates the molecular flexibility of patient albumin. ABiC, BE, and DTE effectively differentiated control patients from those with sepsis or septic shock (AUROC > 0.8). The diagnostic performance of BE showed similarities to procalcitonin. Albumin functionality correlates with parameters for inflammation, hepatic, or renal insufficiency. Albumin-binding function was significantly reduced in critically ill patients with sepsis or septic shock. These findings may help develop patient-specific algorithms for new diagnostic and therapeutic approaches.

Impact of Albumin Binding Function on Pharmacokinetics and Pharmacodynamics of Furosemide.

Background and Objectives: Albumin binding of the loop diuretic furosemide forms the basis for its transport to the kidney and subsequent tubular secretion, which is a prerequisite for its therapeutic effects. Accordingly, high albumin concentrations should result in higher efficacy of furosemide. However, study results on the combination of furosemide in conjunction with albumin, and on the efficacy of furosemide in hypoalbuminemia, did not confirm this hypothesis. The aim of this study was to determine the efficacy of furosemide not only in relation to albumin concentration, but also taking albumin function into account. Materials and Methods: In a prospective and non-interventional clinical observational trial, blood and urine samples from 50 intensive care patients receiving continuous intravenous furosemide therapy were evaluated. Albumin binding capacity (ABiC) determination allowed conclusions to be drawn about the binding site-specific loading state of albumin, by quantifying the unbound fraction of the fluorescent marker dansylsarcosine. In addition, assessment of the total concentration of furosemide in plasma and urine, as well as the concentration of free furosemide fraction in plasma, was performed by HPLC−MS. The efficacy of furosemide was evaluated by the ratio of urine excretion to fluid intake. Results: In patients with an ABiC ≥ 60% free furosemide fraction was significantly lower compared to patients with a lower ABiC (p < 0.001), urinary furosemide concentration was higher (p = 0.136), and a significantly higher proportion of infused furosemide was excreted renally (p = 0.010). ABiC was positively correlated (r = 0.908, p = 0.017) with increase in the urine excretion to fluid input ratio after initiation of furosemide therapy. Conclusions: ABiC could serve as a marker for individual response to furosemide and could be used to generate patient-specific therapeutic regimens. In view of the relatively low number of patients in this study, the relationship between furosemide efficacy and albumin function should be investigated in larger studies in the future.

[Making COVID-19 research data more accessible-building a nationwide information infrastructure]. / COVID-19-Forschungsdaten leichter zugänglich machen ­ Aufbau einer bundesweiten Informationsinfrastruktur.

Public health research and epidemiological and clinical studies are necessary to understand the COVID-19 pandemic and to take appropriate action. Therefore, since early 2020, numerous research projects have also been initiated in Germany. However, due to the large amount of information, it is currently difficult to get an overview of the diverse research activities and their results. Based on the "Federated research data infrastructure for personal health data" (NFDI4Health) initiative, the "COVID-19 task force" is able to create easier access to SARS-CoV-2- and COVID-19-related clinical, epidemiological, and public health research data. Therefore, the so-called FAIR data principles (findable, accessible, interoperable, reusable) are taken into account and should allow an expedited communication of results. The most essential work of the task force includes the generation of a study portal with metadata, selected instruments, other study documents, and study results as well as a search engine for preprint publications. Additional contents include a concept for the linkage between research and routine data, a service for an enhanced practice of image data, and the application of a standardized analysis routine for harmonized quality assessment. This infrastructure, currently being established, will facilitate the findability and handling of German COVID-19 research. The developments initiated in the context of the NFDI4Health COVID-19 task force are reusable for further research topics, as the challenges addressed are generic for the findability of and the handling with research data.

Comparison of changes in albumin binding capacity during hemodiafiltration or hemodialysis with middle cut off membranes.

BACKGROUND: Albumin is important for the transport of protein-bound substances (PBS). Albumin binding capacity (ABiC) is reduced in dialysis patients. This can contribute to worsening of uremic symptoms. It is presumed that open-porous middle cut off filters that is, HDx (Baxter-Theranova) remove high molecular substances more efficiently than conventional treatment. To evaluate HDx for the improvement of ABiC and removal of PBS, HDx was compared to hemodiafiltration (Fresenius-FX80, HDF). METHODS: We included 32 chronic patients on HDF. After inclusion patients were treated with HDx for 14 days. Blood samples were drawn before/after treatments at study entry, first HDx and sixth HDx, to determine ABiC and other study parameters. RESULTS: ABiC improved in HDx (68.4% vs 72.4%) and HDF (69.9% vs 72.4%) without differences between both therapies. No reduction of albumin concentration during HDx treatment was observed. CONCLUSION: HDx is accepted as a safe and equally efficient therapy for removing albumin bound uremic toxins compared to HDF with high flux dialyzers.

Occurrence of Gastrointestinal Parasites in Small Mammals from Germany.

An increase in zoonotic infections in humans in recent years has led to a high level of public interest. However, the extent of infestation of free-living small mammals with pathogens and especially parasites is not well understood. This pilot study was carried out within the framework of the "Rodent-borne pathogens" network to identify zoonotic parasites in small mammals in Germany. From 2008 to 2009, 111 small mammals of 8 rodent and 5 insectivore species were collected. Feces and intestine samples from every mammal were examined microscopically for the presence of intestinal parasites by using Telemann concentration for worm eggs, Kinyoun staining for coccidia, and Heidenhain staining for other protozoa. Adult helminths were additionally stained with carmine acid for species determination. Eleven different helminth species, five coccidians, and three other protozoa species were detected. Simultaneous infection of one host by different helminths was common. Hymenolepis spp. (20.7%) were the most common zoonotic helminths in the investigated hosts. Coccidia, including Eimeria spp. (30.6%), Cryptosporidium spp. (17.1%), and Sarcocystis spp. (17.1%), were present in 40.5% of the feces samples of small mammals. Protozoa, such as Giardia spp. and amoebae, were rarely detected, most likely because of the repeated freeze-thawing of the samples during preparation. The zoonotic pathogens detected in this pilot study may be potentially transmitted to humans by drinking water, smear infection, and airborne transmission.

MEDI0382, a GLP-1/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single-dose, healthy-subject, randomized, Phase 1 study.

AIMS: MEDI0382 is a balanced glucagon-like peptide-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus and non-alcoholic steatohepatitis. The primary objective was to assess the safety of MEDI0382 in healthy subjects. METHODS: In this placebo-controlled, double-blind, Phase 1 study, healthy subjects (aged 18-45 years) were randomized (3:1) to receive a single subcutaneous dose of MEDI0382 or placebo after ≥8 h of fasting. The study consisted of six cohorts that received study drug at 5 µg, 10 µg, 30 µg, 100 µg, 150 µg or 300 µg. The primary objective was safety and tolerability. Secondary endpoints included assessments of pharmacokinetics and immunogenicity. All subjects were followed for up to 28 days. RESULTS: A total of 36 subjects received MEDI0382 (n = 6 per cohort) and 12 subjects received placebo (n = 2 per cohort). Treatment-emergent adverse events (TEAEs) occurred more frequently with MEDI0382 vs. placebo, which was mostly due to an increased occurrence at MEDI0382 doses ≥150 µg. All TEAEs were mild or moderate in severity. The most common TEAEs were vomiting, nausea and dizziness. There appeared to be a dose-dependent increase in heart rate with MEDI0382 treatment. MEDI0382 showed linear pharmacokinetic profile (time to maximum plasma concentration: 4.50-9.00 h; elimination half-life: 9.54-12.07 h). No immunogenicity was observed in the study. CONCLUSIONS: In this single-dose, Phase 1 study in healthy subjects, the safety and pharmacokinetic profiles of MEDI0382 support once-daily dosing and further clinical development of MEDI0382.

Reducing the underreporting of percutaneous exposure incidents: A single-center experience.

Although risk reduction strategies have been implemented throughout the world, underreporting of percutaneous exposure incidents (PEIs) is common among exposed health care workers. The aim of this study was to determine the incidence rate of reported PEIs before and after implementation of an intensified reporting management policy. The introduction of an intensified reporting system led to significantly increased reporting after a PEI has occurred. However, continuous education needs to be provided to improve awareness.

Molecular adsorbent recirculating system and single-pass albumin dialysis in liver failure--a prospective, randomised crossover study.

BACKGROUND: The aim of extracorporeal albumin dialysis (ECAD) is to reduce endogenous toxins accumulating in liver failure. To date, ECAD is conducted mainly with the Molecular Adsorbents Recirculating System (MARS). However, single-pass albumin dialysis (SPAD) has been proposed as an alternative. The aim of this study was to compare the two devices with a prospective, single-centre, non-inferiority crossover study design with particular focus on reduction of bilirubin levels (primary endpoint) and influence on paraclinical and clinical parameters (secondary endpoints) associated with liver failure. METHODS: Patients presenting with liver failure were screened for eligibility and after inclusion were randomly assigned to be started on either conventional MARS or SPAD (with 4% albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model. RESULTS: Sixty-nine crossover cycles of ECAD in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median -68 µmol/L, interquartile range [IQR] -107.5 to -33.5, p = 0.001; SPAD: -59 µmol/L, -84.5 to +36.5, p = 0.001). However, bile acids (MARS: -39 µmol/L, -105.6 to -8.3, p < 0.001; SPAD: -9 µmol/L, -36.9 to +11.4, p = 0.131), creatinine (MARS: -24 µmol/L, -46.5 to -8.0, p < 0.001; SPAD: -2 µmol/L, -9.0 to +7.0/L, p = 0.314) and urea (MARS: -0.9 mmol/L, -1.93 to -0.10, p = 0.024; SPAD: -0.1 mmol/L, -1.0 to +0.68, p = 0.523) were reduced and albumin-binding capacity was increased (MARS: +10%, -0.8 to +20.9%, p < 0.001; SPAD: +7%, -7.5 to +15.5%, p = 0.137) only by MARS. Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were altered by neither MARS nor SPAD. CONCLUSIONS: Both procedures were safe for temporary extracorporeal liver support. While in clinical practice routinely assessed plasma bilirubin levels were reduced by both systems, only MARS affected other paraclinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels). Caution should be taken with regard to metabolic derangements and electrolyte disturbances, particularly in SPAD using regional citrate anti-coagulation. TRIAL REGISTRATION: German Clinical Trials Register ( www.drks.de) DRKS00000371. Registered 8 April 2010.

No sustained impact of intermittent extracorporeal liver support on thrombocyte time course in a randomized controlled albumin dialysis trial.

Reduction of platelets is a common finding in patients with liver disease and can be aggravated by extracorporeal therapies, e.g. artificial liver support. The impact of extracorporeal albumin dialysis on the time count and time course of platelets in liver failure patients was evaluated in a randomized controlled clinical trial. Mean thrombocyte reduction during a single extracorporeal liver support therapy was -15.1% [95%CI: -17.7; -12.5]. No differences were found between treatments of patients with a more reduced platelet count (<100 GPT/L: -15.6% [-19.5; -11.7%]; n = 43) compared to patients with normal or slightly decreased thrombocytes (-14.6% [-18.3%; -11.0%]; n = 43; P = 0.719). The variation of platelet count within 24 h after onset of extracorporeal therapy treatment was less, albeit significant (-3.5% [-6.3%; -0.7%], P < 0.016). Absolute thrombocyte variability was comparable between both groups (with extracorporeal therapy -5.6 GPT/L [-9.7; -1.4], without extracorporeal therapy -1.3 GPT/L [-7.3; 4.7]; P = 0.243), whereas relative decrease of thrombocytes within a 24-h period of extracorporeal therapy was greater than the changes in patients without extracorporeal therapy (-3.5% [-6.3%; -0.7%] vs. 2.0% [-2.0%; 5.9%]; P = 0.026]. Within a period of two weeks after enrollment, no significant differences of platelet count were observed either between the two groups or in the time course (P(group) = 0.337, P(time) = 0.277). Reduction of platelets during intermittent extracorporeal liver support was less pronounced within a 24-h period as before and after a single treatment and was comparable to variations in the control group without extracorporeal therapy.

Fluticasone impact on airway dendritic cells in smokers: a randomized controlled trial.

BACKGROUND: Myeloid Dendritic cells are key drivers of inflammation in smoke-related lung diseases, whereas plasmacytoid DCs play a crucial role in the defense against infections. Effects of inhaled corticosteroids (ICS) on airway DCs in smokers are unknown. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 45 active cigarette smokers inhaled placebo, fluticasone or fluticasone plus salmeterol twice daily for 4 weeks. Bronchoalveolar lavage fluid DCs were analyzed using four-color flow cytometry before and after the inhalation period. In addition, fluticasone effects were tested on T-cell proliferation in co-cultures with blood myeloid DCs from smokers. RESULTS: Inhalation of fluticasone plus salmeterol, but not fluticasone alone or placebo, reduced endobronchial concentrations of myeloid DCs (median decrease: 24%), macrophages (median decrease: 26%) and neutrophils (median decrease: 76%). In contrast, fluticasone reduced plasmacytoid DC concentrations independently of salmeterol. There were no changes in the expression of function-associated surface molecules on myeloid DC (such as CD1a, Langerin, BDCA-1, CD83 or CCR5) in all groups after treatment. Fluticasone (either alone or in combination with salmeterol) suppressed T-cell proliferation in co-cultures with blood myeloid DCs from smokers. CONCLUSIONS: Resistance to ICS monotherapy in smokers might in part be due to lacking effects on airway myeloid DCs, whereas the increased risk for infections during ICS therapy could be attributable to a reduction in plasmacytoid DCs. Combination therapy of fluticasone with salmeterol is associated with a reduction in airway myeloid DCs, but also airway macrophages and neutrophils. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (identifier: NCT00908362) and the European Clinical Trial Database, EudraCT (identifier: 2009-009459-40).

Clinical trial to evaluate the safety and immunogenicity of a trivalent surface antigen seasonal influenza vaccine produced in mammalian cell culture and administered to young and elderly adults with and without A(H1N1) pre-vaccination.

UNLABELLED: Vaccination against influenza is an important means of reducing morbidity and mortality in subjects at risk. The prevalent viral strains responsible for seasonal epidemics usually change annually, but the WHO recommendations for the 2011/2012-season in the Northern hemisphere included the same antigens as for the previous season. We conducted a single-center, single-arm study involving 62 younger (18-60 years) and 64 older (>60 years) adults to test the immunogenicity, safety and tolerability of a trivalent surface antigen, inactivated influenza vaccine produced in mammalian cell-culture. The vaccine contained 15 µg hemagglutinin of each of the virus strains recommended for the 2011-2012 Northern hemisphere winter season (A/California/7/09 (H1N1)-; A/Perth/16/09 (H3N2)-; B/Brisbane/60/08-like strain) in a non-adjuvanted preservative-free formulation. Antibody response was measured by hemagglutination inhibition 21 days after immunization. Adverse events and safety were assessed using subject diary cards and telephone interviews. Seroconversion or a 4-fold antibody increase in antibody titers was detectable against A(H1N1) in 68% of both younger and older adults, against A(H3N2) in 53% and 27%, and against the B influenza strain in 35% and 17%. Antibody titers of 40 or more were observed against A(H1N1) in 87% and 90% of younger and older adults, against A(H3N2) in 98% and 98%, and against the B influenza strain in 93% and 90%. Pre-vaccination antibody titers were protective against A(H1N1), A(H3N2) and B in 38%, 58% and 58%, respectively, of younger and in 43%, 88% and 70% of older adults. Among subjects with previous A(H1N1) vaccination only 48% of younger and 47% of older adults had protective A(H1N1) antibodies at inclusion. Adverse reactions were generally mild. The most frequently reported reactions were pain at the injection site, myalgia and fatigue. The vaccine generated protective antibodies against all three viral strains and had an acceptable safety profile in both younger and older adults. TRIAL REGISTRATION: ClinicalTrials.govNCT01422512.

Pneumocystis jirovecii colonization among renal transplant recipients.

AIM: Renal transplant recipients are at risk of developing Pneumocystis pneumonia (PcP), especially in the first 2 years after transplantation, with a mortality rate of up to 50%. No data are available on pulmonary colonization with Pneumocystis jirovecii in renal transplant recipients. The aim of this study was to determine the prevalence of pulmonary colonization with Pneumocystis jirovecii in renal transplant recipients and to find related risk factors. METHODS: We investigated the induced sputa of 70 renal transplant recipients for the presence of Pneumocystis jirovecii using nested polymerase chain reaction. RESULTS: Thirteen of 70 patients (18.6%) were colonized with Pneumocystis jirovecii. There was no significant correlation between colonization and immunosuppressive medication or regimens. However, colonized subjects had undergone transplantation longer ago than non-colonized subjects. 30.8% of those whose transplantation had taken place more than 8 years previously were colonized, in contrast to 11.4% of those whose transplantation had taken place less than 8 years ago (P = 0.059; odds ratio = 3.467, 95% confidence interval = 0.99-12.09). CONCLUSION: Most cases of Pneumocystis colonization were detected in those patients where renal transplantion had taken place more than 2 years previously. As most PcP cases occur within the first 2 years of transplantation, colonization does not seem to play a role in the development of acute PcP in this period. Though Pneumocystis pneumonia is likely to be a newly acquired infection in the first 2 years after transplantation, colonized patients remain a potential source of transmission of Pneumocystis jirovecii.

Alteration of DSS-mediated immune cell redistribution in murine colitis by oral colostral immunoglobulin.

BACKGROUND: Oral bovine colostrum prophylaxis accelerates the recovery of dextran sulfate sodium (DSS)-induced colitis. In the present study the beneficial effects on acute intestinal inflammation of two major colostral components, secretory immunoglobulin A and lactoferrin, were investigated. Outbred NMRI mice received whole bovine colostrum (BC, 20 mg/kg body weight), colostral bovine lactoferrin (bLf, 150 mg/kg), or secretory immunoglobulin A (sIgA, 1-2 mg/kg body weight) daily by oral gavage, either two weeks before induction of colitis (prophylaxis) or after disease establishment (therapy). Bovine serum albumin (BSA, 150 mg/kg body weight) and immunoglobulin G (IgG, 1 and 2 mg/kg body weight) served as protein controls. Colitis was induced by providing 5% DSS solution ad libitum for seven days. RESULTS: Compared to BSA, BC therapy improved occult blood, stool consistency, and clinical recovery from colitis but did not prevent initial weight loss. In contrast, administration of bLf did not influence the course of colitis in either the prophylactic or the therapeutic setting. Therapeutic application of sIgA promoted weight gain in the recovery phase of colitis but failed to improve other clinical parameters. Prophylactically-fed sIgA influenced immune cell redistribution, normalized peripheral blood CD11c⁺CD83⁺ mature dendritic cells, modulated colonic immune cell infiltration, and altered the numbers of both DSS-induced regulatory γδ TCR⁺ T cells and CD11b⁺Gr-1⁺ myeloid suppressor cells in the lymph nodes and spleens of mice. CONCLUSIONS: These data demonstrated the potential of colostrum in disease recovery and epithelial homeostasis following intestinal injury. Colostral sIgA failed to improve acute disease activity but promoted weight gain and modulated immune cell responses that are involved in the genesis of colitis.

Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial.

UNLABELLED: Acute-on-chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n=95) or to standard therapy (SMT) (n=94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per-protocol (PP) analysis (PP population n=156). Up to 10 6-8-hour MARS sessions were scheduled. The main endpoint was 28-day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28-day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44-1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P=0.02) and bilirubin (P=0.001) and a more frequent improvement in HE (from grade II-IV to grade 0-I; 62.5% versus 38.2%; P=0.07) was observed in the MARS group. Severe adverse events were similar. CONCLUSION: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE.

Albumin-binding capacity (ABiC) is reduced in patients with chronic kidney disease along with an accumulation of protein-bound uraemic toxins.

BACKGROUND: Albumin is an important transport protein for non-water-soluble protein-bound drugs and uraemic toxins. Its transport capacity is reduced in patients with advanced chronic kidney disease (CKD) and unbound fractions of uraemic toxins are related to complications of CKD. We investigated whether this reduction could be quantified and how it correlated with the stages of CKD. Albumin-binding capacity (ABiC) is a dye-based method that quantifies the remaining binding capacity of one major binding site (site II) of the albumin molecule. METHODS: Blood samples from 104 CKD patients were incubated with a binding site-specific fluorescent marker and the amount of unbound marker was determined by means of fluorescence detection after filtration. Measurements in a pooled human plasma were used for reference. Glomerular filtration rate and serum indoxyl sulphate (IS) levels were also determined. RESULTS: Impairment of renal function was associated with a reduction in ABiC (mean ± SD: 118 ± 12; 111 ± 11; 99 ± 8 and 79 ± 9% for Stages 1/2, 3, 4 and 5, respectively; P < 0.001) and an increase in IS (3.9 ± 1.1; 6.2 ± 3.2; 16.3 ± 14.9 and 56.1 ± 28.6 µmol/L for Stages 1/2, 3, 4 and 5, respectively; P < 0.001). In dialysis patients, ABiC was lower in those with urine outputs <500 mL/day than in those with preserved urine output (73.7 ± 6.0 versus 83.8 ± 8.5%; P < 0.001). CONCLUSION: Impaired albumin function in CKD patients can be quantified, is related to severity of kidney disease and is associated with an accumulation of uraemic albumin-bound retention solutes.

Industrial stabilizers caprylate and N-acetyltryptophanate reduce the efficacy of albumin in liver patients.

Liver failure is associated with an accumulation of toxic molecules that exert an affinity to albumin. Some of them have vasoactive activity. So far, albumin has been used as a plasma expander to improve the available circulating blood volume. However, recent studies have suggested that albumin is more effective than starch for this indication. It has not been reported yet whether the industrial stabilizers octanoate and N-acetyltryptophanate, added to albumin, occupy binding sites for vasoactive substances. The aim of this study was to determine whether the presence of the industrial stabilizers octanoate and caprylate has an impact on the effect of the albumin-binding function or circulating blood volume in patients with cirrhosis, portal hypertension, and an indication for albumin. In 25 patients who received albumin via an inline infusion filter that depleted stabilizers, there was an improvement of albumin binding, and there was less deterioration of circulating blood volume and renal function in comparison with a control group. Further studies are needed to confirm the results and identify the potential socioeconomic side effects of industrial stabilizers in commercial albumin solutions.

Increase of octanoate concentrations during extracorporeal albumin dialysis treatments.

Extracorporeal liver support procedures based on albumin dialysis require the use of pharmaceutical-grade human serum albumin (HSA). Those preparations contain octanoate, which is added as stabilizer during the production process. For octanoate, a direct involvement in the pathogenesis of liver failure complications as well as an indirect influence by competitive displacement effects at the albumin molecule have been described. During five Single Pass Albumin Dialysis (SPAD) and three Molecular Adsorbent Recirculating System (MARS) treatments the changes of octanoate concentrations in blood and dialysate were investigated. An octanoate increase in patient blood was observed during passage of the filter for both SPAD (585 micromol/L [338-1022 micromol/L]) (median [range]) and MARS (182 micromol/L [71-437 micromol/L]) during the first three hours of treatment. The molar ratio of octanoate/albumin at the blood outflow was significantly higher during SPAD treatments (1.73 [0.86-2.64] vs. 0.54 [0.31-1.1]; P = 0.001) during MARS. Changes of octanoate blood levels during SPAD were significantly higher than during MARS (P < 0.001). The shift of octanoate from the dialysate to the patient was persistent during SPAD (median 67.6 micromol/min), whereas during MARS a decrease over time was observed (from 25.5 to 7.5 micromol/min). During albumin dialysis procedures a transfer of octanoate into patient blood occurs. The time-course and extent are different between both albumin dialysis procedures. Given the positive clinical effects reported mainly for MARS, the clinical impact of albumin dialysis-associated transfer of octanoate during extracorporeal liver support needs to be evaluated further.

Albumin dialysis MARS: knowledge from 10 years of clinical investigation.

A decade ago, albumin dialysis was introduced as a new extracorporeal detoxification method for patients with liver failure. Today, the molecular adsorbent recirculating system is the most frequently used type of albumin dialysis and most studied liver-support technique. Numerous preclinical and clinical studies demonstrated the importance of albumin as a scavenger for molecules with pathophysiological relevance in liver failure. Albumin dialysis enables the selective regeneration of albumin. The resulting increase of albumin binding capacity is paralleled by improvement of central and local hemodynamics and liver, brain, and kidney functions. The treatment can contribute to liver regeneration and prolongation of patient survival in the context of acute liver failure, decompensated chronic liver disease, and bridging of patients to liver transplantation. Proper patient selection is critical for clinical success. Aggressive treatment of infections and sepsis seems to be a decisive prerequisite for its safe and efficient use. Cautious anticoagulation with heparin is the common standard. Citrate use is recommended for patients prone to bleeding. Taken together, albumin dialysis represents a valuable therapeutic tool for the treatment of various types of liver failure. Ongoing and future studies will help define the optimal patient selection and technical process parameters such as session length and frequency of treatment.

No clinically relevant CYP3A induction after St. John's wort with low hyperforin content in healthy volunteers.

OBJECTIVE: Induction of CYP3A by St. John's wort (SJW) products with high hyperforin content is well described. Since CYP3A induction is mediated by hyperforin in a concentration-dependent manner, and SJW preparations differ significantly in hyperforin content, the aim of the study was to evaluate the effect of an SJW powder with low hyperforin content on CYP3A function. METHODS: Twenty healthy male volunteers received an SJW powder with low hyperforin content for 2 weeks. Midazolam plasma concentration time profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. RESULTS: Midazolam AUC(0-infinity) slightly decreased from 124.0 +/- 62.5 ng/ml.h at baseline to 105.6 +/- 53.2 ng/ml.h after SJW (P < 0.05), representing a mean 11.3% decrease (95% CI: -22.8 to 0.21). No significant change in midazolam C(max), t(1/2) and t(max) was observed. For all pharmacokinetic parameters, the 90% CI for the geometric mean ratio of treatment over baseline were within the no-effect boundaries of 0.70-1.43. CONCLUSION: Administration of an SJW product with low hyperforin content resulted in a mild induction of CYP3A not considered clinically relevant.