Aims
The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each ...patient.
Methods
Data on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed‐effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates.
Results
A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two‐compartment model. The mean absorption rate was 3.6 h−1, clearance was 23.0 l h–1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose:
Dosemg=222nghml–1*22.5lh–1*1.0ifCYP3A5*3/*3or1.62ifCYP3A5*1/*3orCYP3A5*1/*1*1.0ifCYP3A4*1or unknownor0.814ifCYP3A4*22*Age56−0.50*BSA1.930.72/1000
Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model.
Conclusions
For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation.
Objectives The aim of the present analysis was to compare 1-year mortality prediction of Bleeding Academic Research Consortium (BARC)-defined bleeding complications with existing bleeding definitions ...in patients with ST-segment elevation myocardial infarction (STEMI) and to investigate the prognostic value of the individual data elements of the bleeding classifications for 1-year mortality. Background BARC recently proposed a novel standardized bleeding definition. Methods The in-hospital occurrence of bleeding defined according to the BARC, TIMI (Thrombolysis In Myocardial Infarction), GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), and ISTH (International Society on Thrombosis and Haemostasis) bleeding classifications was assessed in 2,002 STEMI patients undergoing primary percutaneous coronary intervention between January 1, 2003, and July 31, 2008. Results BARC types 2, 3, 4, and 5 bleeding occurred in 4.4%, 14.2%, 1.4%, and 0.3% of patients, respectively. By multivariable analysis, GUSTO- and ISTH-defined bleeding was not significantly associated with 1-year mortality, whereas TIMI major and BARC type 3b or 3c bleeding conferred a 2-fold higher risk of 1-year mortality (hazard ratios HRs: 2.00 95% confidence interval (CI): 1.32 to 3.01 and 1.84 95% CI: 1.23 to 2.77, respectively). Data elements most strongly associated with mortality were a hemoglobin decrease ≥5 g/dl (HR: 1.94 95% CI: 1.26 to 2.98), the use of vasoactive agents for bleeding (HR: 2.01 95% CI: 0.91 to 4.44), cardiac tamponade (HR: 2.38 95% CI: 0.56 to 10.1), and intracranial hemorrhage (HRs for 1-year mortality were not computable because there was only 1 patient with intracranial bleeding). Conclusions Both the BARC and TIMI bleeding classification identified STEMI patients at risk of 1-year mortality.
Abstract Objective: To examine whether catch-up growth during childhood modifies the increased risk of death from coronary heart disease that is associated with reduced intrauterine growth. Design: ...Follow up study of men whose body size at birth was recorded and who had an average of 10 measurements taken of their height and weight through childhood. Setting: Helsinki, Finland. Subjects: 3641 men who were born in Helsinki University Central Hospital during 1924-33 and who went to school in Helsinki. Main outcome measures: Hazard ratios for death from coronary heart disease. Results: Death from coronary heart disease was associated with low birth weight and, more strongly, with a low ponderal index at birth. Men who died from coronary heart disease had an above average body mass index at all ages from 7 to 15 years. In a simultaneous regression the hazard ratio for death from the disease increased by 14% (95% confidence interval 8% to 19%; P<0.0001) for each unit (kg/m3) decrease in ponderal index at birth and by 22% (10% to 36%; P=0.0001) for each unit (kg/m2) increase in body mass index at 11 years of age. Body mass index in childhood was strongly related to maternal body mass index, which in turn was related to coronary heart disease. The extent of crowding in the home during childhood, although related to body mass index in childhood, was not related to later coronary heart disease. Conclusion: The highest death rates from coronary heart disease occurred in boys who were thin at birth but whose weight caught up so that they had an average or above average body mass from the age of 7 years. Death from coronary heart disease may be a consequence of poor prenatal nutrition followed by improved postnatal nutrition.
Objectives The aim of this study was to evaluate the effect of a concurrent chronic total occlusion (CTO) in patients with ST-segment elevation myocardial infarction (STEMI) on long-term mortality ...and left ventricular ejection fraction (LVEF). Background The impact of a CTO in a non–infarct-related artery (IRA) on prognosis after STEMI is unknown. Methods Between 1997 and 2005, we admitted 3,277 STEMI patients treated with primary percutaneous coronary intervention. Patients were categorized as single-vessel disease (SVD), multivessel disease (MVD) without CTO, and MVD with a CTO in a non-IRA. We performed a “landmark survival analysis” to 5 years follow-up with a landmark set at 30 days. Additionally, we analyzed the evolution of LVEF within 1 year. Results Of the patients, 2,115 (65%) had SVD, 742 patients (23%) had MVD without CTO, and 420 patients (13%) had a concurrent CTO. Presence of a CTO was a strong and independent predictor for 30-day mortality (hazard ratio HR: 3.6, 95% confidence interval CI: 2.6 to 4.7, p < 0.01), whereas MVD without CTO was a weak predictor (HR: 1.6, 95% CI: 1.2 to 2.2, p = 0.01). In 30-day survivors, CTO remained a strong predictor (HR: 1.9, 95% CI: 1.4 to 2.8, p < 0.01), and MVD lost its independent prognostic value (HR: 1.1, 95% CI: 0.8 to 1.5, p = 0.45). Furthermore, CTO was associated with LVEF ≤40% immediately after STEMI (odds ratio: 1.9, 95% CI: 1.3 to 2.8, p < 0.01) and a further decrease in LVEF within the first year (odds ratio: 3.5, 95% CI: 1.6 to 7.8, p < 0.01). Conclusions The presence of a CTO and not MVD alone is associated with long-term mortality even when early deaths are excluded from analysis. The presence of a CTO is associated with reduced LVEF and further deterioration of LVEF.
Uncontrolled interferon γ (IFNγ)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell ...responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4
T cells. Deficiency in IL-10 signaling dramatically increased IL-1β release by moDCs. IL-1β boosted IFNγ secretion by CD4
T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1β expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFNγ-secreting CD4
T cells in humans and identifies IL-1β as a potential classifier for a subgroup of IBD patients.
Abstract
Background
We evaluated the efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in patients living with human immunodeficiency virus (HIV) with cryptosporidiosis.
Methods
We ...performed a randomized, double-blind, placebo-controlled study. Primary outcomes in part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched individuals living with HIV without cryptosporidiosis.
Results
Twenty part A and 10 part B participants completed the study ATP. Almost all part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared with the placebo group. Over the inpatient period, compared with those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit, 3.82), total stool weight decreased by 45.3 g (P = .37), and number of diarrheal episodes increased by 2.32 (P = .87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. One placebo and 3 CFZ participants died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than in part B controls.
Conclusions
Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons living with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy.
Clinical Trials Registration
NCT03341767.
We evaluated clofazimine for treatment of adults living with human immunodeficiency virus and cryptosporidiosis. Clofazimine was well tolerated but did not reduce Cryptosporidium excretion or diarrhea compared with adults treated with placebo. This trial forms a blueprint for future cryptosporidiosis therapeutic trials.
Background and Objective
Pharmacokinetics (PK) are severely altered in pregnant women due to changes in volume of distribution (Vd) and/or drug clearance (CL), affecting target attainment of ...antibiotics in pregnant women. This review is part of a series that reviews literature on the description of PK and target attainment of antibiotics in pregnant women with specific focus on penicillins.
Methods
A systematic literature search was carried out in PubMed. Articles were labelled as relevant when information on PK of penicillins in pregnant women was available.
Results
Thirty-two relevant articles were included, 8 of which discussed amoxicillin (with and without clavulanic acid), 15 ampicillin, 4 benzylpenicillin, 1 phenoxymethylpenicillin, and 4 piperacillin (with and without tazobactam). No studies were found on pheneticillin and flucloxacillin in pregnant women. Ten out of 32 articles included information on both Vd and CL. During the second and third trimester of pregnancy, a higher CL and larger Vd was reported than in non-pregnant women and in pregnant women during first trimester. Reduced target attainment was described in second and third trimester pregnant women. Only 7 studies reported dosing advice, 4 of which were for amoxicillin.
Conclusion
The larger Vd and higher CL in second and third trimester pregnant women might warrant a higher dosage or shortening of the dosing interval of penicillins to increase target attainment. Studies frequently fail to provide dosing advice for pregnant women, even if the necessary PK information was available.
The rotational fission of asteroids has been studied previously with simplified models restricted to planar motion. However, the observed physical configuration of contact binaries leads one to ...conclude that most of them are not in a planar configuration and hence would not be restricted to planar motion once they undergo rotational fission. This motivated a study of the evolution of initially non-planar binaries created by fission. Using a two-ellipsoid model, we performed simulations taking only gravitational interactions between components into account. We simulate 91 different initial inclinations of the equator of the secondary body for 19 different mass ratios. After disruption, the binary system dynamics are chaotic, as predicted from theory. Starting the system in a non-planar configuration leads to a larger energy and enhanced coupling between the rotation state of the smaller fissioned body and the evolving orbital system, and enables re-impact to occur. This leads to differences with previous planar studies, with collisions and secondary spin fission occurring for all mass ratios with inclinations ... = 40o, and mimics a Lidov-Kozai mechanism. Out of 1729 studied cases, we found that ~14 per cent result in secondary fission, ~25 per cent result in collisions and ~6 per cent have lifetimes longer than 200 yr. In Jacobson & Scheeres stable binaries only formed in cases with mass ratios q < 0.20. Our results indicate that it should be possible to obtain a stable binary with the same mechanisms for cases with mass ratios larger than this limit, but that the system should start in a non-planar configuration. (ProQuest: ... denotes formulae/symbols omitted.)
Introduction
Understanding the pharmacokinetics (PK) of antimicrobial drugs in pregnant women is crucial to provide effective and safe treatment. This study is part of a series that systematically ...reviews literature on the PK and analyzes if, based on the changed PK, evidence-based dosing regimens have been developed for adequate target attainment in pregnant women. This part focusses on antimicrobials other than penicillins and cephalosporins.
Methods
A literature search was conducted in PubMed according to the PRISMA guidelines. Search strategy, study selection, and data extraction were independently performed by two investigators. Studies were labeled as relevant when information on the PK of antimicrobial drugs in pregnant women was available. Extracted parameters included bioavailability for oral drugs, volume of distribution (Vd) and clearance (CL), trough and peak drug concentrations, time of maximum concentration, area under the curve and half-life, probability of target attainment, and minimal inhibitory concentration (MIC). In addition, if developed, evidence-based dosing regimens were also extracted.
Results
Of the 62 antimicrobials included in the search strategy, concentrations or PK data during pregnancy of 18 drugs were reported. Twenty-nine studies were included, of which three discussed aminoglycosides, one carbapenem, six quinolones, four glycopeptides, two rifamycines, one sulfonamide, five tuberculostatic drugs, and six others. Eleven out of 29 studies included information on both Vd and CL. For linezolid, gentamicin, tobramycin, and moxifloxacin, altered PK throughout pregnancy, especially in second and third trimester, has been reported. However, no target attainment was studied and no evidence-based dosing developed. On the other hand, the ability to reach adequate targets was assessed for vancomycin, clindamycin, rifampicin, rifapentine, ethambutol, pyrazinamide, and isoniazid. For the first six mentioned drugs, no dosage adaptations during pregnancy seem to be needed. Studies on isoniazid provide contradictory results.
Conclusion
This systematic literature review shows that a very limited number of studies have been performed on the PK of antimicrobials drugs—other than cephalosporins and penicillins—in pregnant women.
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