Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression

BACKGROUND: In adults, pravastatin reduces the development and progression of transplant vasculopathy, the main long-term risk after cardiac transplantation. The pharmacokinetics of pravastatin is not known in children taking calcineurin inhibitors. Our aim was to determine the single-dose pharmacokinetics and short-term safety of pravastatin in children undergoing regular triple-drug immunosuppressive therapy after cardiac transplantation. METHODS: Nineteen pediatric cardiac transplant recipients (aged 4.4 to 18.9 years) receiving triple immunosuppression therapy consisting of methylprednisolone (19 patients), cyclosporine (INN, cyclosporin) (17 patients) or tacrolimus (2 patients), and azathioprine (18 patients) or mycophenolate mofetil (1 patient) ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 24 hours. Subsequently, the patients took 10 mg pravastatin orally once daily for 8 weeks. The lipid-lowering effect and the safety of pravastatin therapy were studied. RESULTS: The mean peak plasma concentration (C(max)) of pravastatin was 122.2 +/- 88.2 ng/mL (range, 11.4-305.0 ng/mL), and the area under the plasma concentration-time curve of pravastatin from 0 to 10 hours [AUC(0-10)] was 264.1 +/- 192.4 ng.h/mL (range, 30.8-701.6 ng.h/mL). These C(max) and AUC(0-10) values are nearly 10-fold higher than the corresponding values reported in hypercholesterolemic children in the absence of immunosuppressive therapy. The time of peak concentration (t(max)) of pravastatin was 1.1 +/- 0.4 hours (range, 0.5-2 hours), and the mean elimination half-life (t(1/2)) was 1.2 +/- 0.3 hours (range, 0.7-2.2 hours); these parameters were similar to those in the hypercholesterolemic children. By 8 weeks of treatment, the concentration of serum total cholesterol decreased by 13% (P =.005), low-density lipoprotein cholesterol by 27% (P <.0001), and triglycerides by 6% (not significant, P =.28); the concentration of high-density lipoprotein cholesterol increased by 7% (not significant, P =.30). No clinically significant increases in serum ALT, creatine kinase, or creatinine levels were observed. CONCLUSIONS: The plasma concentrations of pravastatin in pediatric cardiac recipients receiving triple immunosuppressive medication are nearly 10-fold higher than in hypercholesterolemic children after the same pravastatin dose. However, the short-term therapy of pravastatin was well tolerated and effective in lowering serum cholesterol levels in cardiac recipients.     

The chloroplast proteome: a survey from the <Emphasis Type="Italic">Chlamydomonas reinhardtii</Emphasis> perspective with a focus on distinctive features

The unicellular green alga Chlamydomonas reinhardtii has emerged to be an important model organism for the study of oxygenic eukaryotic photosynthesis as well as other processes occurring in the chloroplast. However, the chloroplast proteome in C. reinhardtii has only recently been comprehensively characterized, made possible by proteomics emerging as an accessible and powerful tool over the last decade. In this review, we introduce a compiled list of 996 experimentally chloroplast-localized proteins for C. reinhardtii, stemming largely from our previous proteomic dataset comparing chloroplasts and mitochondria samples to localize proteins. In order to get a taste of some cellular functions taking place in the C. reinhardtii chloroplast, we will focus this review particularly on metabolic differences between chloroplasts of C. reinhardtii and higher plants. Areas that will be covered are photosynthesis, chlorophyll biosynthesis, carbon metabolism, fermentative metabolism, ferredoxins and ferredoxin-interacting proteins.     

How are asthmatics included in the derivation of guideline values for emergency planning and response?

Guideline values for emergency planning and response are aimed to protect the general public, including asthmatics and other susceptible groups, during sudden airborne releases of chemicals. A precondition of asthma may increase the individual susceptibility to acute exposures. This paper studies to what extent experimental data on asthmatics are included in the rationale and derivation of guideline values. An analysis of the Technical Support Documents (TSDs) of the Acute Exposure Guideline Levels (AEGLs) shows that only 23 of the 176 TSDs include references to experimental studies on asthmatics, 30 include a statement on asthmatics but no reference to experimental data, and 123 lack any explicit statement on asthmatics. The TSDs were further compared with the support documents of nine other programs for acute or occupational short-term values. All programs were incomplete with respect to experimental data on asthmatics. Omission of asthmatics may interfere with trustful and efficient health protective actions. We suggest that the availability of data on asthmatics should be carefully examined in the development of guideline values, and that the lack of such data should be explicitly noted. In the latter case, available data for other irritants may be used to justify an appropriate assessment factor.     

Repeated ethanol but not phencyclidine impairs spontaneous alternation behaviour in the Y-maze

Prolonged consumption of ethanol produces prefrontal cortex (PFC) dysfunction in patients, and this has been demonstrated using structural, physiological and psychological measurements. We therefore wanted to develop an animal model of PFC dysfunction to study whether this state changes sensitivity for ethanol or other behavioural/motivational measures. Adolescent Wistar rats were first screened in the novel object recognition task to establish a pre-treatment baseline measure of locomotor activity, anxiety-like behaviour and PFC function. Animals were divided into four treatment groups [saline, 5 mg/kg phencyclidine (PCP), 2.5g/kg ethanol, ethanol + PCP] and injected i.p. for 5 days followed by a 2-day washout. On the 8th day, animals were allowed to explore a Y-maze for 10 min. and spontaneous alternations were recorded using the ANY-maze tracking system. PCP, a classic drug used to induce PFC dysfunction in animals, did not significantly reduce the % correct alternations relative to the 70% level achieved by the saline group. Ethanol and the combination of Ethanol + PCP, however, significantly reduced alternations to approximately 30%. The combined dose was not additive in terms of Y-maze impairment, and these animals had less total distance travelled and greater time immobile relative to the other groups. We therefore concluded that injection of 2.5 g/kg ethanol for 5 days in Wistar rats produces a more substantial, consistent and valid PFC dysfunction than 5 mg/kg PCP.     

A Pilot Study on Using Eye Tracking to Understand Assessment of Surgical Outcomes from Clinical Photography

Appearance changes resulting from breast cancer treatment impact the quality of life of breast cancer survivors, but current approaches to evaluating breast characteristics are very limited. It is challenging, even for experienced plastic surgeons, to describe how different aspects of breast morphology impact overall assessment of esthetics. Moreover, it is difficult to describe what they are looking for in a manner that facilitates quantification. The goal of this study is to assess the potential of using eye-tracking technology to understand how plastic surgeons assess breast morphology by recording their gaze path while they rate physical characteristics of the breasts, e.g., symmetry, based on clinical photographs. In this study, dwell time, transition frequency, dwell sequence conditional probabilities, and dwell sequence joint probabilities were analyzed across photographic poses and three observers. Dwell-time analysis showed that all three surgeons spent the majority of their time on the anterior–posterior (AP) views. Similarly, transition frequency analysis between regions showed that there were substantially more transitions between the breast regions in the AP view, relative to the number of transitions between other views. The results of both the conditional and joint probability analyses between the breast regions showed that the highest probabilities of transitions were observed between the breast regions in the AP view (APRB, APLB) followed by the oblique views and the lateral views to complete evaluation of breast surgical outcomes.     

Peripheral blood regulatory T cell measurements correlate with serum vitamin D levels in patients with multiple sclerosis

Vitamin D has been associated with a decreased risk of multiple sclerosis (MS). In this study, serum 1, 25-dihydroxyvitamin D (1, 25-(OH)2 vitD) and 25-hydroxyvitamin D (25-OH vitD), regulatory T cell percentages and naïve and memory T helper cell subsets were measured in 26 patients with multiple sclerosis, 21 who were not on treatment with disease modifying therapy. These studies showed an inverse correlation between 25-OH vitD levels and Treg cell percentages and a direct correlation between Treg cell percentages and 1, 25-(OH)2 vitD:25-OH vitD ratios. In addition, 25-OH vitD levels correlated directly and 1, 25-(OH)2 vitD:25-OH vitD ratios correlated inversely with CXCR3+ naïve T helper cell percentages and CXCR3+naïve:CXCR3+ memory T helper cell ratios. All together, these data demonstrate that vitamin D measurements can reflect measures of immune status among patients with MS.     

Pharmacokinetics and pharmacodynamics of growth hormone in patients on chronic haemodialysis compared with matched healthy subjects: an open, nonrandomized, parallel-group trial

BACKGROUND: GH may be beneficial in treating patients with end-stage renal disease (ESRD). However, the efficacy and safety of GH could be compromised by the potential for accumulation in the circulation. OBJECTIVE: The objective was to investigate the pharmacokinetics and safety of GH treatment in ESRD patients. DESIGN: This was an open, nonrandomized, single-centre parallel-group study lasting 8-9 days. SUBJECTS: Eleven adult ESRD patients and 10 matched healthy individuals received recombinant human GH (50 microg/kg/day for 7 days) by subcutaneous injection; there were two dose reductions (25%) from Day 5/7. ESRD patients underwent dialysis four times. MEASUREMENTS: Serum concentrations of GH, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-I (IGFBP-I), IGFBP-III and GHBP were measured. The primary end-point was GH exposure [area-under-the-curve (AUC) calculated from the 24-h profile] on Days 7-8. RESULTS: GH AUC(0-24 h) was greater for patients (387.91 +/- 134.13 microg h/l) than healthy subjects (225.35 +/- 59.63 microg h/l) and the 90% confidence interval (CI) for the estimated patient : healthy subject ratio (1.40-2.07) was not within the acceptance interval (0.67-1.50). GH AUC(18-24 h) for patients and healthy subjects (3.03 +/- 2.71 microg h/l and 6.37 +/- 4.21 microg h/l) returned approximately to baseline (2.86 +/- 3.91 microg h/l and 1.09 +/- 1.43 microg h/l); terminal half-life (t(1/2,z)) was shorter for patients (2.28 +/- 00.43 h vs. 3.23 +/- 00.75 h). No major safety issues were identified. CONCLUSIONS: Results demonstrate a difference between patients and healthy subjects regarding GH AUC(0-24 h). However, GH concentrations for both groups were comparable to baseline by 20-22 h, thus GH was not retained in the circulation of ESRD patients.