Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis

Morbi-mortality in cystic fibrosis (CF) is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy

The BELFRAIL (BFC80+) study: a population-based prospective cohort study of the very elderly in Belgium

In coming decades the proportion of very elderly people living in the Western world will dramatically increase. This forthcoming "grey epidemic" will lead to an explosion of chronic diseases. In order to anticipate booming health care expenditures and to assure that social security is funded in the future, research focusing on the relationship between chronic diseases, frailty and disability is needed. The general aim of the BELFRAIL cohort study (BFC80+) is to study the dynamic interaction between health, frailty and disability in a multi-system approach focusing on cardiac dysfunction and chronic heart failure, lung function, sarcopenia, renal insufficiency and immunosenescence

A case of fatal diquat poisoning: toxicokinetic data and autopsy findings.

CASE REPORT: A 37-year-old man ingested in a suicide attempt 300 mL of a diquat solution (equivalent to 60 g diquat ion). The initial diquat serum concentration was 64 microg/mL 4 hours after poisoning. The clinical course was characterized by a progressive anuria and by neurological disorders (coma and seizures). The patient died 26 hours after poisoning from refractory cardiocirculatory collapse. Extracorporeal techniques removed 1.09 g of diquat which could be considered as significant in regard to the total amount that was likely absorbed, but they did not influence the clinical outcome. There was marked renal tubular damage at autopsy and the highest diquat tissue concentration was found in the kidneys

High-throughput liquid chromatography-tandem mass spectrometric analysis of sirolimus in whole blood.

Sirolimus appears as a new potent immunosuppressive agent taking advantage of therapeutic drug monitoring to optimize its use in organ transplantation. In the absence of any available commercial immunoassay it was mandatory to develop chromatographic assays. Some methods have already been proposed to quantify sirolimus in whole blood, based either on HPLC-UV, liquid chromatography-mass spectrometry (LC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). We have developed a new faster and simpler LC-MS/MS method to quantify sirolimus in blood using ascomycin as an internal standard and multiple reaction monitoring (MRM) acquisition mode. This method displays a limit of detection of 0.3 microg/l, and the intra-assay reproducibility ranges from 4.1-7.9%. The pre-analytical preparation steps are quite similar to those required for semi-automated immunoassays. Ascomycin and sirolimus present retention times of 0.89 and 0.93 min, respectively, and the turnaround time for a result (2.5 min) is also similar to that observed using a clinical analyzer. The comparison performed between HPLC-UV and LC-MS/MS displays good correlation (r = 0.949). The LC-MS/MS method described above has been used routinely for more than 2000 patient blood specimens and may present several advantages over existing methods, e.g., specificity with sufficient sensitivity, rapidity, and small blood sampling (10 microl), making it particularly adapted for routine clinical use

Repeated Doses of Activated-charcoal and Cholestyramine for Digitoxin Overdose - Pharmacokinetic Data and Urinary Elimination

A 48-year-old man chronically treated with digitoxin and verapamil for prevention of atrial fibrillation voluntarily ingested 2.2 mg of digitoxin. Serum digitoxin concentrations and the urinary elimination of the drug were followed over a 12-day period. Urinary data indicate that a large percentage (50 %) of the drug was eliminated renally despite administration of multiple doses of activated charcoal, cholestyramine and hyperosmotic laxatives. The possible interaction with two other drugs, heparin and verapamil, is also discussed

Two cases of acute methanol poisoning partially treated by oral 4-methylpyrazole.

OBJECTIVE: Since the use of 4-methylpyrazole (4-MP) in the treatment of humans with methanol poisoning is poorly documented, we report two cases of acute methanol intoxication partially treated by this potent alcohol dehydrogenase (ADH) inhibitor. SETTING: Intensive Care Unit in a university hospital. PATIENTS: A 56-year-old man and an 18-year-old woman were observed, respectively, 41 and 16 h after the voluntary ingestion of an unknown amount of methanol. INTERVENTION: In both cases, ethanol was used as the first antidote. In the first patient, hemodialysis was also performed on admission because a high methanol level (0.72 g/l) and visual impairment were noted. In the second patient, ethanol therapy was withdrawn after 12 h when clinical and biological signs of acute pancreatitis became evident. Both patients received multiple oral doses of 4-MP. No recurrence of metabolic acidosis occurred and the 4-MP therapy was well tolerated. CONCLUSION: While the use of 4-MP is better documented in cases of ethylene glycol poisoning, it could also become an accepted option for the management of methanol poisoning since 4-MP offers advantages over ethanol therapy

Results from eqas for antibiotics show the need to improve the quality of the pharmacokinetic interpretation during monitoring

A mandatory external quality assessment scheme for Therapeutic Drug Monitoring is operational in Belgium. This quality scheme aims to provide an assessment of the state of the art of Therapeutic Drug Monitoring as practiced in the Belgian laboratories. The external quality assessment scheme' main objective is to evaluate laboratories on their ability to approach their peer group's median value. In addition to the analytical result, an interpretation for some parameters such as aminoglycosides is frequently asked by using case reports. Even when analytical performance is good, many laboratories encounter problems interpreting the results especially when the intervals of blood collections are uncommon. Results illustrate the added value of the use of dedicated software to support pharmacokinetic interpretation

Promotion of an applied pharmacokinetic software, named pharmonitor, developed to optimize individual dosage regimen through a national quality control program

To improve the practice of therapeutic drug monitoring, the Belgian Health Authorities have decided to support the development of an upgraded version of a pharmacokinetic program, so-called PharMonitor 1.0.0. Based on the Sawchuk-Zaske method, this software is a valuable and user-friendly tool for individually adjusting dosage regimens of aminoglycosides. It allows maximal speed, flexibility, reliability and optimal traceability. Moreover, the software is easily customized according to the user's selection (language, concentration units, drug target ranges, creatinine clearance, ...). Reports can be generated in PDF format after appropriate validation. The software can be connected to most laboratory information systems. Additional applications should be developed on PharMonitor 1.0.0. (other classes of drugs, Bayesian approach, ...). Once freely distributed to all Belgian laboratories, this software is expected to reduce the variability observed through external quality assessment schemes (EQAS), in the interpretation of drug concentrations

How appropriate is therapeutic drug monitoring for lithium? Data from the Belgian external quality assessment scheme

Background: Lithium remains a mainstay in the management of mood disorders. As with many psychotropic drugs, lithium treatment requires continuous observation for adverse effects and strict monitoring of serum concentrations. The present study aimed to assess the appropriateness of lithium assays used by Belgian laboratories, and to evaluate acceptability of their clinical interpretations. Methods: Nine in-house serum samples spiked with predetermined concentrations of lithium were distributed to 114 participants in the Belgian external quality assessment scheme. Laboratories were requested to report the assay technique, lithium measurements and interpretations with regard to measured concentrations. Inter/intramethod imprecision and bias were reported and acceptability of clinical interpretations was assessed. The intramethod variability was evaluated by selecting methods used by 6 laboratories or more. Flame photometry (IL 943) was considered as the reference method. Results: Laboratories returned assay results using colorimetry (69.3%), ion selective electrode (15.8%), flame photometry (8.8%), atomic absorption spectroscopy (5.2%) or mass spectrometry (0.9%). Lithium concentrations were systematically higher when measured with the Vitros assay (median bias: 4.0%), and were associated with consecutive biased interpretations. In contrast, the Thermo Scientific Infinity assay showed a significant negative bias (median bias: 9.4%). 36.0% of laboratories reported numerical values below their manufacturer cut-off for the blank sample; 16.6% of these laboratories detected residual lithium concentrations. Conclusions: The present study revealed assay-related differences in lithium measurements and their interpretations. Overall, there appeared to be a need to continue EQA of therapeutic drug monitoring for lithium in Belgium