Risk and the sense of safety

International Journal of Clinical Pharmacy -     

Epithelium-Free Area in The Thymic Cortex of Rats

The histology of epithelium-free areas in the subcapsular region of the thymus was studied in Wistar rats. Lymphocytes in these areas were CD4/CD8 double-positive, TCR α/β positive in low intensity, and in CD5 labeling either negative or positive in low intensity. There was a high proliferative activity as assessed by bromodeoxyuridine incorporation in vivo and detected by immunohistochemistry. Various macrophage types were observed. They were either large and round to slightly dendritic, or small and dendritic. Most large cells were positive for MHC Class II, and labeled by the antimacrophage antibodies ED1 and ED2. A few cells were strongly positive for Sudan black, Oil red O, nonspecific esterase, and acid phosphatase; they resembled the large rounded macrophages in the corticomedullary zone, although their MHC Class II and ED2 staining was more intense. A few cells showed features of tingible body macrophages, as they contained cellular debris.Serial sections showed that epithelium-free areas run from the subcapsular area to deep in the cortex, and often border the medulla. This opens the opportunity for immature lymphocytes to move into the medulla and corticomedullary zone without contacting and potential selection with cortical stromal elements other than macrophages in the epithelium-free areas. In this case, the epithelium-free areas may offer a separate intrathymic pathway for T lymphocytes.     

Inability to Work Fulltime,Prevalence and Associated Factors Among Applicants for Work Disability Benefit

Journal of Occupational Rehabilitation - Purpose Inability to work fulltime is an important outcome in the assessment of workers applying for a disability benefit. However, limited knowledge is...     

Risk assessment in clinical pharmacy

Medication error forms a major proportion of the errors in the medical system. Despite many studies of adverse drug events, there are no systematic ways of ensuring safety, or of assessing how safe a pharmaceutical system is. Risk assessment is required in hazardous industries such as nuclear power or oil and gas. Risk assessments involve identifying the defences and assessing their effectiveness and are relatively uncommon in clinical pharmacy , as opposed to reactive approaches involving incident analyses. Risk factors, that degrade barriers, can be identified and their effect measured. A risk assessment structure for pharmacy processes is proposed that can also be used to support incident investigation and analysis processes and provide a standard for audit.     

Detection and quantification of beta cells by PET imaging: why clinical implementation has never been closer

In this issue of Diabetologia, Alavi and Werner ( https://doi.org/10.1007/s00125-018-4676-1) criticise the attempts to use positron emission tomography (PET) for in vivo imaging of pancreatic beta cells, which they consider as ‘futile’. In support of this strong statement, they point out the limitations of PET imaging, which they believe render beta cell mass impossible to estimate using this method. In our view, the Alavi and Werner presentation of the technical limitations of PET imaging does not reflect the current state of the art, which leads them to questionable conclusions towards the feasibility of beta cell imaging using this approach. Here, we put forward arguments in favour of continuing the development of innovative technologies enabling in vivo imaging of pancreatic beta cells and concisely present the current state of the art regarding putative technical limitations of PET imaging. Indeed, far from being a ‘futile’ effort, we demonstrate that beta cell imaging is now closer than ever to becoming a long-awaited clinical reality.     

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( ± SD) of C_max, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 ± 9 ng kg/mg ml, 210 ± 70 ng h kg/mg ml and 2.6 ± 0.9 ng kg/mg ml, respectively. For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rejection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/kg–150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mg/kg–100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ng/ml and 700 ng/ml. Received: 1 October 1997 Revised: 20 April 2001 Accepted: 7 June 2001     

Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions

Flucytosine (5-FC) is a synthetic antimycotic compound, first synthesized in 1957. It has no intrinsic antifungal capacity, but after it has been taken up by susceptible fungal cells, it is converted into 5-fluorouracil (5-FU), which is further converted to metabolites that inhibit fungal RNA and DNA synthesis. Monotherapy with 5-FC is limited because of the frequent development of resistance. In combination with amphotericin B, 5-FC can be used to treat severe systemic mycoses, such as cryptococcosis, candidosis, chromoblastomycosis and aspergillosis. Recently, 5-FC has been combined with newer azole antifungal agents; it also plays an important role in a new approach to the treatment of cancer. The severe side effects of 5-FC include hepatotoxicity and bone-marrow depression. In most patients, these side effects are concentration dependent, predictable, possibly avoidable with close monitoring to maintain 5-FC concentrations at <100 mg/L, and reversible with drug discontinuation or reduction of dose. 5-FC is well absorbed after oral administration, penetrates into body tissues well and is excreted mainly by the kidneys. In renal failure, major dose adjustments have to be made. The most important drug interaction of 5-FC occurs with concomitant administration of 5-FC and nephrotoxic drugs, especially amphotericin B. Owing to the crucial role of glomerular filtration in 5-FC elimination, drugs that impair this mechanism will decrease the elimination of 5-FC and thus prolong its half-life.     

Inter- and intraindividual variability of riluzole serum concentrations in patients with ALS.

All patients with amyotrophic lateral sclerosis (ALS) are treated with the same dose of riluzole: 50 mg twice daily. Reasonably large interindividual differences in clearance of the drug have been reported. The relatively small group of patients with high blood concentrations of riluzole has probably primarily influenced the efficacy and the incidence of side-effects in the previously conducted clinical trials with riluzole. Individual dosing of the drug may, in the case of large interindividual differences in serum concentrations of the drug, be necessary in the future. Exact data concerning the plasma and serum concentrations of riluzole in patients with ALS, after standardized intake of the drug, diet and blood sampling are unknown so far. In this study, inter- and intraindividual variability of serum and plasma levels of riluzole in 21 patients with "probable" or "definite" ALS were determined. The interindividual variability of peak serum levels (coefficient of variation=74%) was significantly larger than intraindividual variability (p<0.001). Serum levels were not correlated with age or smoking status. The determination of a correlation between riluzole serum concentrations and survival of patients with ALS will be the aim of further studies.     

MRI of adamantinoma of long bones in correlation with histopathology

OBJECTIVE: The purposes of this retrospective study were to assess specific MRI features of adamantinoma, including classic adamantinoma and its osteofibrous dysplasia-like variant, and to assess the role of adamantinoma in surgical planning. MATERIALS AND METHODS: MR images of 22 patients with histologically proven adamantinoma, subtyped according to defined criteria, were analyzed, with emphasis on morphologic features, signal intensities, and enhancement parameters. Intra- and extraosseous tumor extent was determined. In all patients, examination of the corresponding resected specimens was performed with regard to tumor extent and presence of multicentricity. Moreover, radiographs were reviewed, and radiographic features derived from the literature were determined. RESULTS: All tumors were primarily localized in the tibia diaphysis (including one patient with additional lesions in the fibula), most frequently in the anterior cortical bone (19/22) with extension toward the bone marrow in 12 patients. We distinguished two morphologic patterns: a solitary lobulated focus versus a pattern of multiple small nodules in one or more foci. Separated tumor foci, defined as foci of high signal intensity on either T2-weighted images or T1-weighted contrast-enhanced images, interspersed with normal-appearing cortical or spongious bone were seen in six patients. All tumors showed intense and homogeneous static enhancement, but there was no uniform dynamic enhancement pattern. No relationship between MRI features and histologic subtype of adamantinoma was found. CONCLUSION: Some uniform MRI characteristics, along with those of radiography, may contribute to the diagnosis of adamantinoma; however, these are not related to the histologic subtype. MRI is pivotal for precise locoregional staging, especially for depiction of distant cortical foci, soft tissue, and intramedullary extension and thus is useful for determining tumor-free margins and strategies for reconstructive surgery.