Adverse drug reactions in hospitals: a narrative review

The serious nature of adverse drug reactions (ADRs) has been highlighted in a number of instances over the last forty years, the most recent of these being the occurrence of serious thrombotic events with the use of COX-2 inhibitors. ADRs are estimated to be between the 4(th) and 6(th) leading cause of death in the USA, with fatal ADRs occurring in 0.32% of patients. A recent UK study showed that 6.5% of hospital admissions were related to ADRs. ADRs can therefore be regarded as a significant public health and economic problem. There is an urgent need to develop better preventive strategies to reduce the burden of ADRs. Because ADRs can affect any bodily system, can have many different clinical presentations, and are of widely variable severity, prevention will not be easy and will have to be multifactorial in its approach. This paper reviews the epidemiology of ADRs in hospitals and evaluates the research that has been undertaken to date to prevent ADRs.     

Biogenetic relationships between Annonaceous acetogenins: squamocin is not a precursor of chamuvarinin based on a semisynthetic study

In the course of reactivity studies on squamocin (1), a highly cytotoxic acetogenin from the plant family Annonaceae, two diastereomers, 3 and 4, of chamuvarinin (2) were synthesized. Based on this, a plausible relative configuration was proposed for 2, demonstrating the absence of any biogenetic link between 1 and 2. The new analogues 3, 4, and 7 were also tested for their ability to induce apoptosis.     

Phase I cancer trials methodology

The main objective of phase I cancer trials is to determine precisely the recommended dose of an anticancer agent as a single agent or in a context of combinations of anticancer agents (including cytotoxic agents, immunotherapy, radiotherapy...), that is administered for the first time in man, to further proceed clinical development with phase II and III trials. The recommended dose must have the greatest efficiency with acceptable toxicity. For the anticancer agents, the ratio risk/benefit is high, since toxicities associated with many cancer therapeutic agents are substantial and because the efficacy is often limited. Thus, phase I cancer trials present unique challenges in comparison to other therapeutic areas. Indeed, it is essential to minimize the numbers of patients treated at subefficient dose levels, and in the same time not to expose the patients to unacceptable toxicity. Historically, the first method that has been used is the Fibonacci escalation. The major problems raised with this method have been the lengths of the trials and the risk to treat substantial numbers of patients at nontherapeutix doses. Thus, novel methods have been then developed modifying the numbers of patients included at each dose level and the rapidity of dose escalation. These methods include pharmacologically guided dose escalation, escalation with overdose control and the continual reassessment method which are both statistically based dose escalation methods, and the accelerated titration designs. Concerning the targeted anticancer therapies, the therapeutic effect on the target, due to their higher specificity, can be obtained using doses that have few toxicity. Using the toxicity to determine the recommended dose for phase II trials, as it is the case for "classical > anticancer agents, does not seem to be sufficient. Alternatives to determine the optimal biological dose include measurement of target inhibition, pharmacokinetic analysis and functional imaging.     

Is there still a role for surgery in esophageal carcinoma in 2007?

Regarding curative treatment of oesophageal carcinoma, many therapeutic options could be planned. Surgery is traditionally considered as the most appropriate treatment for locoregional control and long-term survival. Because of the poor prognosis, muldisciplinary approach is necessary, including surgery, radiotherapy and chemotherapy, alone or in association. However, because of the small number of well randomised trials, the question of which treatment is the most appropriate is still under debate. In 2007, following therapeutic strategies could be drawn: surgery is the main treatment, used alone for stages I and IIa, in association with neoadjuvant chemotherapy (CT) or chemoradiation (CRT) for stages IIb. For locally advanced tumours (stage III), adenocarcinomas required neoadjuvant CT or CRT followed by surgery, whereas for squamous cell carcinomas exclusive CRT is the main treatment with following important conditions : (i) response to CRT, (ii) curative salvage surgery in case of non response after 2 cycles or persistent tumour after 4 cycles, (iii) long-term survival may be probably enhanced by adjuvant surgery in experienced centres for selected patients.     

Standard preoxygenation vs two techniques in children

BACKGROUND: Preoxygenation is recommended in pediatric anesthesia but it has been poorly assessed. Fractional expired oxygen concentration (F(ET)O(2)) is a preoxygenation monitor. The aim of this prospective study in children was to compare three techniques of preoxygenation by the measurement of F(ET)O(2). METHODS: Twenty children (6-15 years) were included. F(ET)O(2) was measured with the child in a supine position, holding the face mask. The F(ET)O(2) value was measured after 3 min of calm breathing of room air (baseline) and during the three preoxygenation techniques performed in random order: 3 min of tidal volume breathing using an O(2) flow of 9 l x min(-1) (TV x 3 min)--four deep breaths within 30 s using an O(2) flow of 15 l x min(-1) (4 DB)--eight deep breaths within 1 min using an O(2) flow of 15 l x min(-1) (8 DB). Between each technique, at least 5 min breathing room air was allowed to return to baseline F(ET)O(2). Fisher's exact test was used and P < 0.05 was considered significant. RESULTS: Twenty children were studied (age: 11.5 +/- 3 years, weight: 42 +/- 21 kg). The F(ET)O(2) > or = 90% was found to be 79% in 74 +/- 40 s with TV x 3 min, 11% with 4 DB, and 68% with 8 DB. CONCLUSIONS: In children, Vt x 3 min is the most efficient preoxygenation technique to reach F(ET)O(2) > or = 90%.     

DNA-methylation-dependent alterations of claudin-4 expression in human bladder carcinoma

The expression pattern of tight junction (TJ) proteins is frequently disrupted in epithelial tumors. In particular, isoform- and organ-specific alterations of claudins have been detected in human cancers, highlighting them as interesting tools for the prognosis or treatment of various carcinomas. However, the molecular mechanisms responsible for these alterations are seldom identified. Here, we analyzed the expression and localization of claudins 1, 4, and 7 in human bladder carcinoma. Claudin-4 expression was significantly altered in 26/39 tumors, contrasting with the rare modifications detected in the expression of claudins 1 and 7. Overexpression of claudin-4 in differentiated carcinomas was followed by a strong downregulation in invasive/high-grade tumors, and this expression pattern was associated to the 1-year survival of bladder tumor patients. A CpG island was identified within the coding sequence of the CLDN4 gene, and treatment with a methyl-transferase inhibitor restored expression of the protein in primary cultures prepared from high-grade human bladder tumors. In addition, claudin-4 expression correlated with its gene methylation profile in healthy and tumoral bladders from 20 patients, and downregulation of claudin-4 expression was detected in the urothelium of mice overexpressing DNA methyl transferase 3a (Dnmt3a). Delocalization of claudins 1 and 4 from TJs was observed in most human bladder tumors and in the bladder tumor cell line HT-1376. Although the CLDN4 gene was unmethylated in these cells, pharmacological inhibition of methyl transferases re-addressed the two proteins to TJs, resulting in an increase of cell polarization and transepithelial resistance. These biological effects were prevented by expression of claudin-4-specific siRNAs, demonstrating the important role played by claudin-4 in maintaining a functional regulation of homeostasis in urothelial cells. Results of this study indicate that the TJ barrier is disrupted from early stages of urothelial tumorigenesis. In addition, we identified hypermethylation as the mechanism leading to the alteration of claudin-4 expression, and maybe also localization, in bladder carcinoma.     

Histological and transcriptional study of angiogenesis and lymphangiogenesis in uninvolved skin,acute pinpoint lesions and established psoriasis plaques: An approach of vascular development chronology in psoriasis

BackgroundDysregulation of angiogenesis and lymphangiogenesis could participate in psoriasis pathogenesis. Analysis of nascent psoriasis lesions should help at identifying early vascular anomalies.ObjectiveTo analyse vascular development, angiogenesis and lymphangiogenesis markers expression in uninvolved skin in psoriatic patients (N), early psoriasis lesions or pinpoints (PP) and psoriasis plaques (PSO).MethodsSkin biopsies were taken in 17 patients in N and in PSO and/or PP. The mRNA steady-state level of angiogenesis and lymphangiogenesis markers was measured by RT-PCR. Immunohistochemistry was performed for von Willebrand factor, podoplanin, Ki-67 and VEGFR3. Blood (BV) and lymphatic (LV) vessels expansion was measured by computer-assisted morphometry.ResultsClinical and epidermal aspects indicated that PP are intermediate between N and PSO. While total BV area was already increased in PP similarly to PSO as compared to N, LV area in PP was intermediate between N and PSO. Mean LV size was identical in N and PP and increased in PSO, mean BV size in PP being intermediate between N and PSO. VEGF-A 189 variant was increased in PP as compared to N and PSO. As compared to N, angiogenesis markers (VEGF-A isoforms, PlGF, VEGFR2, NRP-1), VEGF-C and NRP-2 were similarly increased in PP and PSO. Keratin 16 and the lymphangiogenesis markers (VEGFR3, prox-1) were intermediate in PP.ConclusionThese data suggest that the expansion of lymphatic vessels occurs after blood vascular development in psoriasis. Expansion of BV in PP could be followed by vessel enlargement during progression to PSO, in parallel with a decreased VEGF-A 189/VEGF-A 121 balance in plaques.