[Evaluation of permanent disability levels in occupational pulmonary diseases]. / Comment évaluer en 2019 les taux d'incapacité permanente des pathologies professionnelles pulmonaires ?

Compensation for occupational pulmonary diseases requires the establishment of guidelines based on standardized and objective criteria, in order to provide compensation that is as fair as possible to patients who suffer from them. A review of the elements necessary for the examination of an individual file was carried out by a working group. It is accepted that respiratory functional exploration is the key element in assessing the level of permanent disability in all of these conditions, with the exception of thoracic malignancies. Guiding scales have been developed for the respiratory impairment of three types of conditions: occupational asthma, thoracic malignancy, and other respiratory diseases. Additional criteria for increasing the permanent disability level are also proposed in order to take into account professional prejudice, in particular the possibility or not of continuing the occupational activity, in the same job or after changing to another. For certain respiratory diseases, a periodic reassessment of the initially attributed permanent disability level is recommended as well as the initial one at the time of definitive cessation of occupational activity.

Estimation of the binding free energy by Linear Interaction Energy models.

Since Hansch's extra thermodynamic multi-parameter approach, originally coined as Linear Free Energy Relationship, great efforts in medicinal chemistry have been made to properly estimate the binding free energy. Despite the often small amount, its value is however very critical in determining a successful binding. As a result, its correct estimation may provide a guide for a prospective rational drug design. The calculation of the absolute binding free energies is however a very challenging task as it requires a rigorous treatment of a number of physical terms that are both very time demanding and to some extent not immediately interpretable. In view of this, the introduction of some numerical approximations has permitted to develop the so called Linear Interaction Energy method that, at present, constitutes the best compromise among accuracy, speed of computation and easy interpretation. The initially developed Linear Interaction Energy method was subsequently revisited and several important improvements have been made. Significant examples are the Extended Linear Response, the surface generalized Born LIE, the molecular mechanics generalized Born surface area, the linear interaction energy in continuum electrostatics as well as its quantum mechanics variant. Principles and selected applications of these methods will be herein reviewed.

New strategies in the chemotherapy of leukemia: eradicating cancer stem cells in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the Philadelphia-positive chromosome deriving from a translocation between chromosomes 22 and 9. The oncogenic product of this aberrant chromosome is the constitutively active tyrosine kinase BCR-ABL that is responsible for leukemic cell growth, proliferation and survival driven by the dysregulation of a large array of signal transduction pathways. Inhibition of BCR-ABL with tyrosine kinase inhibitors proved to be an efficient therapy of CML in the chronic phase. Unfortunately, the impressive success of BCR-ABL inhibitors as front-line therapy in CML has been tempered by problems of disease persistence or relapse arising from different mechanisms, including mutations in the kinase domain of the enzyme BCRABL and mechanisms independent from BCR-ABL activity. Growing evidence has also suggested a pivotal role of persistent leukemic cancer stem cells, characterized by high self-renewal and pluripotency, in CML maintenance and/or relapse. The present review deals with the most recent advances in this challenging field and focuses on the development of new drugs and therapeutic approaches to eradicate the subtle and dangerous leukemic stem cells responsible for maintaining and sustaining tumor growth.

Targeting monoamine oxidases with multipotent ligands: an emerging strategy in the search of new drugs against neurodegenerative diseases.

The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.

BCR-ABL inhibitors in chronic myeloid leukemia: process chemistry and biochemical profile.

Chronic myeloid leukemia (CML) is a myeloproliferative disease originating from a constitutively active tyrosine kinase, called BCR-ABL, expressed by an oncogene resulting from a reciprocal translocation between chromosome 9 and chromosome 22, coded as (t[9,22][q34;q11]). Inhibition of BCR-ABL with tyrosine kinase inhibitors (TKI) proved to be an efficient targeted therapy of Philadelphia-positive (Ph+) CML in the chronic phase. This review mainly addresses the synthetic pathways and process chemistry leading to the large scale preparation for pre-clinical demands and clinical supply of the three TKIs approved for Ph+ CML, i.e., imatinib, dasatinib and nilotinib and three more investigational drugs, i.e., bosutinib, ponatinib and bafetinib. Recent progress on the biochemical profiling of the six examined TKIs has been also reported.

Quinolizidinyl derivatives of bi- and tricyclic systems as potent inhibitors of acetyl- and butyrylcholinesterase with potential in Alzheimer's disease.

On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e.g. 15: IC50 versus BChE=0.15 µM; SI=47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e.g. 46: IC50 versus AChE=0.35 µM; SI=0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multi-target drugs.

[Chronic obstructive pulmonary disease (COPD) in the elderly]. / La bronchopneumopathie chronique obstructive (BPCO) du sujet âgé en huit questions/réponses.

Chronic obstructive pulmonary disease (COPD) is a chronic disease characterized by incompletely reversible airflow limitation, measured by a decrease of FEV(1)/FVC ratio. International consensus does not agree on a single threshold for this ratio, which can define airflow obstruction. Although the prevalence of COPD in the elderly population varies according to the definition used, it definitely increases with age and could reach 15% in those over 65 years of age. Therefore, ageing of the population should result in increased prevalence and socioeconomical costs of COPD during coming years. In France, diagnosis of COPD in the elderly is difficult, late and insufficient. Management, which has the same goals as in younger populations, has to be global and coordinated. Some points should be considered with particular attention considering the cumulative risks related on the one hand to COPD and on the other to ageing: pharmacological side-effects, decreased physical and social autonomy, nutritional impairment, comorbidities. Given the lack of specific data in elderly populations, pharmacological indications are generally considered to be the same as in younger populations, but some additional precautionary measures are necessary. Pulmonary rehabilitation seems to be beneficial at any age. Palliative care comes up against important difficulties: an indefinite beginning of the palliative stage in COPD; insufficient palliative care resources; insufficient communication; insufficient utilization of palliative care resources. Global COPD management in elderly requires coordination, best reached in health care network organizations involving medical and/or social professionals.

Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase.

A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3-100 microM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease beta-amyloid deposition.

Inhibition of monoamine oxidases by functionalized coumarin derivatives: biological activities, QSARs, and 3D-QSARs.

A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of the compounds acted preferentially on MAO-B with IC(50) values in the micromolar to low-nanomolar range; high inhibitory activities toward MAO-A were also measured for sulfonic acid esters. The most active compound was 7-[(3, 4-difluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC(50) value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumarin derivatives acting on MAO-B yielded good statistical results (q(2)() = 0.72, r(2)() = 0.86), revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties. CoMFA was performed on two data sets of MAO-A and MAO-B inhibitors. The GOLPE procedure, with variable selection criteria, was applied to improve the predictivity of the models and to facilitate the graphical interpretation of results.

Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: effects of lipophilicity and structure-activity relationships.

A number of condensed pyridazines and pyrimidines were synthesized and tested for their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. Their lipophilicity was examined by measuring partition coefficients and RP-HPLC capacity factors, revealing some peculiar electronic and conformational effects. Further insights were obtained by X-ray crystallography and a thermodynamic study of RP-HPLC retention. Structure-activity relations highlighted the main factors determining both selectivity and inhibitory potency. Thus, while most of the condensed pyridazines were reversible inhibitors of MAO-B with little or no MAO-A effects, the pyrimidine derivatives proved to be reversible and selective MAO-A inhibitors. Substituents on the diazine nucleus modulated enzyme inhibition. A QSAR analysis of X-substituted 3-X-phenyl-5H-indeno[1,2-c]pyridazin-5-ones showed lipophilicity to increase MAO-B and not MAO-A inhibitory activity.

The significance of bone islands, cystic areas and sclerotic areas in dysbaric osteonecrosis.

Dysbaric osteonecrosis is a major hazard to compressed air workers and an increasing hazard to divers. Symptomless osteonecrosis is best recognised by radiology and it is of fundamental importance that interpretation be reliable and accurate. There is much controversy concerning the significance of bone islands and cystic areas; several authors report bone islands and cystic areas to be up to eight times more frequent in compressed air workers and divers and believe that these represent positive evidence of osteonecrosis. Skeletal radiographs of 100 Royal Navy divers, all of whom were at risk to osteonecrosis were matched for age and rank with 100 controls, none of whom had been exposed to high pressures. The radiographs were interpreted by three radiologists working independently without knowing whether the radiographs were in the diving or control group. It is concluded that bone islands, cystic areas and sclerotic areas, as described in this text, occur with equal frequency in divers as in the normal population and do not represent positive evidence of osteonecrosis. The report includes autopsy studies of the proximal femur and proximal humerus in six diving fatalities. Five bone islands in the proximal humerus and one in the femoral neck were studied in bones removed from five divers. In the sixth case a cyst was seen to develop radiologically in the femoral neck and then reduce in size over 3 years and 10 months. Slab radiographs and histological section in all cases show no evidence of osteonecrosis.