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Angiotensin I-converting enzyme (ACE, kininase II) is a single-chain protein containing two active site domains (named N-and C-domains according to position in the chain). ACE is bound to plasma membranes by its C-terminal hydrophobic transmembrane anchor. Deal fluid, rich in ACE activity, obtained from patients after surgical colectomy was used as the source. Column chromatography, including modified affinity chromatography on lisinopril-Sepharose, yielded homogeneous ACE after only a 45-fold purification. N-terminal sequencing of ileal ACE and partial sequencing of CNBr fragments revealed the presence of an intact N terminus but only a single N-domain active site, ending between residues 443 and 559. Thus, ileal-fluid ACE is a unique enzyme differing from the widely distributed two-domain somatic enzyme or the single C-domain testicular (germinal) ACE. The molecular mass of ileal ACE is 108 kDa and when deglycosylated, the molecular mass is 68 kDa, indicating extensive glycosylation (37% by weight). In agreement with the results reported with recombinant variants of ACE, the ileal enzyme is less C1-dependent than somatic ACE; release of the C-terminal dipeptide from a peptide substrate was optimal in only 10 mM Cl. In addition to hydrolyzing at the C-terminal end of peptides, ileal ACE efficiently cleaved the protected N-terminal tripeptide from the luteinizing hormone-releasing hormone and its congener 6-31 times faster, depending on the Cl concentration, than the C-domain in recombinant testicular ACE. Thus we have isolated an active human ACE consisting of a single N-domain. We suggest that there is a bridge section of about 100 amino acids between the active N-and C-domains of somatic ACE where it may be proteolytically cleaved to liberate the active N-domain. These findings have potential relevance and importance in the therapeutic application of ACE inhibitors.

This study's aims were: 1) to extract a comprehensive overview of the knowledge, experience and opinions of both community pharmacists and hospital pharmacists regarding biosimilar medicines in France; and 2) to identify the perceived problems and solutions to promoting their prescription. A 2015 web-based survey was conducted by the Observatoire des Médicaments, des Dispositifs Médicaux et de l'Innovation Thérapeutique of Alsace. A total of 802 pharmacists responded to the survey. Many (536, 66.8%, [95% confidence interval (CI) 63.6-70.1]) indicated that they were not familiar with biosimilars. Half of community pharmacists (95% CI 42.7-57.3) stated that they were not at all informed about biosimilar drugs, compared with 15.7% (95% CI 12.9-18.6) of hospital pharmacists. Almost all respondents (781, 97.4%, [95% CI 96.3-98.5]) had at least one pending question on biosimilars. Most of the questions were related to the manufacturing process, safety, substitution rules and the international non-proprietary name prescription. At the time of the study, 467 pharmacists (58.2%, [95% CI 54.8-61.6]) had already validated a prescription for a biosimilar drug, mainly for filgrastim. These latter were more comfortable in explaining the benefit of biosimilar medicines to the patient. Pharmacists were rather favorable to biosimilar drugs, and about 9 of 10 quoted healthcare cost savings as incentives to their prescription. However, many did not agree with allowing biosimilar substitution. "Patients' wishes to be treated with the originator" and "indication extrapolation" were the two main constraints identified. The survey highlighted the need to provide French pharmacists with accurate and comprehensive information regarding biosimilar medicines.

Our survey gave a better appreciation of the concerns associated with biosimilar prescriptions. Targeted communication initiatives, deeper experience and availability of new clinical data may help to address the outstanding questions and should overcome the misunderstandings surrounding biosimilar drugs among rheumatologists.

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The coronavirus disease 2019 pandemic has caught the scientific community and hospitals off-guard, and the race is on as clinicians grapple with novel treatment strategies and constantly changing recommendations. Patients with mental health disorders are particularly vulnerable to the coronavirus outbreak for various reasons, including cognitive impairment, little awareness of risk, diminished efforts regarding personal protection and more barriers in accessing timely health services. 1Only few therapeutic options are being tested for COVID-19 with no evidence yet of effectiveness or safety. One of the options presently under evaluation is the combination of (hydroxy)chloroquine with azithromycin. 2 Despite the limited clinical data on the use of (hydroxy)chloroquine in COVID-19, this drug is attracting considerable attention from the media. Individuals and lobby groups have called for widespread prescription of these drugs. This attention is undermining the structured approach with which any drug should be evaluated.In this rapidly evolving situation, we need to alert prescribers that the extensive use of (hydroxy)chloroquine-azithromycin would place patients, and particularly those with mental health conditions, at an important increased risk of QTc-prolonging and, consequently, torsade de pointes (TdP) and death. Only a few clinical studies have analysed the cardiovascular effects of these drugs, 3 although they are clearly acknowledged with a known risk for QTc-prolonging according to CredibleMeds (on the list 1 of drugs with a known risk for TdP).CredibleMeds provides the American official lists of drugs associated with a risk of QTc-prolongation, powered by international pharmacovigilance data. 4,5 However, patients with mental health problems are already highly exposed to the risk of increased QT for a number of reasons. First, many psychoactive substances are associated with an increased risk of QTc-prolonging, such as antipsychotics (chlorpromazine, levomepromazine, haloperidol, pimozide, sulpiride, sultopride and thioridazine), antidepressants (citalopram and escitalopram), methadone, cocaine or donepezil. Second, our patients have often numerous comorbidities and underlying risk factors making cases of COVID-19 more challenging to treat. For instance, patients on antipsychotics are more likely to be men, at a higher risk of obesity, hypertension, metabolic syndrome and for more serious health outcomes. Moreover, their sedentary lifestyle and other risk factors, such as smoking and poor diet, put them at an elevated risk of respiratory failure and early death. Thus, a careful and thorough assessment of risk factors is crucial in these patients, including sex, age, smoking, acute electrolytes disturbances, metabolic syndrome, cardiac and pulmonary disease.The COVID-19 pandemic calls for rapid testing of new treatment strategies. However, special care is needed when treating vulnerable populations. If the combination of (hydroxyl)chloroquineazithromycin is recommended in the near future for COVID-19, we ...

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