Gastric volumetry for the assessment of fundic compliance and visceral hypersensitivity in patients with gastroparesis: a retrospective comparative study.

BACKGROUND/AIMS: The evaluation of visceral hypersensitivity and gastric accommodation in patients with gastroparesis (GP) is difficult. CT-scan gastric volumetry allows to test the distension of different regions of the stomach. We aimed to study gastric volumes and patient's sensitivity to gastric distension between in patients with GP compared to patients with GERD. METHOD: Retrospective study including patients who had CT-scan volumetry for GP or GERD. Two CT-scan series were made after gastric distension: left lateral decubitus 30° (LLD30) for antrum and right lateral decubitus (RLD) for body. Pain and discomfort were assessed using visual analogue scale (VAS). Gastric volumes were measured for LLD30 and RLD. RESULTS: 13 patients (7 GP and 6 GERD) were included. Mean age was 35.6+/-7.3 years. Median gastric volume in the RLD was lower in GP vs GERD (927+/-208 ml vs. 1115+/-163 ml; p = 0.046) while it was similar for LLD30 (1053+/-228 ml vs. 1054+/-193 ml; p = 0.603). GP patients had significantly more pain and discomfort during the procedure: pain VAS for GP was 6[0-9] versus 0[0-2] for GERD, p = 0.004, discomfort VAS for GP was 7[4-10] versus 4[0-5] for GERD, p = 0.007. 66.7% of GERD patients felt no pain vs. 14.3% in GP, p = 0.053. CONCLUSION: This pilot study suggests that GP could be associated with a reduced gastric volume compared to GERD in RLD after gaseous distension. In contrast, patient self-assessment of pain related to gastric distension was greater int GP patients. A lack of fundus accommodation and visceral hypersensitivity could explain some mechanisms in the genesis of GP symptoms.

Gastroparesis is associated with lower volumes in right lateral decubitus suggesting a lower distensibility of the fundus.Gastric volumetry is more painful in patients with gastroparesis than GERD controls, suggesting visceral hypersensitivity to mechanical distension.

Refractory Pseudomonas aeruginosa Bronchopulmonary Infection After Lung Transplantation for Common Variable Immunodeficiency Despite Maximal Treatment Including IgM/IgA-Enriched Immunoglobulins and Bacteriophage Therapy.

Recipients transplanted for bronchiectasis in the context of a primary immune deficiency, such as common variable immunodeficiency, are at a high risk of severe infection in post-transplantation leading to poorer long-term outcomes than other transplant indications. In this report, we present a fatal case due to chronic Pseudomonas aeruginosa bronchopulmonary infection in a lung transplant recipient with common variable immunodeficiency despite successful eradication of an extensively drug-resistant (XDR) strain with IgM/IgA-enriched immunoglobulins and bacteriophage therapy. The fatal evolution despite a drastic adaptation of the immunosuppressive regimen and the maximal antibiotic therapy strategy raises the question of the contraindication of lung transplantation in such a context of primary immunodeficiency.

Synthesis and Anti-Trypanosoma cruzi Biological Evaluation of Novel 2-Nitropyrrole Derivatives.

Human American trypanosomiasis, called Chagas disease, caused by T. cruzi protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti-Trypanosoma cruzi derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product. All the designed derivatives follow Lipinski's rule of five. The cytotoxicity evaluation on CHO cells showed no significant cytotoxicity, except for compound 3 (CC50 = 24.3 µM). Compound 18 appeared to show activity against T. cruzi intracellular amastigotes form (EC50 = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound 18 showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.

Update on glasdegib in acute myeloid leukemia - broadening horizons of Hedgehog pathway inhibitors.

Numerous new emerging therapies, including oral targeted chemotherapies, have recently entered the therapeutic arsenal against acute myeloid leukemia (AML). The significant shift toward the use of these novel therapeutics, administered either alone or in combination with intensive or low-intensity chemotherapy, changes the prospects for the control of this disease, especially for elderly patients. Glasdegib, an oral Hedgehog pathway inhibitor, showed satisfactory response rates associated with moderate toxicity and less early mortality than standard induction regimens in this population. It was approved in November 2018 by the FDA and in June 2020 by the EMA for use in combination with low-dose cytarabine as a treatment of newly-diagnosed AML in patients aged ≥ 75 and/or unfit for intensive induction chemotherapy. The current paper proposes an extensive, up-to-date review of the preclinical and clinical development of glasdegib. Elements of its routine clinical use and the landscape of ongoing clinical trials are also stated.

Synthesis and in vitro evaluation of new 5-substituted 6-nitroimidazooxazoles as antikinetoplastid agents.

In continuation of our pharmacomodulation work on the nitroimidazooxazole series, we report the synthesis of new 5-substituted 6-nitroimidazooxazole derivatives. Our aim was to evaluate how functionalization of the 5-position of the 6-nitroimidazooxazole scaffold affects antileishmanial and antitrypanosomal in vitro activities. Twenty-one original compounds were synthesized and evaluated for their in vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) properties. Pallado-catalyzed cross-coupling reactions were used to introduce an aryl or ethynyl aryl substituent in 5-position from a 5-brominated-6-nitroimidazooxazole starting product. Unfortunately, the first series of compounds bearing an aryl group in 5-position presented limited in vitro activities against L. donovani and T. cruzi, with IC50 > 10 µM (vs 0.18 µM and 2.31 µM for the reference drugs amphotericin B and benznidazole respectively). Interestingly, the second series of compounds bearing an ethynyl aryl substituent in 5-position showed more promising, particularly against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had better activity than the reference drug benznidazole (0.92 µM ≤ IC50 ≤ 2.18 µM vs IC50 = 2.31 µM), whereas the non-functionalized 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b]oxazole 2 was not active against T. cruzi (IC50 > 10 µM).

Development and evaluation of an elective course of pharmacist's roles in disaster management in France.

PURPOSE: To describe Faculty of Pharmacy experience in the development of an elective course of pharmacist's roles in disaster management for third-year pharmacy students and to evaluate the effectiveness of this innovative teaching module in students' knowledge and their perception of the introduction of this specific course into their curriculum. METHODS: An expert team of physicians, surgeons and pharmacists of the Service de Santé des Armées, pharmacists teaching at the Faculty and pharmacists of Bataillon des Marins Pompiers de Marseille defined the program of a 30-hour module in disaster response in line with previously published recommendations, literature analysis and international guidelines on disaster response training. Students' knowledge of key competencies was assessed after each teaching session through a multiple-choice questionnaire. Assessment of self-perceived students' knowledge, teaching quality and students' degree of satisfaction was carried out using a volunteer survey just after the last teaching, the November 15th. RESULTS: The creation of the final curriculum resulted in a course of 6 modules. Concerning the students' knowledge of key competencies, a mean score of 19/25 for the multiple-choice questionnaire was obtained. 98.3% of students reported that this teaching allowed them to improve their knowledge in the field of pharmacist's roles in disaster management. 79.3% of them will recommend this optional course. CONCLUSION: This teaching represents a potential to increase the number of pharmacists prepared to respond to disasters. It also expands students' understanding of pharmacist's roles and stimulates their interest in emergency preparedness. Further formation, including emergency simulation in mass triage will be conducted next year.

2,4-Disubstituted 5-Nitroimidazoles Potent against Clostridium difficile.

Metronidazole is one of the first-line treatments for non-severe Clostridium difficile infections (CDI). However, resistance limits its use in cases of severe and complicated CDI. Structure-activity relationships previously described for the 5-nitroimidazole series have shown that functionalization at the 2- and 4-positions can impart better activity against parasites and anaerobic bacteria than metronidazole. Herein we report the synthesis of new 2,4-disubstituted 5-nitroimidazole compounds that show potent antibacterial activity against C. difficile. We used a vicarious nucleophilic substitution of hydrogen (VNS) reaction to introduce a phenylmethylsulfone at the 4-position and a unimolecular radical nucleophilic substitution (SRN 1) reaction to introduce an ethylenic function at the 2-position of the 5-nitroimidazole scaffold.

Management of adult Clostridium difficile digestive contaminations: a literature review.

Clostridium difficile infections (CDI) dramatically increased during the last decade and cause a major public health problem. Current treatments are limited by the high disease recurrence rate, severity of clinical forms, disruption of the gut microbiota, and colonization by vancomycin-resistant enterococci (VRE). In this review, we resumed current treatment options from official recommendation to promising alternatives available in the management of adult CDI, with regard to severity and recurring or non-recurring character of the infection. Vancomycin remains the first-line antibiotic in the management of mild to severe CDI. The use of metronidazole is discussed following the latest US recommendations that replaced it by fidaxomicin as first-line treatment of an initial episode of non-severe CDI. Fidaxomicin, the most recent antibiotic approved for CDI in adults, has several advantages compared to vancomycin and metronidazole, but its efficacy seems limited in cases of multiple recurrences. Innovative therapies such as fecal microbiota transplantation (FMT) and antitoxin antibodies were developed to limit the occurrence of recurrence of CDI. Research is therefore very active, and new antibiotics are being studied as surotomycin, cadazolid, and rinidazole.

An Efficient One-Pot Catalyzed Synthesis of 2,4-Disubstituted 5-Nitroimidazoles Displaying Antiparasitic and Antibacterial Activities.

A one-pot regioselective bis-Suzuki-Miyaura or Suzuki-Miyaura/Sonogashira reaction on 2,4-dibromo-1-methyl-5-nitro-1H-imidazole under microwave heating was developed. This method is applicable to a wide range of (hetero)arylboronic acids and terminal alkynes. Additionally, this approach provides a simple and efficient way to synthesize 2,4-disubstituted 5-nitroimidazole derivatives with antibacterial and antiparasitic properties.

Practical and Metal-Free Synthesis of Novel Enantiopure Amides Containing the Potentially Bioactive 5-Nitroimidazole Moiety.

We report here a practical and metal-free synthesis of novel enantiopure amides containing the drug-like 5-nitroimidazole scaffold. The first step was a metal-free diastereoselective addition of 4-(4-(chloromethyl)phenyl)-1,2-dimethyl-5-nitro-1H-imidazole to enantiomerically pure N-tert-butanesulfinimine. Then, the N-tert-butanesulfinyl-protected amine was easily deprotected under acidic conditions. Finally, the primary amine was coupled with different acid chlorides or acids to give the corresponding amides. The mild reaction conditions and high tolerance for various substitutions make this approach attractive for constructing pharmacologically interesting 5-nitroimidazoles.