Quinoxaline Moiety: A Potential Scaffold against Mycobacterium tuberculosis.

Background. The past decades have seen numerous efforts to develop new antitubercular agents. Currently, the available regimens are lengthy, only partially effective, and associated with high rates of adverse events. The challenge is therefore to develop new agents with faster and more efficient action. The versatile quinoxaline ring possesses a broad spectrum of pharmacological activities, ensuring considerable attention to it in the field of medicinal chemistry. Objectives. In continuation of our program on the pharmacological activity of quinoxaline derivatives, this review focuses on potential antimycobacterial activity of recent quinoxaline derivatives and discusses their structure-activity relationship for designing new analogs with improved activity. Methods. The review compiles recent studies published between January 2011 and April 2021. Results. The final total of 23 studies were examined. Conclusions. Data from studies of quinoxaline and quinoxaline 1,4-di-N-oxide derivatives highlight that specific derivatives show encouraging perspectives in the treatment of Mycobacterium tuberculosis and the recent growing interest for these scaffolds. These interesting results warrant further investigation, which may allow identification of novel antitubercular candidates based on this scaffold.

Quinoxaline Derivatives as Antiviral Agents: A Systematic Review.

BACKGROUND: In recent decades, several viruses have jumped from animals to humans, triggering sizable outbreaks. The current unprecedent outbreak SARS-COV-2 is prompting a search for new cost-effective therapies to combat this deadly pathogen. Suitably functionalized polysubstituted quinoxalines show very interesting biological properties (antiviral, anticancer, and antileishmanial), ensuring them a bright future in medicinal chemistry. OBJECTIVES: Focusing on the promising development of new quinoxaline derivatives as antiviral drugs, this review forms part of our program on the anti-infectious activity of quinoxaline derivatives. METHODS: Study compiles and discusses recently published studies concerning the therapeutic potential of the antiviral activity of quinoxaline derivatives, covering the literature between 2010 and 2020. RESULTS: A final total of 20 studies included in this review. CONCLUSIONS: This review points to a growing interest in the development of compounds bearing a quinoxaline moiety for antiviral treatment. This promising moiety with different molecular targets warrants further investigation, which may well yield even more encouraging results regarding this scaffold.

A review of melioidosis cases imported into Europe.

Melioidosis is a tropical bacterial infection, rarely encountered, and poorly known by clinicians. In non-endemic areas, a misdiagnosis can lead to a fatal outcome. This study aims to identify the main characteristics of imported and diagnosed melioidosis cases in Europe to increase clinician's awareness of this diagnosis. A literature review of imported and diagnosed human melioidosis cases in Europe was performed. PubMed and Web of Science search engines were used for retrieving articles from 2000 to November 2018. Seventy-seven cases of imported melioidosis into Europe described in the literature were identified. More than half of the cases were acquired in Thailand (53%) by men (73%). Patients were usually exposed to Burkholderia pseudomallei during a holiday stay (58%) of less than 1 month (23%) and were hospitalized during the month following their return to Europe (58%). Among travelers, melioidosis is less often associated with risk factor (16%), diabetes being the most frequently comorbidity related (19%). The clinical presentation was multifaceted, pneumonia being the most common symptom (52%), followed by cardiovascular form (45%) and skin and soft tissues damages (35%). The diagnosis was obtained by culture (92%), often supplemented by morphological, biochemical, and molecular identification (23%). Misdiagnoses were common (21%). Over half of the patients received a complete and adapted treatment (56%). Mortality is lower for returning traveler (6%). Imported melioidosis cases into Europe have their own characteristics. This possibility should be considered in patients with pneumonia, fever, and/or abscess returning from endemic areas even years after.

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.

Factors limiting adherence to antiepileptic treatment: A French online patient survey.

WHAT IS KNOWN AND OBJECTIVE: There are various reasons why antiepileptic treatment can fail. One is drug-resistant epilepsies, but non-adherence, or poor adherence, to treatment may make some patients' treatment ineffective. The consequences of poor adherence include treatment failure or introduction of more complex treatments involving greater toxicity with uncertain prognosis. This study contributes to a critical research area focused on antiepileptic drug adherence and aims to assess the main factors limiting adherence, as well as psychosocial factors influencing on risk of non-adherence. METHODS: An opinion survey was conducted among patients and parents of children treated for epilepsy and members of a French online support group. RESULTS AND DISCUSSION: A total of 263 questionnaires were collected. Of the patients, 79% said they never forget their medication, whereas 21% admitted occasional or frequent omissions. The main treatment-related factors that can limit adherence were adverse effects (limiting factors reported for 70% of patients) and number of tablets or number of intake per day (limiting factors reported for 32% of patients). Galenic (liquid) formulation (18%), drug taste (18%), tablet size (14%) and concern about the perception of others (17%) were cited in roughly equivalent terms as limiting adherence to treatment. Among the 55 patients who were genuinely non-adherent to their treatment, the occupational difficulties induced by following the treatment were a main cause of non-adherence. WHAT IS NEW AND CONCLUSION: Improving adherence in patients with epilepsy is a difficult and complex problem. Community pharmacists could play a major role in the determination of patients' adherence and should be aware of the risk of non-adherence.

Anaphylactic reaction to pemetrexed: a case report.

Pemetrexed is approved to treat non-small cell lung cancer and has an overall favorable toxicity profile. We describe a 58-year-old man who developped an anaphylactic shock within few minutes from the beginning of pemetrexed perfusion. Pemetrexed was discontinued and the patient's symptoms gradually resolved with administration of symptomatic treatment. Serum tryptase level remained normal and intra dermal skin tests were negative eventhough a nonspecific papule was noted. This case suggests that caution should be exercised when prescribing pemetrexed and clinicians must be warranted for the possibility of serious adverse events associated with pemetrexed use.

Synthesis of new quinoxalines containing an oxirane ring by the TDAE strategy and in vitro evaluation in neuroblastoma cell lines.

Neuroblastoma is an aggressive pediatric malignancy with significant chemotherapeutic resistance. In order to obtain new compounds active on neuroblastoma cell lines, we investigated the reactivity of carbanion formed via TDAE in quinoxaline series. The new synthesized compounds were tested for their anti-proliferative activity on two neuroblastoma cell lines, and seven oxirane derivatives obtained interesting activities.

[mediEVAL: a new evaluating tool for the medication-use system]. / mediEVAL : un nouvel outil d'évaluation de la prise en charge médicamenteuse.

PURPOSES: A new methodology to evaluate the medication-use system based on a risk cartography tool, has been developed. This work has been promoted by the Observatoire du médicament et des dispositifs médicaux stériles et de l'innovation thérapeutique (OMEDIT) from Provence-Alpes-Côte d'Azur (PACA)-Corse regions. METHODS: This new methodology has been developed with Excel (Microsoft(®)) and has led to the mediEVAL tool. It consists in two categories of Excel files: evaluating Excel files (1 for each job of the medication-use system) and synthesis Excel files which allow to compile a group of evaluating files for a defined area (department, hospital…). RESULTS AND CONCLUSION: mediEVAL is a new tool to evaluate quality and risk management of the entire medication-use system which has to be used by private or public hospitals of PACA and Corsica areas in their appropriate medication-use contract. Then, the OMEDIT can get data to provide an inventory of fixtures of the PACA-Corse area medication-use system situation.

Quinoxaline derivatives: Recent discoveries and development strategies towards anticancer agents.

Cancer is a leading cause of death and a major health problem worldwide. While many effective anticancer agents are available, most drugs currently on the market are not specific, raising issues like the common side effects of chemotherapy. However, recent research hold promises for the development of more efficient and safer anticancer drugs. Quinoxaline and its derivatives are becoming recognized as a novel class of chemotherapeutic agents with activity against different tumors. The present review compiles and discusses studies concerning the therapeutic potential of the anticancer activity of quinoxaline derivatives, covering articles published between January 2018 and January 2023.

Efficacy and toxicity of factor Xa inhibitors.

Venous thromboembolism (VTE) is a serious disease that is often neglected, and effective and safe antithrombotic treatments are a public health priority. New antithrombotics such as rivaroxaban, apixaban, betrixaban, edoxaban, darexaban, TAK-442, LY517717, eribaxaban, otamixaban are being developed to overcome current therapeutic limitations. The new oral anticoagulants and parenteral otamixaban are under evaluation in clinical trials for VTE treatment, for VTE prevention in orthopedic surgery, for stroke prevention in patients with atrial fibrillation and for cardiovascular event prevention in patients with acute coronary syndrome. These antithrombotic agents directly and selectively inhibit factor Xa, and do not require coagulation monitoring and dose adjustment. Several of these drugs have shown promising results and have the potential to either replace or act as alternatives to traditional anticoagulants (heparins, vitamin K antagonists).

[Amyotrophic lateral sclerosis: update on etiological treatment]. / Actualités dans le traitement étiologique de la sclérose latérale amyotrophique.

Amyotrophic lateral sclerosis is a rare neurodegenerative disease. It is characterized by motoneurons progressive degeneration. Associated with a paralysis of the legs, arms and the respiratory muscles, its evolution is lethal. Riluzole is the only drug available with an marketing authorisation (autorisation de mise sur le marché [AMM]) in this indication. In the beginning stages of the disease it demonstrated a modest efficacy by prolonging survival for a few months. Although the physiopathological mechanisms of this disease have not been totally solved, the progression of knowledge in recent years in this area led to the development of a large number of neuroprotective agents which showed effective results in animal models of ALS and which could be good candidates for the treatment of ALS. Several clinical trials have been conducted about antiglutamatergic, antioxidant, antiapoptotic agents and growing cell factors but they failed to demonstrate efficacy on survival or quality of life. Therefore, clinical trials using innovative therapeutics and stem cells are ongoing and offer more distant hope.

Organic glues or fibrin glues from pooled plasma: efficacy, safety and potential as scaffold delivery systems.

Since 1976, fibrin glues have been attracting medical interest, spreading from their initial use as a hemostatic agent in cardiovascular surgery to other fields of surgery. Studies have compared the efficacy of fibrin glues vs sutures in surgery. However, few comparisons have been made of the efficacy and safety of the different fibrin glues commercially available. Recently, fibrin glues have been tested as a scaffold delivery system for various substances inside the body (drugs, growth factors, stem cells). The infectious risk (viruses, new germs) of this blood-derived product was also studied in assays on viral inactivation methods. The development of autologous fibrin glues offers a solution to the problem of infectious risk. This review examines the current state of knowledge on the efficacy, safety and future potential of fibrin glues.

[Targeted based therapies in metastatic breast cancer: future evolution]. / Perspectives des thérapies ciblées dans le cancer du sein métastatique.

Research on molecular alteration process mechanisms leading to cancerogenesis permitted the elaboration of many targeted therapies. Some therapeutic classes appeared recently and are currently being tested, including HER-2 dimerization inhibitors. However, most of these therapies are mostly ineffective with monotherapy. Clinical trials are ongoing, testing their efficiency in association with other molecules of the therapeutic arsenal which is available in oncology. Nevertheless, breast cancer remains a pathology life-threatening, most of the time. Within this review will be introduced the most efficient of these targeted therapies, including their eventual association with other cytotoxic molecules.

[News on infantile hemangioma therapy by beta-blocker]. / Mise au point sur le traitement de l'hémangiome du nourrisson par bêta-bloquant.

Hemangiomas are benign tumors most commonly encountered in infancy and early childhood. While most of them regress spontaneously, some require treatment due to a significant proliferation, which may be complicated by ulceration, deformation aesthetic deformation or worse impairment vital. Among the treatments used corticosteroids is the standard treatment but its use in high doses expose to potential risks. In 2008, the discovery by "chance" of the effectiveness of propranolol in the management of hemangioma revolutionizes the first line treatment. Its mechanism of action is not yet well understood and establishment of such treatment should be done by a hospital paediatrician in the absence of any contraindications. This article proposes focus on effectiveness and tolerance of ß-blockers used as treatment of infantile hemangiomas.

Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives.

The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIß inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane ring present antiproliferative properties against neuroblastoma cell lines SK-N-SH and IMR-32. Likewise, quinoxalines with an arylethynyl group displayed promising antineoplastic properties against glioblastoma and lung cancer cell lines, U87-MG and A549 respectively. Here, 40 new quinoxaline derivatives bearing an oxirane ring were synthesized using a tetrakis(dimethylamino)ethylene (TDAE) strategy and a Sonogashira cross-coupling reaction. Each reaction with TDAE furnished a pair of diastereoisomers cis and trans. These new compounds formed two series according to the substitution of position 2 on the quinoxaline core, with chlorine or phenylacetylene respectively. Each of these isomers was evaluated for antiproliferative activity against neuroblastoma cell lines SK-N-SH and IMR-32 by MTT assay. All cell viability assay results were analyzed using R programming, as well as a statistical comparison between groups of compounds. Our evaluation showed no difference in drug sensitivity between the two neuroblastoma cell lines. Moreover, trans derivatives were observed to display better activities than cis derivatives, leading us to conclude that stereochemistry plays an important role in the antiproliferative activity of these compounds. Further support for this hypothesis is provided by the lack of improvement in antineoplastic activity following the addition of the phenylacetylene moiety, probably due to steric hindrance. As a result, compounds with nitrofuran substituents from the TDAE series demonstrated the highest antiproliferative activity with IC50 = 2.49 ± 1.33 µM and IC50 = 3.96 ± 2.03 µM for compound 11a and IC50 = 5.3 ± 2.12 µM and IC50 = 7.12 ± 1.59 µM for compound 11b against SK-N-SH and IMR-32, respectively. Furthermore, an in silico study was carried out to evaluate the mechanism of action of our lead compounds and predict their pharmacokinetic properties.

[Efficacy and future of the aerosoltherapy in the treatment of cystic fibrosis patients infected by Pseudomonas aeruginosa]. / Efficacité et avenir de l'aérosolthérapie dans le traitement des infections à Pseudomonas aeruginosa chez les patients atteints de mucoviscidose.

Pseudomonas aeruginosa is considered as the most redoubtable pathogenic agent at cystic fibrosis patients. Its eradication is a priority to avoid the passage to chronic infection, the real turning point of the disease. For this, a wide therapeutic panel of intravenous antibiotics exists, and for some years, the research teams concentrate more and more on the inhaled way. The synthesis of the literature data presented herein focuses on both already experienced molecules (colistin and tobramycin), and on new therapeutics. This review aims at loosening advantages and inconveniences of each of these therapeutic options, while bringing to light the necessity of follow-up studies in order to prove the therapeutic interests of molecules in development.

Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning.

INTRODUCTION: Ricin, a toxic glycoprotein derived from the castor bean plant, is one of the most potent poisons known in the world. Ricin intoxication is a fatal and uncommon medical condition and recently its use as a potential bioterrorism agent has also been reported. This study aims to identify the main characteristics of diagnosed ricin poisoning cases worldwide in order to raise awareness of this toxin among the population and clinicians. METHODS: A collection of human case studies of ricin intoxication in the world was produced. The databases Pubmed, Sciencedirect and Google Scholar were used to extract articles from January 1980 to June 2020. RESULTS: Fifty ricin-intoxicated patients worldwide described in the literature have been identified. Most cases were found in Asia (19 cases), Europe (12 cases) and America (15 cases). Intoxication was mostly accidental (37 cases). Intoxication by castor bean is characterized by acute gastroenteritis-like disease as primary manifestations leading to severe fluid and electrolyte imbalance. The mechanism of death was peripheral vascular collapse and progressing multiple organ failure occurring 10h-72h after intoxication. The questioning of patients and family made it possible to retrieve an history of castor seeds or castor oil ingestion Patients received symptomatic treatment consisting mostly to rehydration with intravenous fluids and digestive decontamination performed with activated charcoal and/or gastric lavage within one day after the ingestion, to reduce gastrointestinal absorption of ricin. This decontamination treatment administered early has been very effective. Only six deaths were observed. DISCUSSION: Currently, no antidote, vaccine, or other specific effective treatment is available for ricin poisoning or prevention. Prompt treatment with supportive care was necessary to limit morbidity and mortality. To date, patient education is essential to prevent this accidental poisoning. CONCLUSION: Clinicians and health care professionals should have a high level of suspicion when faced with an outbreak of serious respiratory or gastrointestinal illness.

Real-world efficacy and safety of pembrolizumab in patients with non-small cell lung cancer: a retrospective observational study.

BACKGROUND: Pembrolizumab, a humanized immunoglobulin monoclonal antibody directed against the programmed cell death 1 receptor, demonstrated robust efficacy and a manageable safety profile across multiple tumor types in clinical trials. AIM: To investigate the efficacy and safety of first-line pembrolizumab for patients with non-small cell lung cancers (NSCLCs) in clinical practice. METHODS: In this observational monocentric retrospective study, 38 patients with PD-L1 >50% were enrolled between November 2017 and November 2018. RESULTS: The global median overall survival was 11.08 months (95% confidence interval [CI], 5.98-not reached) and the global median progression-free survival was 6 months (95% CI, 3-not reached). In the univariate analysis, clinical performance status score and the development of immune-related adverse events were the only 2 clinical factors significantly correlated with overall survival. CONCLUSION: The results of the present study suggest that pembrolizumab seems less effective in the real-life population than in the pivotal clinical trials in patients with NSCLC but remains an effective treatment option for patients with NSCLC. Longer follow-up is needed.

Safety review: squalene and thimerosal in vaccines.

Few studies show the reluctance of the people to get vaccinated against A (H1N1) influenza for fear of side effects of squalene (MF59, AS03, AF03) and thimerosal. The aim of this paper is to assess the safety in using these adjuvants and preservative reviewing data of clinical trials relative to which formulation includes these compounds. In the current state of knowledge, these vaccines have proved to be effective even though they more frequently give local adverse events than non-adjuvanted influenza vaccines. Systemic side effects are generally not serious. In the studies, adjuvanted vaccines do not increase neither the risk of Guillain Barre syndrome nor auto-immune diseases. There is no convincing evidence that exposure to thimerosal in vaccines had any deletorious effect on physiological outcome.

Antibody-Drug Conjugates in Thoracic Malignancies: Clinical Trials Reveal Both Promise and Challenges.

Thoracic malignancies are the main cause of cancer-related deaths worldwide. The need to develop new therapies is therefore urgent. The recognition of new potential therapeutic targets in thoracic malignancies has prompted the development of a number of antibody-drug conjugates. This new class of potent anticancer agents is supposed to more specifically and directly target the tumor while limiting toxicity for healthy tissues by delivering a toxic payload to tumor cells that are recognized by the presence of specific cell surface antigens. Progress in the development of antibody-drug conjugates over the last decade has been significant, with several promising advances. Unfortunately, many failures have also been encountered, often because of unexpectedly severe toxicities that contradicted the assumed mechanism of action, and major challenges remain. Various techniques to reduce the toxicities associated with antibody-drug conjugates are being studied, and the panorama of antibody-drug conjugates in clinical stages continues to increase and evolve. Current efforts in the conjugation and linker chemistries could result in the successful construction of clinically effective compounds. The future clinical development of antibody-drug conjugates could benefit from the identification of such payloads that can provide more safe and effective derivatives. Highly potent compounds with reasonable aqueous solubility, non-immunogenic profile, and stability in storage and the bloodstream should be important aspects of research into cytotoxic payloads.