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.

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.

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.

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.

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.

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.

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.

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.

Efficacy and safety of nivolumab in patients with non-small cell lung cancer: a retrospective study in clinical practice.

Nivolumab, a fully human immunoglobulin monoclonal antibody inhibiting the programmed cell death protein-1 receptor, demonstrated robust efficacy and a manageable safety profile across multiple tumor types in clinical trials. The aim of the present study was to investigate the efficacy and safety of nivolumab for pretreated patients with non-small cell lung cancers in clinical practice. In this observational monocentric retrospective study, 98 patients were enrolled between February 2015 and February 2016. The global median overall survival was 6.34 months (95% confidence interval (CI) : 4.11-10.88) and the global median progression free survival was 1.84 months (95% CI: 1.68-2.73). In the univariate analysis, clinical performance status score was the only factor significantly correlated with overall survival. The safety profile of nivolumab is consistent with that described in prior studies, with only 7% undesirable effects requiring the discontinuation of treatment. The results of the present study demonstrate that nivolumab affords clinical efficacy and manageable tolerability in patients with non-small cell lung cancers.

Chickenpox: An update.

Despite its benign characteristics, chickenpox is a childhood disease responsible for complications and deaths, particularly in the high-risk population. VariZIG®, not commercialized in France, is a good alternative for seronegative individuals exposed to the virus and not eligible for vaccination. The efficacy of routine vaccination has been demonstrated with a decrease in chickenpox incidence and with the development of herd immunity. Over time, the protective antibody titer of vaccinated people decreases and can be maintained by two doses of the vaccine. A tetravalent measles-mumps-rubella-chickenpox vaccine, used in the United States, has a good tolerability in spite of the occurrence of fever and febrile seizures. Routine vaccination would contribute to make savings in France, by reducing direct and indirect costs of chickenpox.

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.

News on therapeutic management of MDR-tuberculosis: a literature review.

In 2015, the World Health Organization registered 10.4 million people who developed tuberculosis worldwide and 480,000 new cases of multidrug-resistant tuberculosis were identified. The care of multi and extensively drug-resistant tuberculosis is based on a combination of pyrazinamide and second-line drugs. These regimens are lengthy, partially effective and poorly tolerated. The challenge is to re-evaluate the use of existing molecules and to develop new agents more effective against resistant strains with shorter treatment duration. This literature review gives an overview of the latest research addressing these therapeutic objectives. Some molecules are in late stage clinical development among which pretomanid is showing promising results. Bedaquiline and delamanid have been recently approved by the Food and Drug Administration. The efficacy of drug regimens combining these molecules is under evaluation.

Body image and psychological distress in women with breast cancer: a French online survey on patients' perceptions and expectations.

BACKGROUND: Altered body image caused by alopecia, loss of eyebrows or eyelashes, or mastectomy is a major source of psychological distress in women with breast cancer. OBJECTIVE: To identify and to assess patients' perceptions and expectations regarding altered body image. METHOD: Opinion survey conducted among patients treated for breast cancer and member of French online support groups. Anonymous online self-administered survey sent to women with breast cancer. RESULTS: 85% of the women interviewed experienced alopecia during treatment and 67% of them loss of eyebrows or eyelashes. About half of patients suffering alopecia and loss of eyebrows or eyelashes reported fearing what others think. Mastectomy was experienced by 84% of the women in our study, but only 32% of them reported fearing what others think. 87% of our study cohort received information about the possibility of adverse events. 70, 56, and 60% of women felt helped by information they received for the management of alopecia, loss of eyebrows or eyelashes, or mastectomy, respectively. CONCLUSION: This study confirms that altered body image is a critical psychosocial issue for women with breast cancer. Effective information can be a source of reassurance and may constitute one of the most important sources of emotional support.

Synthesis and evaluation of in vitro antiproliferative activity of new ethyl 3-(arylethynyl)quinoxaline-2-carboxylate and pyrido[4,3-b]quinoxalin-1(2H)-one derivatives.

We report a novel series of quinoxaline derivatives from which agents with antiproliferative activity have been identified. Two ethyl 3-(arylethynyl)quinoxaline-2-carboxylates demonstrated substantial antiproliferative activity against both human non-small cell lung carcinoma (A549) and glioblastoma (U87-MG) cell lines. Pyrido[4,3-b]quinoxalin-1(2H)-ones demonstrated poor activity against A549 and U87-MG cell lines. Three of the derivatives in ethyl 3-(arylethynyl)quinoxaline-2-carboxylate series demonstrated substantial antiproliferative activity. The arylethynyl derivative 2a and 2d proved to be the most cytotoxic with an IC50 value of 3.3 µM for both A549 and U87-MG cell lines.

Safe Cytotoxic Drug Preparation Using Closed-system Transfer Device: Technical and Practical Evaluation of a New Device (Vialshield/Texium) Comparatively to a Reference One (Phaseal).

Closed-system transfer devices enhance the drug handlers' protection against hazardous drugs exposure by prohibiting the escape of liquid or vapor from the system. PhaSeal (Becton Dickinson), a reference closed-system transfer device, includes a vial protector with an expansion chamber, and an injector with an enclosed needle. VialShield (CareFusion) is another more recent closed-system transfer device including an expansion-chamber and a non-return valve, designed to be used in association with Texium (CareFusion), a closed, needle-free male luer with its preassembled syringe. Evaluation of VialShield/Texium was done comparatively to a classic spike device (Spike Swan, Codan) and PhaSeal. Evaluation methods consisted in practical evaluation by pharmacy technicians (evaluation of ease to use by nine operators in practical conditions during a complete week of production), microbiological safety performance (by Media Fill Test), and leakage assessment (fluorescein, titanium tetrachloride smoke, and radioactive tracer). Results showed that 100% of those operators evaluated would be ready to use VialShield/Texium for daily use, whereas only 75% of them would be ready to use PhaSeal. The use of PhaSeal and VialShield/Texium increased the duration of preparations compared to Spike Swan. No microbiological growth was observed with any of the three devices. A leakage of smoke was observed only with Spike Swan. Fluorescein leakage assessment confirmed that PhaSeal is a performing closed system with a dry connection. Spike Swan showed fluorescein leaks. Fluorescein drops were visible on the connection sites of the VialShield/Texium. Nevertheless, no fluorescein was found on compress after connections swapping. Transfer performance, assessed using technetium-99m, was 98.1 ± 1.4%, 97.9 ± 1.1% and 97.0 ± 1.3% and dead volume of the devices, were 1.0 ± 0.8%, 1.7 ± 0.6%, and 3.0 ± 1.1% for Spike Swan, PhaSeal, and VialShield/Texium, respectively. VialShield/Texium appeared as a very interesting device with performances close to PhaSeal (except dry connection), with a higher satisfaction assessment from the operators.

Stability of a highly concentrated solution of epirubicin for conventional transcatheter arterial chemoembolization.

INTRODUCTION: Epirubicin is widely used for conventional transcatheter arterial chemoembolization (cTACE) in patients with hepatocellular-carcinoma. However, there is no data about its stability in solution at concentration higher than 2 mg/L, yet needed when mixing it with a standard volume of Lipiodol(®) to produce an efficient water-in-oil emulsion. The aim of this study was therefore to evaluate the stability of a highly concentrated solution of epirubicin for cTACE and verify whether epirubicin solution could be prepared in advance. MATERIALS AND METHODS: Fifty milligrams of epirubicin were dissolved in 6 mL of 0.9% sodium chloride and conditioned in brown polypropylene syringe. Physical and chemical stability assays including particles and HPLC-DAD analysis were performed in triplicate, using series of 5 syringes stored over 72 h at 4±2 °C followed by 4h at 22±4°C. RESULTS: Neither weight loss nor pH or spectrum change occurred. No haze or turbidity was observed and the number of subvisible particles was below the recommended limits. Epirubicin concentration remained above 95% of the initial value over the 72 h of storage at +4 °C followed by 4h at 22±4 °C and no degradation was observed. CONCLUSION: Epirubicin at 50mg/6 mL in 0.9% NaCl conditioned in brown propylene syringe is stable for at least 72 h at 4±2 °C with additional 4h at 22±4 °C allowing its preparation in advance for programmed cTACE and the standardization of its use in clinical practice.

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.