The chemistry of nitrogen-containing heterocyclic compound pyrrole and pyrrolidine has been a versatile field of study for a long time for its diverse biological and medicinal importance. Biomolecules such as chlorophyll, hemoglobin, myoglobin, and cytochrome are naturally occurring metal complexes of pyrrole. These metal complexes play a vital role in a living system like photosynthesis, oxygen carrier, as well storage, and redox cycling reactions. Apart from this, many medicinal drugs are derived from either pyrrole, pyrrolidine, or by its fused analogs. This review mainly focuses on the therapeutic potential of pyrrole, pyrrolidine, and its fused analogs, more specifically anticancer, anti-inflammatory, antiviral, and antituberculosis. Further, this review summarizes more recent reports on the pyrrole, pyrrolidine analogs, and their biological potential. 

/pdf/therapeutic-potential-of-pyrrole-and-pyrrolidine-analogs-an-252o3fv2.pdf

Therapeutic potential of pyrrole and pyrrolidine analogs: an update

Importance In the past decade, ERBB2 (formerlyHER2)–directed antibody-drug conjugates (ADCs) have substantially changed treatment of both advanced and early-stage ERBB2-positive breast cancer. Novel conjugates are now showing activity in trials of other ERBB2-associated tumors, leading to the recent US Food and Drug Administration approval of trastuzumab deruxtecan for ERBB2-positive gastric cancer, as well as beneficial results in colorectal, lung, and bladder cancer. It is thus possible that anti-ERBB2 ADCs may become a treatment option for multiple types of tumors because many have at least some expression ofERBB2. Despite an improved overall therapeutic index, clinical observations have recently raised a concern regarding potential lung toxicity of anti-ERBB2 ADCs. Deaths related to interstitial lung disease (ILD) have been reported with variable incidence in trials testing anti-ERBB2 conjugates, warranting appropriate training of clinicians for the identification and management of this toxic effect. Observations Although no specific guidelines are available for the diagnosis and management of ADC-related ILD, some recommendations can be derived based on general principles adopted for drug-induced and immunotherapy-related ILD. Overall, in symptomatic ILD, the ADC should be discontinued. Reintroduction of the conjugate can be considered only in asymptomatic cases after complete resolution. Corticosteroids represent the cornerstone of ILD treatment, and dosing should be adapted according to the severity of the event. Additional treatments can be considered based on the clinical scenario. Conclusions and Relevance This review summarizes the current knowledge on the pathogenesis and epidemiologic characteristics of anti-ERBB2 ADC-related lung toxicity, proposing strategies for its diagnosis and treatment. Earlier diagnosis and more adequate treatment of ADC-induced ILD may improve the therapeutic index of this important class of anticancer agents, allowing for a safe expansion of anti-ERBB2 ADCs across tumor types.

https://jamanetwork.com/journals/jamaoncology/articlepdf/2784880/jamaoncology_tarantino_2021_rv_210007_1633016658.72674.pdf

Interstitial Lung Disease Induced by Anti-ERBB2 Antibody-Drug Conjugates: A Review

Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs.To develop recommendations for the diagnosis and management of DIILD in cancer patients.Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events.The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis.These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD. 

Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment

Current mortality rate in patients with COVID-19 disease is about 2%, whereas 5% of patients require admission to the intensive care unit. It is assumed that interleukin (IL)-6 may be involved in t...

https://journals.sagepub.com/doi/pdf/10.1177/1756284820959183

Tocilizumab and liver injury in patients with COVID-19

Introduction: The AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, German Gynecological Oncology Group) Task Force on Diagnosis and Treatment of Breast Cancer as an interdisciplinary team consists of specialists from gynecological oncology, pathology, diagnostic radiology, medical oncology, and radiation oncology with a special focus on breast cancer. Methods: The updated evidence-based treatment recommendation 2022 for early breast cancer (EBC) and metastatic breast cancer of the AGO Task Force has been released. Results and Conclusion: This paper captures the update of EBC.

/pdf/ago-recommendations-for-the-diagnosis-and-treatment-of-2uqw4gpy.pdf

AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2022

We assessed pulmonary toxicity of cyclin-dependent kinase (CDK)4/6 inhibitors by analyzing the publicly available FDA Adverse Event Reporting System (FAERS). Reports of interstitial lung disease (ILD) were characterized in terms of demographic information, including daily dose, latency, concomitant drugs known to be associated with ILD, and causality assessment (adapted WHO system). Disproportionality analyses were carried out by calculating reporting odds ratios (RORs) with 95% confidence interval (CI), accounting for major confounders, including notoriety and competition biases. ILD reports (N = 161) represented 2.1% and 0.3% of all reports for abemaciclib and palbocilcib/ribociclib, respectively, with negligible proportion of concomitant pneumotoxic drugs. Increased reporting was found for CDK4/6 inhibitors when compared to other drugs (ROR = 1.50; 95%CI = 1.28–1.74), and abemaciclib vs other anticancer agents (4.70; 3.62–5.98). Sensitivity analyses confirmed a strong and consistent disproportionality for abemaciclib. Higher-than-expected reporting emerged for palbociclib (1.38; 1.07–1.77) and ribociclib (2.39; 1.34–3.92) only when removing Japan reports. ILD occurred at recommended daily doses, with median latency ranging from 50 (abemaciclib) to 253 (ribociclib) days. Causality was highly probable in 55% of abemaciclib cases, probable in 68% of palbociclib cases. Increased reporting of ILD with CDK4/6 inhibitors calls for further comparative population-based studies to characterize and quantify the actual risk, taking into account drug- and patient-related risk factors. These findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals through FAERS and other real-world data, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of CDK4/6 inhibitors when diagnosing a lung injury.

/pdf/cyclin-dependent-kinase-4-6-inhibitors-and-interstitial-lung-3kvpy9ynf0.pdf

Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment

Given its approval for the treatment of cytokine release syndrome, tocilizumab is under investigation in severe coronavirus disease-2019. To characterize serious adverse events (AEs) with tocilizumab, we queried the worldwide FDA Adverse Event Reporting System and performed disproportionality analysis, selecting only designated medical events (DMEs) where tocilizumab was reported as suspect, with a focus on hepatic reactions. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL 95% CI) > 1. A total of 2,433 reports of DMEs were recorded with tocilizumab, mainly in rheumatic diseases. Statistically significant RORs emerged for 13 DMEs, with drug-induced liver injury (n = 91; LL 95% CI 3.07), pancreatitis (151; 1.41), and pulmonary fibrosis (222; 7.21) as unpredictable AEs. A total of 174 cases of liver-related DMEs were retrieved (proportion of deaths = 18.4%), with median onset of 27.5 days. These serious unpredictable reactions occurring in chronic real-world tocilizumab use may support patient care and monitoring of ongoing clinical trials.

Serious adverse events with tocilizumab: Pharmacovigilance as an aid to prioritize monitoring in COVID-19.

We analyzed thromboembolic events, recognized (AESIs), with cyclin-dependent kinase (CDK)4/6 inhibitors, using the Food and Drug Administration adverse event reporting system Methods: Thromboembolic events were characterized in terms of spectrum [venous and arterial thromboembolism (VTE; ATE)] and clinical features by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment Results: A total of 1722 thromboembolic events were retained Increased VTE reporting emerged for CDK4/6 inhibitors in the exploratory analyses (n = 659; ROR = 151; 95% CI = 139–163), with consistent disproportionality in the consolidated analyses (eg, deep vein thrombosis with abemaciclib: 17; 198; 122–319) Higher-than-expected ATE reporting was found for ribociclib, including myocardial infarction (41; 182; 133–248), with rapid onset (median latency 1 vs 6 months for other CDK4/6 inhibitors) Causality was highly probable or probable in 832% of cases, with a negligible proportion of pre-existing drug- and patient-related risk factors except for cardiovascular comorbidities (26%) Conclusions: Although causal association cannot be firmly inferred, oncologists should proactively monitor the occurrence of VTE with CDK4/6 inhibitors The unexpected distinctive increased ATE reporting with ribociclib deserves urgent clarification though large comparative population-based studies We support pharmacovigilance for the post-marketing characterization of AESIs, thus promoting real-time safe prescribing in oncology

Thromboembolic Events with Cyclin-Dependent Kinase 4/6 Inhibitors in the FDA Adverse Event Reporting System.

As chimeric antigen receptor T-cell therapies are becoming increasingly available in the armamentarium of the hematologist, there is an emerging need to monitor post-marketing safety.We aimed to better characterize their safety profile by focusing on cytokine release syndrome and identifying emerging signals.We queried the US Food and Drug Administration Adverse Event Reporting System (October 2017-September 2020) to analyze suspected adverse drug reactions to tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Disproportionality analyses (reporting odds ratio) were performed by comparing chimeric antigen receptor T-cell therapies with (a) all other drugs (reference group 1) and (b) other onco-hematological drugs with a similar indication, irrespective of age (reference group 2), or (c) restricted to adults (reference group 3). Notoriety was assessed through package inserts and risk management plans. Adverse drug reaction time to onset and cytokine release syndrome features were investigated.Overall, 3225 reports (1793 axi-cel; 1433 tisa-cel) were identified. The reported toxicities were mainly: cytokine release syndrome (52.2%), febrile disorders (27.7%), and neurotoxicity (27.2%). Cytokine release syndrome and neurotoxicity were often co-reported and 75% of the events occurred in the first 10 days. Disproportionalities confirmed known adverse drug reactions and showed unexpected associations: for example, axi-cel with cardiomyopathies (reporting odds ratio = 2.3; 95% confidence interval 1.2-4.4) and gastrointestinal perforations (2.9; 1.2-7.3), tisa-cel with hepatotoxicity (2.5; 1.1-5.7) and pupil disorders (15.3; 6-39.1).Our study confirms the well-known adverse drug reactions and detects potentially emerging safety issues specific for each chimeric antigen receptor T-cell therapy, also providing insights into a stronger role for tisa-cel in inducing some immunodeficiency-related events (e.g., hypogammaglobulinemia, infections) and coagulopathies, and for axi-cel in neurotoxicity. 

https://link.springer.com/content/pdf/10.1007/s40264-022-01194-z.pdf

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

BACKGROUND Estimating the morbidity of a population is strategic for health systems to improve healthcare. In recent years administrative databases have been increasingly used to predict health outcomes. In 1992, Von Korff proposed a Chronic Disease Score (CDS) to predict 1-year mortality by only using drug prescription data. Because pharmacotherapy underwent many changes over the last 3 decades, the original version of the CDS has limitations. The aim of this paper is to report on the development of the modified version of the CDS. METHODS The modified CDS (M-CDS) was developed using 33 variables (from drug prescriptions within two-year before 01/01/2018) to predict one-year mortality in Bologna residents aged ≥50 years. The population was split into training and testing sets for internal validation. Score weights were estimated in the training set using Cox regression model with LASSO procedure for variables selection. The external validation was carried out on the Imola population. The predictive ability of M-CDS was assessed using ROC analysis and compared with that of the Charlson Comorbidity Index (CCI), that is based on hospital data only, and of the Multisource Comorbidity Score (MCS), which uses hospital and pharmaceutical data. RESULTS The predictive ability of M-CDS was similar in the training and testing sets (AUC 95% CI: training [0.760-0.770] vs. testing [0.750-0.772]) and in the external population (Imola AUC 95% CI [0.756-0.781]). M-CDS was significantly better than CCI (M-CDS AUC = 0.761, 95% CI [0.750-0.772] vs. CCI-AUC = 0.696, 95% CI [0.681-0.711]). No significant difference was found between M-CDS and MCS (MCS AUC = 0.762, 95% CI [0.749-0.775]). CONCLUSIONS M-CDS, using only drug prescriptions, has a better performance than the CCI score in predicting 1-year mortality, and is not inferior to the multisource comorbidity score. M-CDS can be used for population risk stratification, for risk-adjustment in association studies and to predict the individual risk of death.

/pdf/modified-chronic-disease-score-m-cds-predicting-the-valqeed8gf.pdf

Michele Fusaroli

Papers

Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment

Serious adverse events with tocilizumab: Pharmacovigilance as an aid to prioritize monitoring in COVID-19.

Thromboembolic Events with Cyclin-Dependent Kinase 4/6 Inhibitors in the FDA Adverse Event Reporting System.

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Modified-Chronic Disease Score (M-CDS): Predicting the individual risk of death using drug prescriptions.