scholarly journals Current progress of fluoroquinolones-increased risk of aortic aneurysm and dissection

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Cui Jun ◽  
Bian Fang
Keyword(s):  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
False Lumen ◽  
The United States ◽  
Black Box ◽  
Research Progress ◽  
Major Life ◽  
Increased Risk ◽  
Aortic Aneurysm And Dissection ◽  
Black Box Warnings

AbstractAortic aneurysm (AA) and aortic dissection (AD) are major life-threatening diseases around the world. AA is a localized or diffuse dilation of the aorta, while AD is the separation of the layers creating a false lumen within the aortic wall. Fluoroquinolones (FQ) remain one of the most important kind of antibiotics and have a wider clinical use and broad antibacterial spectrum. FQ were also reported to treat infected AA. The most common adverse events (AEs) of FQ are mild and reversible, like headaches, diarrhea and nausea. Due to FQ-related serious AEs, such as tendonitis and tendon rupture, chondrotoxicity, or retinal detachment, QT-prolongation and dysglycemia, the United States Food and Drug Administration (FDA) issued a black box warning for FQ for systemic use in 2016 and updated warnings for FQ several times since then. Of note, in December 2018, FDA issued several “black box warnings” against FQ with the latest safety announcement warning about an increased risk of ruptures in the aorta blood vessel in certain patients. Recently, many studies have indicated an association between FQ and an increase risk of AA and AD. However, the exact mechanism of FQ-induced AA/AD remains unclear. This review aims to highlight the latest research progress of the alarming association between FQ and AA/AD. Moreover, molecular mechanisms of FQ in increasing risk of AA and AD are explored. Hopefully, this review can provide novel insights into FQ-increased the risk of AA/AD and a starting place for stewardship interventions.

An audit of Black Box Warnings (BBWs) in the United States Food and Drug Administration (US-FDA) database - a five-year analysis

2021 ◽  
Vol 16 ◽  
Author(s):  
Debdipta Bose ◽  
Nithya Gogtay ◽  
Tejusv Goel ◽  
Mahanjit Konwar
Keyword(s):  
The United States ◽  
Black Box ◽  
Primary Objective ◽  
Molecular Entity ◽  
Therapeutic Class ◽  
The Us ◽  
United States Food ◽  
Black Box Warnings ◽  
States Food ◽  
Us Fda

Background: The black-box warning (BBW) is the most serious warning that US-FDA can ask for on a drug’s labelling. BBWs represent key safety concerns uncovered either during dossier review or post-approval. We have conducted the present study with the primary objective of assessing BBWs issued by the US-FDA. Methods: BBW’s were identified on US-FDA’s website from 1st January 2015 to 31st December 2019. Prescribing information was used to identify and characterize BBWs into new and minor/major update on a previous BBW. The therapeutic class of the drug, nature [Biological/New Molecular entity (NME)], formulation type, expected duration of use along with the year of first approval of the molecule with BBWs were evaluated. Results: A total of n = 167 BBWs were issued by FDA of which 53 (31.7%) had major updates, 57(34.1%) had minor updates and 57(34.1%) were new BBWs. A total of 137(82%) of BBWs were with NME’s whereas 30(18%) were with biologics. Drugs for neurology 40(25.5%)had the highest number of BBWs followed by oncology 38(24.2%). Among type of BBWs, cardiovascular risk 31 (15%) were the highest. Conclusion: Practicing physicians need to understand that benefit-risk of a drug is dynamic and keep abreast of new data related to it.

scholarly journals Molecular Mechanisms and Emerging Therapeutics for Osteoporosis

2020 ◽  
Vol 21 (20) ◽  
pp. 7623 ◽  
Author(s):  
Ji-Yoon Noh ◽  
Young Yang ◽  
Haiyoung Jung
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Risk Groups ◽  
The United States ◽  
Bone Architecture ◽  
Global Challenge ◽  
Emerging Therapies ◽  
Metabolic Bone ◽  
Increased Risk ◽  
Control Disease

Osteoporosis is the most common chronic metabolic bone disease. It has been estimated that more than 10 million people in the United States and 200 million men and women worldwide have osteoporosis. Given that the aging population is rapidly increasing in many countries, osteoporosis could become a global challenge with an impact on the quality of life of the affected individuals. Osteoporosis can be defined as a condition characterized by low bone density and increased risk of fractures due to the deterioration of the bone architecture. Thus, the major goal of treatment is to reduce the risk for fractures. There are several treatment options, mostly medications that can control disease progression in risk groups, such as postmenopausal women and elderly men. Recent studies on the basic molecular mechanisms and clinical implications of osteoporosis have identified novel therapeutic targets. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for osteoporosis management in the future. Here, we review the etiology of osteoporosis and the molecular mechanism of bone remodeling, present current pharmacological options, and discuss emerging therapies targeting novel mechanisms, investigational treatments, and new promising therapeutic approaches.

scholarly journals Fluoroquinolones and Aortic Diseases: Is There a Connection

Aorta ◽  
2019 ◽  
Vol 07 (02) ◽  
pp. 035-041 ◽  
Author(s):  
Davide Carino ◽  
Mohammad A. Zafar ◽  
Mrinal Singh ◽  
Bulat A. Ziganshin ◽  
John A. Elefteriades
Keyword(s):  
Retinal Detachment ◽  
Aortic Aneurysm ◽  
Adverse Effects ◽  
Achilles Tendon ◽  
Broad Spectrum ◽  
Tendon Rupture ◽  
Achilles Tendon Rupture ◽  
Aortic Diseases ◽  
Increased Risk ◽  
Aortic Aneurysm And Dissection

AbstractFluoroquinolones (FQs) are one of the most commonly prescribed classes of antibiotics. Their high tissue distribution and broad-spectrum antibacterial coverage make their use very attractive in numerous infectious diseases. Although generally well tolerated, FQs have been associated with different adverse effects including dysglycemia and arrhythmias. FQs have been also associated with a series of adverse effects related to collagen degradation, such as Achilles tendon rupture and retinal detachment. Recently, an association between consumption of FQs and increased risk of aortic aneurysm and dissection has been proposed. This article reviews the pathogenesis of thoracic aortic diseases, the molecular mechanism of FQ-associated collagen toxicity, and the possible contribution of FQs to aortic diseases.

scholarly journals Oxidative ornithine metabolism supports non-inflammatory C. difficile colonization

2022 ◽  
Author(s):  
Kali M. Pruss ◽  
Fatima Enam ◽  
Eric Battaglioli ◽  
Mary DeFeo ◽  
Oscar R. Diaz ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
The United States ◽  
Wild Type ◽  
Targeted Metabolomics ◽  
Disease Symptoms ◽  
Increased Risk ◽  
Infection And Inflammation ◽  
Gnotobiotic Mice ◽  
Single Operon ◽  
Type Strains

AbstractThe enteric pathogen Clostridioides difficile (Cd) is responsible for a toxin-mediated infection that causes more than 200,000 recorded hospitalizations and 13,000 deaths in the United States every year1. However, Cd can colonize the gut in the absence of disease symptoms. Prevalence of asymptomatic colonization by toxigenic Cd in healthy populations is high; asymptomatic carriers are at increased risk of infection compared to noncolonized individuals and may be a reservoir for transmission of Cd infection2,3. Elucidating the molecular mechanisms by which Cd persists in the absence of disease is necessary for understanding pathogenesis and developing refined therapeutic strategies. Here, we show with gut microbiome metatranscriptomic analysis that mice recalcitrant to Cd infection and inflammation exhibit increased community-wide expression of arginine and ornithine metabolic pathways. To query Cd metabolism specifically, we leverage RNA sequencing in gnotobiotic mice infected with two wild-type strains (630 and R20291) and isogenic toxin-deficient mutants of these strains to differentiate inflammation-dependent versus -independent transcriptional states. A single operon encoding oxidative ornithine degradation is consistently upregulated across non-toxigenic Cd strains. Combining untargeted and targeted metabolomics with bacterial and host genetics, we demonstrate that both diet- and host-derived sources of ornithine provide a competitive advantage to Cd, suggesting a mechanism for Cd persistence within a non-inflammatory, healthy gut.

scholarly journals The disease of theories: unravelling the mechanisms of pre-eclampsia

2017 ◽  
Vol 39 (1) ◽  
pp. 22-25 ◽  
Author(s):  
Eric M. George
Keyword(s):  
United States ◽  
Cardiovascular Disease ◽  
Premature Birth ◽  
Molecular Mechanisms ◽  
The United States ◽  
Life Meaning ◽  
Increased Risk ◽  
Health Complications ◽  
Developed World

Perhaps no disease of pregnancy has been more thoroughly studied than pre-eclampsia (PE), and yet despite all of our efforts we are only beginning to understand the molecular mechanisms which underpin the disease. Many people are surprised by the frequency of PE in the population, as it is believed to occur in approximately one pregnancy out of 20 in the United States, with similar rates throughout the developed world. In severe cases the disorder can progress to eclampsia, which is characterized by maternal seizures and can lead to death. PE can only be treated by ending the pregnancy, often by inducing labour prior to term, making PE a leading cause of premature birth and all of the associated health complications which accompany it. All in all, PE is one of the leading causes of maternal and fetal morbidity and mortality. It is now also becoming apparent that PE disposes both the mother and the baby to increased risk of cardiovascular disease throughout life, meaning that we still don't fully understand the long-term implications of the disease.

scholarly journals Metabolic Host–Microbiota Interactions in Autophagy and the Pathogenesis of Inflammatory Bowel Disease (IBD)

2021 ◽  
Vol 14 (8) ◽  
pp. 708
Author(s):  
Alexander S. Dowdell ◽  
Sean P. Colgan
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Association Studies ◽  
The United States ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is a family of conditions characterized by chronic, relapsing inflammation of the gastrointestinal tract. IBD afflicts over 3 million adults in the United States and shows increasing prevalence in the Westernized world. Current IBD treatments center on modulation of the damaging inflammatory response and carry risks such as immunosuppression, while the development of more effective treatments is hampered by our poor understanding of the molecular mechanisms of IBD pathogenesis. Previous genome-wide association studies (GWAS) have demonstrated that gene variants linked to the cellular response to microorganisms are most strongly associated with an increased risk of IBD. These studies are supported by mechanistic work demonstrating that IBD-associated polymorphisms compromise the intestine’s anti-microbial defense. In this review, we summarize the current knowledge regarding IBD as a disease of defects in host–microbe interactions and discuss potential avenues for targeting this mechanism for future therapeutic development.

scholarly journals Pancreatic Cancer and Obesity: Molecular Mechanisms of Cell Transformation and Chemoresistance

2018 ◽  
Vol 19 (11) ◽  
pp. 3331 ◽  
Author(s):  
Priscilla Cascetta ◽  
Alessandro Cavaliere ◽  
Geny Piro ◽  
Lorena Torroni ◽  
Raffaela Santoro ◽  
...  
Keyword(s):  
Risk Factor ◽  
Molecular Mechanisms ◽  
Local Level ◽  
The United States ◽  
Cancer Type ◽  
Preventable Risk Factor ◽  
Response To Chemotherapy ◽  
Increased Risk ◽  
Incidence And Mortality

Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases. Considerable epidemiologic evidence correlates overweight and obese conditions to an increased risk of several types of cancer, including PDAC. Besides being a risk factor for multiple metabolic disorders, the tumor-promoting effects of obesity occur at the local level via inflammatory mediators that are associated with adipose inflammation and metabolic or hormones mediators and microbiota dysbiosis. Although an excess of body mass index (BMI) represents the second most modifiable risk factor for PDAC with an increased cancer related-death of more than 20–40%, still little is known about the molecular mechanisms that underlie this strong association. In this review, we focused on the role of obesity as a preventable risk factor of PDAC, discussing the molecular mechanisms linking obesity to cancer initiation and progression. Moreover, we highlighted the role of obesity in defining chemoresistance, showing how a high BMI can actually reduce response to chemotherapy.

Interleukin-3 stimulates matrix metalloproteinase 12 production from macrophages promoting thoracic aortic aneurysm/dissection

2018 ◽  
Vol 132 (6) ◽  
pp. 655-668 ◽  
Author(s):  
Chang Liu ◽  
Congcong Zhang ◽  
Lixin Jia ◽  
Boya Chen ◽  
Luxin Liu ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Interleukin 3 ◽  
Pathological Mechanism ◽  
The Matrix ◽  
Aortic Aneurysm And Dissection ◽  
Aneurysm Dissection ◽  
Extracellular Regulated Protein Kinases

Thoracic aortic aneurysm and dissection (TAAD) is due to degeneration of the aorta and causes a high mortality rate, while molecular mechanisms for the development of TAAD are still not completely understood. In the present study, 3-aminopropionitrile (BAPN) treatment was used to induce TAAD mouse model. Through transcriptome analysis, we found the expression levels of genes associated with interleukin-3 (IL-3) signaling pathway were up-regulated during TAAD development in mouse, which were validated by real-time PCR. IL-3 positive cells were increased in TAAD mouse aortas, especially for smooth muscle cells (SMCs). IL-3 deficiency reduced BAPN-induced TAAD formation. We then examined the matrix metalloproteinases (MMPs) expression during TAAD formation in both wild-type and IL-3 deficient mice, showing that MMP12 were significantly down-regulated in IL-3 deficient aortas. Mechanistically, we found recombinant IL-3 could increase MMP12 production and activity from macrophages in vitro. Silencing of IL-3 receptor β, which was mainly expressed in macrophages but not SMCs, diminished the activation of c-Jun N terminal kinase (JNK)/extracellular-regulated protein kinases 1/2 (ERK1/2)/AP-1 signals, and decreased MMP12 expression in IL-3 stimulated macrophages. Moreover, both circulating and aortic inflammation were decreased in IL-3 deficient aortas. Taken together, our results demonstrated that IL-3 stimulated the production of MMP12 from macrophages by a JNK- and ERK1/2-dependent AP-1 pathway, contributing to TAAD formation. Thus, the IL-3/IL-3Rβ/MMP12 signals activation may be an important pathological mechanism for progression of TAAD.

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