Review: Toxicology testing of new medicines for children (Preprint)

2020 ◽  
Author(s):  
Dardan Dreshaj ◽  
Flaka Pasha
Keyword(s):  
Current Knowledge ◽  
Study Finding ◽  
New Drugs ◽  
Toxicity Studies ◽  
Toxicology Study ◽  
Drug Companies ◽  
Initial Stage ◽  
Improve Compliance ◽  
Pediatric Trial ◽  
Medicines For Children

UNSTRUCTURED Abstract -Objectives This review represents a critical and constructive analysis of literature in the content of toxicology testing of new medicines for children. The review is generated through summary, classification, analysis and comparison of already existing material and researches on field. -Materials and methods Databases as Scopus, PubMed, Medline and Web of Science were used to extract data for the review. Search terms like “juvenile toxicity studies”, “children toxicology”, “testing of new drugs” were used. Out of 150 research articles screened, 25 most relevant studies are included in this review. -Results Whether juvenile animal toxicology studies are truly useful or necessary to support pediatric drug development is still doubtful. The current knowledge on cross-species functional and kinetic differences is not reliable, meaning that extrapolation of any toxicology study finding to an immature human may not be relevant, especially if performed at the wrong time and in the wrong species. -Conclusion Even though, great improvements and regulatory initiatives regarding juvenile toxicity studies have been accomplished, unfortunately testing new drugs in children still remains on its initial stage and lags behind to other scientific developments. In order to narrow down the juvenile toxicity studies loophole, we need to improve compliance by drug companies and research sponsors with pediatric trial obligations.

Experimental Rodent Models of Vascular Dementia: A Systematic Review

2021 ◽  
Vol 19 ◽  
Author(s):  
Nidhi Tiwari ◽  
Jyoti Upadhyay ◽  
Mohd Nazam Ansari ◽  
Syed Shadab Raza ◽  
Wasim Ahmad ◽  
...  
Keyword(s):  
Vascular Dementia ◽  
Small Vessel Disease ◽  
Current Knowledge ◽  
Vascular Cognitive Impairment ◽  
Experimental Models ◽  
New Drugs ◽  
Amyloid Angiopathy ◽  
Vessel Disease ◽  
The Brain ◽  
Large Vessel Disease

: Vascular dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of vascular cognitive impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small vessel disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and cerebral amyloid angiopathy (CAA),which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as diabetes mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.

scholarly journals New Perspectives in Stroke Management: Old Issues and New Pathways

2021 ◽  
Vol 11 (6) ◽  
pp. 767
Author(s):  
Fabio Pilato ◽  
Rosalinda Calandrelli ◽  
Fioravante Capone ◽  
Michele Alessiani ◽  
Mario Ferrante ◽  
...  
Keyword(s):  
Time Window ◽  
Enhanced Recovery ◽  
Current Knowledge ◽  
Oral Anticoagulants ◽  
Chronic Phase ◽  
Stroke Care ◽  
New Drugs ◽  
Stroke Patients ◽  
Social Burden ◽  
Novel Approaches

Stroke is a leading cause of disability and death worldwide and social burden is huge in terms of disabilities, mortality and healthcare costs. Recently, in an acute stroke setting, renewed interest in disease-modifying therapies and novel approaches has led to enhanced recovery and the reduction of long-term disabilities of patients who suffered a stroke. In the last few years, the basic principle “time is brain” was overcome and better results came through the implementation of novel neuroimaging tools in acute clinical practice, allowing one to extend acute treatments to patients who were previously excluded on the basis of only a temporal selection. Recent studies about thrombectomy have allowed the time window to be extended up to 24 h after symptoms onset using advanced neuroradiological tools, such as computer tomography perfusion (CTP) and magnetic resonance imaging (MRI) to select stroke patients. Moreover, a more effective acute management of stroke patients in dedicated wards (stroke units) and the use of new drugs for stroke prevention, such as novel oral anticoagulants (NOACs) for atrial fibrillation, have allowed for significant clinical improvements. In this editorial paper, we summarize the current knowledge about the main stroke-related advances and perspectives and their relevance in stroke care, highlighting recent developments in the definition, management, treatment, and prevention of acute and chronic complications of stroke. Then, we present some papers published in the Special Issue “Clinical Research on Ischemic Stroke: Novel Approaches in Acute and Chronic Phase”.

scholarly journals Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 909
Author(s):  
Krzysztof Kotowski ◽  
Jakub Rosik ◽  
Filip Machaj ◽  
Stanisław Supplitt ◽  
Daniel Wiczew ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Treatment Options ◽  
Protein Structures ◽  
New Drugs ◽  
Proliferating Cells ◽  
Cancer Tissues ◽  
The Impact ◽  
Rate Limiting ◽  
Synthesis And Degradation

Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.

scholarly journals Unannounced Evacuation Experiment in a High-Rise Hotel Building with Evacuation Elevators: A Study of Evacuation Behaviour Using Eye-Tracking

2020 ◽  
Author(s):  
Axel Mossberg ◽  
Daniel Nilsson ◽  
Kristin Andrée
Keyword(s):  
Eye Tracking ◽  
Current Knowledge ◽  
Guidance System ◽  
Hotel Room ◽  
High Rise ◽  
Eye Fixations ◽  
Improve Compliance ◽  
Exit Choice ◽  
Questionnaire Studies ◽  
Evacuation Experiment

Abstract Past studies suggest that people are often reluctant to use occupant evacuation elevators in case of fire. However, existing research is scarce and current knowledge is based on questionnaire studies and laboratory experiments. An unannounced evacuation experiment was therefore performed on the 16th floor of a 35-floor high-rise hotel building. Sixty-seven participants took part and eye-tracking glasses were used to collect data on exit choice and eye fixations. Three different scenarios were studied, including two different hotel room locations on the floor and a variation of guidance system for one of these locations, i.e., flashing green lights next to the evacuation sign at the elevators. Results suggest that people typically choose the elevator for evacuation, even if their hotel room was located closer to the evacuation stair. Flashing green lights next to an evacuation sign made people look more at this sign. However, in spite of looking more at the sign, the flashing light was not shown to significantly improve compliance with the sign. Also, the results suggest that a detector activated self-closing fire door without vision panels to the elevator lobby made it more difficult to find the evacuation elevators in an emergency.

scholarly journals Dysregulation of Rho GTPases in Human Cancers

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1179 ◽  
Author(s):  
Haiyoung Jung ◽  
Suk Ran Yoon ◽  
Jeewon Lim ◽  
Hee Jun Cho ◽  
Hee Gu Lee
Keyword(s):  
Cancer Progression ◽  
Rho Gtpases ◽  
Cell Cycle Progression ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
New Drugs ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Human Cancers ◽  
Cytoskeletal Dynamics

Rho GTPases play central roles in numerous cellular processes, including cell motility, cell polarity, and cell cycle progression, by regulating actin cytoskeletal dynamics and cell adhesion. Dysregulation of Rho GTPase signaling is observed in a broad range of human cancers, and is associated with cancer development and malignant phenotypes, including metastasis and chemoresistance. Rho GTPase activity is precisely controlled by guanine nucleotide exchange factors, GTPase-activating proteins, and guanine nucleotide dissociation inhibitors. Recent evidence demonstrates that it is also regulated by post-translational modifications, such as phosphorylation, ubiquitination, and sumoylation. Here, we review the current knowledge on the role of Rho GTPases, and the precise mechanisms controlling their activity in the regulation of cancer progression. In addition, we discuss targeting strategies for the development of new drugs to improve cancer therapy.

scholarly journals Efflux Pump Inhibitors against Nontuberculous Mycobacteria

2020 ◽  
Vol 21 (12) ◽  
pp. 4191
Author(s):  
Laura Rindi
Keyword(s):  
Drug Resistance ◽  
Efflux Pump ◽  
Nontuberculous Mycobacteria ◽  
Current Knowledge ◽  
New Drugs ◽  
Human Pathogens ◽  
Intracellular Accumulation ◽  
Promising Strategy ◽  
Combined Use ◽  
Efflux Pump Inhibitors

Over the last years, nontuberculous mycobacteria (NTM) have emerged as important human pathogens. Infections caused by NTM are often difficult to treat due to an intrinsic multidrug resistance for the presence of a lipid-rich outer membrane, thus encouraging an urgent need for the development of new drugs for the treatment of mycobacterial infections. Efflux pumps (EPs) are important elements that are involved in drug resistance by preventing intracellular accumulation of antibiotics. A promising strategy to decrease drug resistance is the inhibition of EP activity by EP inhibitors (EPIs), compounds that are able to increase the intracellular concentration of antimicrobials. Recently, attention has been focused on identifying EPIs in mycobacteria that could be used in combination with drugs. The aim of the present review is to provide an overview of the current knowledge on EPs and EPIs in NTM and also, the effect of potential EPIs as well as their combined use with antimycobacterial drugs in various NTM species are described.

scholarly journals Improving Compliance With Hand Hygiene in Hospitals

2000 ◽  
Vol 21 (6) ◽  
pp. 381-386 ◽  
Author(s):  
Didier Pittet
Keyword(s):  
Hand Hygiene ◽  
Healthcare Workers ◽  
Current Knowledge ◽  
Easy Access ◽  
Hygiene Behavior ◽  
Compliance Level ◽  
Improve Compliance ◽  
Timely Fashion ◽  
Hygiene Compliance ◽  
Knowledge Strategies

Hand hygiene prevents cross-infection in hospitals, but compliance with recommended instructions often is poor among healthcare workers. Although some previous interventions to improve compliance have been successful, none has achieved lasting improvement. This article reviews reported barriers to appropriate hand hygiene and factors associated with poor compliance.Easy access to hand hygiene in a timely fashion and the availability of skin-care lotion both appear to be necessary pre-requisites for appropriate hand-hygiene behavior. In particular, in high-demand situations, hand rub with an alcohol-based solution appears to be the only alternative that allows a decent compliance. The hand-hygiene compliance level does not rely on individual factors alone, and the same can be said for its promotion. Because of the complexity of the process of change, it is not surprising that solo interventions often fail, and multimodal, multidisciplinary strategies are necessary. A framework that includes parameters to be considered for hand-hygiene promotion is proposed, based on epidemiologically driven evidence and review of the current knowledge. Strategies for promotion in hospitals should include reasons for noncompliance with recommendations at individual, group, and institutional levels. Potential tools for change should address each of these elements and consider their interactivity.

scholarly journals Genetics of Psoriasis and Pharmacogenetics of Biological Drugs

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Rocío Prieto-Pérez ◽  
Teresa Cabaleiro ◽  
Esteban Daudén ◽  
Dolores Ochoa ◽  
Manuel Roman ◽  
...  
Keyword(s):  
Immune Response ◽  
Genetic Factors ◽  
Current Knowledge ◽  
Twin Studies ◽  
Chronic Inflammatory Disease ◽  
New Drugs ◽  
Biological Drugs ◽  
The Many ◽  
Phase Ii And Iii ◽  
Efficacy Of Treatment

Psoriasis is a chronic inflammatory disease of the skin. The causes of psoriasis are unknown, although family and twin studies have shown genetic factors to play a key role in its development. The many genes associated with psoriasis and the immune response includeTNFα, IL23, andIL12. Advances in knowledge of the pathogenesis of psoriasis have enabled the development of new drugs that target cytokines (e.g., etanercept, adalimumab, and infliximab, which target TNFα, and ustekinumab, which targets the p40 subunit of IL23 and IL12). These drugs have improved the safety and efficacy of treatment in comparison with previous therapies. However, not all patients respond equally to treatment, possibly owing to interindividual genetic variability. In this review, we describe the genes associated with psoriasis and the immune response, the biological drugs used to treat chronic severe plaque psoriasis, new drugs in phase II and III trials, and current knowledge on the implications of pharmacogenomics in predicting response to these treatments.

In silico investigation by conceptual DFT and molecular docking of antitrypanosomal compounds for understanding cruzain inhibition

2016 ◽  
Vol 15 (03) ◽  
pp. 1650021 ◽  
Author(s):  
Toufik Salah ◽  
Salah Belaidi ◽  
Nadjib Melkemi ◽  
Ismail Daoud ◽  
Salima Boughdiri
Keyword(s):  
Molecular Docking ◽  
Density Functional ◽  
Current Knowledge ◽  
Protozoan Parasite ◽  
Binding Mode ◽  
New Drugs ◽  
Conceptual Density Functional Theory ◽  
Docking Analysis ◽  
Life Threatening Illness ◽  
Molecular Docking Analysis

Current knowledge about Chagas disease, the potentially life-threatening illness caused by the protozoan parasite (Trypanosoma cruzi), has led to the development of new drugs and the understanding of their mode of action. The Conceptual Density-Functional Theory was applied to determine the active center sites of trypanocidal compounds, extended by the Molecular Docking analysis to identify the most favorable ligand conformation when bound to the active site of cruzain. Results such as CHELPG charges, Fukui function, MESP, and Molecular Docking analysis are reported and discussed in the present investigation. Whereas, a close agreement with experimental results was found to explain the possibility of studying the receptor-binding mode using these different axes.

Particularities of IBD Trials in Children

2019 ◽  
Vol 25 (1) ◽  
pp. 69-72 ◽  
Author(s):  
Dan Turner
Keyword(s):  
Recent Trend ◽  
Safety Data ◽  
New Drugs ◽  
Phase 3 ◽  
Non Invasive ◽  
Randomized Controlled ◽  
Adult Phase ◽  
Bowel Diseases ◽  
Pediatric Trial ◽  
Inflammatory Bowel

Pediatric inflammatory bowel diseases (IBD) are similar to the adult-onset type in many aspects, including the necessity of high-quality randomized controlled trials. However, recruiting children into clinical trials is conceptually more challenging than in adults. Furthermore, the long delay between adult and pediatric approval of new drugs leads not only to the unbearable extensive use of these drugs as off-label without appropriate dosing and safety data but also to more challenges when eventually the pediatric trial is performed. This review offers possible solutions to age-specific pitfalls in performing trials in pediatric IBD. Many of the challenges could be adequately addressed by accepting full extrapolation of efficacy from adult trials. This is advisable if small pharmacokinetics/ pharmacodynamics (PK/PD) studies show similarity to adult data. Then, pediatric trials can focus on dosing and safety while avoiding the controversial use of placebo. Judicious use of non-invasive activity scores and biomarkers, providing immediate and effective treatment in active disease and ensuring equipoise of treatments both within and outside the trial are the mainstay of a feasible trial in children. The recent trend of including adolescents in adult phase-3 trials addresses some obstacles but introduces others. Acknowledging and addressing these age-specific challenges would facilitate pediatric drug development in IBD.

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