Examining the Benefits of the Boron-Based Mechanism of Action and Physicochemical Properties of Tavaborole in the Treatment of Onychomycosis

2018 ◽  
Vol 108 (1) ◽  
pp. 12-19 ◽  
Author(s):  
Bryan Markinson ◽  
Mahmoud Ghannoum ◽  
Tate Winter ◽  
Anthony Rycerz ◽  
Fernando Rock ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Water Solubility ◽  
Nail Plate ◽  
Trichophyton Mentagrophytes ◽  
The United States ◽  
Trna Synthetase ◽  
Fungal Cell ◽  
Boron Chemistry ◽  
Clinical Benefits ◽  
Fungal Protein Synthesis

Onychomycosis is a fungal infection of the nail primarily caused by the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. The topical-based treatment of onychomycosis remains a challenge because of the difficulty associated with penetrating the dense, protective structure of the keratinized nail plate. Tavaborole is a novel small-molecule antifungal agent recently approved in the United States for the topical treatment of toenail onychomycosis. The low molecular weight, slight water solubility, and boron chemistry of tavaborole maximize nail penetration after topical application, allowing for effective targeting of the infection in the nail bed. The efficacy of tavaborole is associated with its novel mechanism of action, whereby it inhibits the fungal leucyl-tRNA synthetase (LeuRS) enzyme. Because LeuRS is an essential component in fungal protein synthesis, inhibition of LeuRS ultimately leads to fungal cell death. Tavaborole is the first boron-based antifungal medication approved for the treatment of mild-to-moderate onychomycosis and presents patients with a new topical option. Previously, ciclopirox and efinaconazole were the only approved topical treatments for onychomycosis. This article details the properties that are at the core of the clinical benefits associated with tavaborole.

scholarly journals Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview

2019 ◽  
pp. 1-12 ◽  
Author(s):  
A.S. V. Prasad
Keyword(s):  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Organic Anion ◽  
Density Lipoprotein ◽  
The United States ◽  
Mechanisms Of Action ◽  
Lipid Lowering ◽  
Intervention Trial ◽  
Ligand Interaction ◽  
Cholesterol Acyl Transferase

Fibrates are a class of medication that mainly lowers the blood triglyceride levels. They reduce the LDL and increase the levels of HDL C, in the blood. Clofibrate, the first member to be discovered  in 1962 , and introduced in USA in 1967, is withdrawn in 2002, due to unexplained hepatomegaly, hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early 1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk , progression of atherosclerosis and metabolic syndrome,  macrovascular and microvascular diabetic complications  like stroke, myocardial infarction, peripheral vascular disease  and  diabetic  retinopathy .Various clinical trials like VA-HIT trial (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial) ,  FIELD trail.  (the Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study,   ACCORD -Lipid trial  (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial ) and  BIP (Bezafibrate Infarction Prevention Study)  trial and angiography trials, like LOCAT (Lopid Coronary Angiography Trial)  and BECLAIT (Bezafibrate Coronary Atherosclerosis Intervention Trial) demonstrated the  beneficial effects of gemfibrozil and fenofibrate.  Their mechanism of action remained obscure for three decades, ie till 1990s, when their mode of action was found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL)  modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involving  the various  enzymes like LCAT (Lecithin-cholesterol acyl transferase)  and CYP7A1 etc.  (cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) ) ,  transporters like ABC , CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP, OATP (Na+-dependent taurocholate transporter / organic anion transporters) . These are the.) and nuclear factors like LXR, PPAR alfa etc. (liver orphan receptor α , and peroxisome proliferative nuclear factor) , in relation to the mechanisms  of action of fibrates are discussed . Areas of current interests in literature are briefed.

The programming of differentiation and its control by juvenile hormone in saturniids

Development ◽  
1969 ◽  
Vol 22 (1) ◽  
pp. 27-44
Author(s):  
Judith H. Willis
Keyword(s):  
United States ◽  
Juvenile Hormone ◽  
Recent Work ◽  
Mechanism Of Action ◽  
The United States ◽  
Considerable Progress ◽  
Complex Nature ◽  
Preliminary Stage ◽  
Developmental Program ◽  
Pupal Cuticle

Although considerable progress has been made with the chemistry of juvenile hormone (Dahm, Roeller & Trost, 1968), studies on its mechanism of action in immature insects are still in a preliminary stage. Much of the recent work has been interpreted as showing an effect of juvenile hormone on the morphogenetic program through which an insect passes in the course of its ontogeny (Williams, 1961). It is the purpose of this paper to describe three studies which illustrate the complex nature of this developmental program in saturniid moths. Materials and Methods The saturniids (Antheraea polyphemus, Samia cynthia and Hyalophora cecropia) used in the present study were reared or purchased from dealers in the United States and England. Staging of animals was carried out by examining the state of the epidermis and the differentiation of adult structures through the pupal cuticle as described by Schneiderman & Williams (1954).

scholarly journals Preface

2006 ◽  
Vol 78 (7) ◽  
pp. iv
Author(s):  
Yoshinori Yamamoto
Keyword(s):  
The United States ◽  
Molecular Structures ◽  
Synthetic Methods ◽  
International Meeting ◽  
Boron Compounds ◽  
Research Areas ◽  
Research Fields ◽  
Boron Chemistry ◽  
Poster Presentations ◽  
Oral Presentations

This volume summarizes the present status of research in the field of organic and inorganic boron chemistry, presented by the invited speakers at the 12th International Meeting on Boron Chemistry (IMEBORON-XII), held in Sendai, Japan, 11-15 September 2005. IMEBORON-XII consisted of 1 plenary lecture, 22 invited lectures, 24 keynote lectures, 48 short oral presentations, and 99 poster presentations. In all, 280 chemists contributed to a truly international meeting, with participants representing China, Czech Republic, Germany, Israel, Japan, Mexico, Poland, Russia, South Korea, Spain, Sweden, the United Kingdom, and the United States.The presentations at IMEBORON-XII covered all aspects of boron chemistry including theoretical studies, synthetic methods of organic and inorganic boron compounds, novel molecular structures, application of organic and inorganic boron compounds to organic synthesis as catalysts or as reagents, medicinal applications, and creation of new materials (liquid crystals, supramolecular clusters, nanocylinders, molecular electronic devices, nanomachines, ceramics, etc.). Not only the distinguished senior members of the boron community, but also young boron chemists took an active part in the conference. Not only traditional boron chemistry, but also new evolving research areas of boron chemistry were presented. Accordingly, I feel that a new generation of both researchers and research fields is coming in boron chemistry. A selection of the invited contributions to IMEBORON-XII is presented in the 14 papers in this issue.The importance of scientific exchange in this field was recognized during IMEBORON-XII. Therefore, the continuation of this series of conferences was discussed, and the venue for IMEBORON-XIII in 2008 will be organized by Prof. F. Teixidor at the Institut de Ciencia de Materials de Barcelona, C.S.I.S., Campus U.A.B., Ballaterra, Spain.Yoshinori YamamotoChairman of IMEBORON-XII

scholarly journals Mechanism of action and therapeutic benefit of rifaximin in patients with irritable bowel syndrome: a narrative review

2020 ◽  
Vol 13 ◽  
pp. 175628481989753 ◽  
Author(s):  
William D. Chey ◽  
Eric D. Shah ◽  
Herbert L. DuPont
Keyword(s):  
Irritable Bowel Syndrome ◽  
Gut Microbiota ◽  
Mechanism Of Action ◽  
Bacterial Overgrowth ◽  
Gastrointestinal Disorder ◽  
Small Intestinal Bacterial Overgrowth ◽  
The United States ◽  
Clinical Effects ◽  
Healthy Individuals ◽  
Irritable Bowel

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder with a multifactorial pathophysiology. The gut microbiota differs between patients with IBS and healthy individuals. After a bout of acute gastroenteritis, postinfection IBS may result in up to approximately 10% of those affected. Small intestinal bacterial overgrowth (SIBO) is more common in patients with IBS than in healthy individuals, and eradication of SIBO with systemic antibiotics has decreased symptoms of IBS in some patients with IBS and SIBO. The nonsystemic (i.e. low oral bioavailability) antibiotic rifaximin is indicated in the United States and Canada for the treatment of adults with IBS with diarrhea (IBS-D). The efficacy and safety of 2-week single and repeat courses of rifaximin have been demonstrated in randomized, placebo-controlled studies of adults with IBS. Rifaximin is widely thought to exert its beneficial clinical effects in IBS-D through manipulation of the gut microbiota. However, current studies indicate that rifaximin induces only modest effects on the gut microbiota of patients with IBS-D, suggesting that the efficacy of rifaximin may involve other mechanisms. Indeed, preclinical data reveal a potential role for rifaximin in the modulation of inflammatory cytokines and intestinal permeability, but these two findings have not yet been examined in the context of clinical studies. The mechanism of action of rifaximin in IBS is likely multifactorial, and further study is needed.

Analysis of new molecular entity trends from 2006 to 2015 in Japan

2020 ◽  
Vol 16 (4) ◽  
pp. 161-170
Author(s):  
Shoyo Shibata ◽  
Daigo Fukumoto ◽  
Koken Ozaki ◽  
Takeshi Suzuki
Keyword(s):  
Musculoskeletal System ◽  
Comparative Method ◽  
The United States ◽  
New Drugs ◽  
Molecular Entity ◽  
Pharmaceutical Markets ◽  
Performance Indexes ◽  
Clinical Benefits ◽  
Conducting Research ◽  
Japanese Companies

Japan is one of the largest pharmaceutical markets in the world, and as such, pharmaceutical companies are intensively conducting research and development of new drugs in Japan. However, information on Japanese pharmaceutical market profiles is limited. In this context, we elucidated the market characteristics and trends of new molecular entities approved between 2006 and 2015 in Japan. Among antineoplastic and immunomodulating agents, the highest number was first approved in the United States, and for nervous system drugs, the highest number was first approved in Europe. The alimentary tract and metabolism and the musculoskeletal system were the therapeutic areas for which the most drugs were approved for the first time in Japan. Most of the musculoskeletal system drugs were developed by Japanese companies, and most of the antineoplastic and immunomodulating agents were developed outside of Japan. Using various performance indexes, such as market forecasts and significance of clinical benefits, we determined that the number of new molecular entities and market size increased and the number of drugs with significant clinical benefits decreased. These results suggest that new molecular entity innovation by Japanese companies has been decreasing and the government’s comparative method for pricing does not work well in Japan.

scholarly journals Deciphering the mechanism of action of 089, a compound impairing the fungal cell cycle

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Irene Stefanini ◽  
Lisa Rizzetto ◽  
Damariz Rivero ◽  
Silvia Carbonell ◽  
Marta Gut ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mechanism Of Action ◽  
Fungal Cell

Purified, Fermented, Extract of Triticum Aestivum Has Significant Independent Lymphomacidal Activity and Augments the Activity of Rituximab

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2857-2857
Author(s):  
Laura Newell ◽  
Joseph Tuscano ◽  
Robert o'Donnell ◽  
Yunpeng Ma
Keyword(s):  
Triticum Aestivum ◽  
T Cells ◽  
Cell Death ◽  
Cell Lines ◽  
Nude Mice ◽  
Mechanism Of Action ◽  
Wheat Germ ◽  
The United States

Abstract Abstract 2857 Background: Non-Hodgkin's lymphoma (NHL) affects over 400,000 people in the United States and its incidence increases with age. Treatment options include cytotoxic chemotherapy, which is often poorly tolerated by elderly patients, and monoclonal antibody (mAb) therapy. Nearly 70% of NHL patients eventually die of the disease. Development of effective alternate treatments with favorable toxicity profiles is necessary. Fermented wheat germ extract (FWGE) has shown anticancer potential in laboratory animals as well as in some small clinical studies; it is produced under GMP conditions in Europe and sold as Avemar™. The mechanism of action of FWGE is unclear, but is thought to involve metabolic pathways involved in tumor cell death. We examined the effects of FWGE on NHL and found significant lymphomacidal activity using in vitro and in vivo assays. We then further purified and characterized the active components of FWGE in order to develop a more potent form and to understand the mechanism of action, physiologic, and immunologic properties. Methods: FWGE was produced by fermenting purified wheat germ (Triticum aestivum) with Baker's yeast. The FWGE was further purified by removing insoluble material, precipitating proteins, freeze drying, fractionating with Sepharose and Sephadex columns, and then dialyzing to remove small molecules. The resultant fermented wheat germ proteins (FWGP) were assessed for in vitro cytotoxicity and pro-apoptotic activity using a panel of NHL cell lines. In vivo lymphomacidal activity was assessed in nude mice bearing Raji lymphoma xenografts. Mice were treated with increasing daily doses of FWGE by gastric lavage and compared to untreated controls as well as the commercially available fermented wheat germ product, Avemar. Results: In vitro killing assays with FWGE (regardless of the source) demonstrated lymphomacidal properties in three NHL cell lines (Jurkat, Raji, and Ramos). Pre-treatment of FWGE with heat or proteinase K reduced the lymphomacidal activity, suggesting that the active component was a protein. Nude mice bearing Raji lymphoma xenografts treated with FWGE confirmed the lymphomacidal properties of FGWE; there was no detectable toxicity as assessed by observation, mouse weight, or blood counts. The purified low molecular weight proteins (FWGP) also demonstrated lymphomacidal properties by cytotoxicity assays and murine NHL models, but at 1/1000th of the original dose. When FWGP was combined with rituximab, there was enhanced in vitro lymphomacidal activity, with over a 4000-fold reduction in the IC50. FWGP-induced NHL cell death was mediated by caspase-3-dependent apoptosis. FWGP augmented the host immune effector mechanisms, including ADCC and CDC, along with potent activation of NK-T cells (CD3/69/16), CD4+ T-cells and monocytes. Conclusions: FWGE can be easily produced and has cytotoxic effects in in vitro assays and in vivo. The purified FWGP are quantifiable, and are 10–1000 times more potent than FWGE. The mechanism of FWGP activity is based on direct pro-apoptotic effects as well as augmentation of host immune mediators. FWGP has activity against various subtypes of NHL. Studies are ongoing to further characterize the immune effects and anti-cancer properties of FWGP, as is planning for a human clinical trial +/− rituximab in patients with NHL. Disclosure: No relevant conflicts of interest to declare.

scholarly journals Barriers and facilitators to self-care communication during medical appointments in the United States for adults with type 2 diabetes

2014 ◽  
Vol 10 (4) ◽  
pp. 303-313 ◽  
Author(s):  
Marilyn D Ritholz ◽  
Elizabeth A Beverly ◽  
Kelly M Brooks ◽  
Martin J Abrahamson ◽  
Katie Weinger
Keyword(s):  
Type 2 Diabetes ◽  
Self Care ◽  
The United States ◽  
Barriers And Facilitators ◽  
Provider Communication ◽  
Semistructured Interview ◽  
Interview Guide ◽  
Clinical Benefits ◽  
Patient Provider Communication

Objective Diabetes self-care is challenging and requires effective patient–provider communication to achieve optimal treatment outcomes. This study explored perceptions of barriers and facilitators to diabetes self-care communication during medical appointments. Design Qualitative study using in-depth interviews with a semistructured interview guide. Participants Thirty-four patients with type 2 diabetes and 19 physicians who treat type 2 diabetes. Results Physicians described some patients as reluctant to discuss their self-care behaviors primarily because of fear of being judged, guilt, and shame. Similarly, patients described reluctant communication resulting from fear of being judged and shame, particularly shame surrounding food intake and weight. Physicians and patients recommended trust, nonjudgmental acceptance, open/honest communication, and providing patients hope for living with diabetes as important factors for improving self-care communication. Further, patients stressed the clinical benefits of physicians directly addressing poor self-care behaviors while physicians described having few strategies to address these difficulties. Conclusions Physician–patient self-care communication barriers included patients’ reluctance to discuss self-care behaviors and physicians’ perceptions of few options to address this reluctance. Treatment recommendations stressed the importance of establishing trusting, nonjudgmental and open patient–provider communication for optimal diabetes treatment. Medical education is needed to improve physicians’ strategies for addressing self-care communication during medical appointments.

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