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Lu Zhang, Marie Aloia, Barbara Pielecha-Safira, Honghao Lin, Prarthana Manoj Rajai, Kuriakose Kunnath, Rajesh N Davé
Although strip films are a promising platform for delivery of poorly water-soluble drug particles via slurry casting, the effect of critical materials attributes (CMAs), e.g., super-disintegrants on critical quality attributes (CQAs), including film disintegration time (DT), remains under-explored. A two-level factorial design is considered to examine the impact of the super-disintegrant (SDI) type (sodium starch glycolate and croscarmellose sodium), their amount, and film thickness. SDIs were used with hydroxypropyl methylcellulose (HPMC-E15LV) and glycerin solutions along with viscosity matching...
April 14, 2018: Journal of Pharmaceutical Sciences
Estelle J A Suys, David K Chalmers, Colin W Pouton, Christopher J H Porter
The ability of lipid based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastro-intestinal (GI) fluids has generated significant interest in the last decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers to the formulation that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs). In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations...
April 16, 2018: Molecular Pharmaceutics
Frank Theil, Johanna Milsmann, Sankaran Anantharaman, Holger van Lishaut
The preparation of an amorphous solid dispersion (ASD) by dissolving a poorly water-soluble active pharmaceutical ingredient (API) in a polymer matrix can improve the bioavailability by orders of magnitude. Crystallization of the API in the ASD, though, is an inherent threat for bioavailability. Commonly, the impact of crystalline API on the drug release of the dosage form is studied with samples containing spiked crystallinity. These spiked samples possess implicit differences compared to native crystalline samples, regarding size and spatial distribution of the crystals as well as their molecular environment...
April 12, 2018: Molecular Pharmaceutics
Hidenori Arai, Shizuya Yamashita, Koutaro Yokote, Eiichi Araki, Hideki Suganami, Shun Ishibashi
AIM: To verify the superiority of pemafibrate over placebo and the non-inferiority of pemafibrate to the maximum dose of fenofibrate for determining the percent change in fasting serum triglyceride (TG) levels and to investigate safety by assessing the incidence of adverse events (AEs) and adverse drug reactions (ADRs). METHODS: This phase III, placebo/active drug-controlled, randomized, double-blind, parallel group comparison study enrolled patients with high TG and low high-density lipoprotein cholesterol levels...
April 7, 2018: Journal of Atherosclerosis and Thrombosis
Mariana Cerqueira Losacco, Carolina Fernanda Theodora de Almeida, Andressa Harumi Torelli Hijo, Paula Bargi-Souza, Patricia Gama, Maria Tereza Nunes, Francemilson Goulart-Silva
AIMS: High fat diet consumes and thyroid hormones (THs) disorders may affect nutrients metabolism, but their impact on the absorptive epithelium, the first place of nutrients access, remains unknown. Our aim was to evaluate the intestinal morphology and nutrients transporters content in mice fed standard (LFD) or high fat (HFD) diets in hypo or hyperthyroidism-induced condition. MATERIAL AND METHODS: C57BL/6 male mice fed LFD or HFD diets for 12 weeks, followed by saline, PTU (antithyroid drug) or T3 treatment up to 30 days...
April 4, 2018: Life Sciences
Charles L Bisgaier, Daniela C Oniciu, Rai Ajit K Srivastava
Gemcabene, a late-stage clinical candidate, has shown efficacy for LDL-C, non-HDL cholesterol, apoB, triglycerides and hsCRP reduction, all risk factors for cardiovascular disease (CVD). In rodents, gemcabene showed changes in targets, including apoC-III, apoA-I, peroxisomal enzymes, considered regulated via PPAR gene activation, suggesting a PPAR-mediated mechanism of action for the observed hypolipidemic effects observed in rodents and humans. In the current study, the gemcabene agonist activity against PPAR subtypes of human, rat and mouse were compared to known lipid lowering PPAR activators...
March 21, 2018: Journal of Cardiovascular Pharmacology
Dawei Wang, Yanqiu Wang
RATIONALE: Fenofibrate is a fibric acid derivative indicated for use in hypertriglyceridemia and mixed dyslipidemia treatment among adults. Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle contents into the systemic circulation, which is the most serious and fatal side effect of fenofibrate. The objective of this paper is to discuss fatal side effect of fenofibrate and keep safe medication. PATIENT CONCERNS: A patient with hypothyroidism who presented with rhabdomyolysis during fenofibrate monotherapy for hypertriglyceridemia was reported...
April 2018: Medicine (Baltimore)
Jie Yuan, Hongdan Mo, Jing Luo, Suhong Zhao, Shuang Liang, Yu Jiang, Maomao Zhang
The cytoskeleton serves an important role in maintaining cellular morphology and function, and it is a substrate of calpain during myocardial ischemia/reperfusion (I/R) injury (MIRI). Calpain may be activated by endoplasmic reticulum (ER) stress during MIRI. The activation of peroxisome proliferator‑activated receptor α (PPARα) may inhibit ischemia/reperfusion damage by regulating stress reactions. The present study aimed to determine whether the activation of PPARα protects against MIRI‑induced cytoskeletal degradation, and investigated the underlying mechanism involved...
March 16, 2018: Molecular Medicine Reports
Yuta Yamamoto, Kenta Takei, Sundaram Arulmozhiraja, Vladimir Sladek, Naoya Matsuo, Son-Iee Han, Takashi Matsuzaka, Motohiro Sekiya, Takaki Tokiwa, Mitsuo Shoji, Yasuteru Shigeta, Yoshimi Nakagawa, Hiroaki Tokiwa, Hitoshi Shimano
Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor involved in the regulation of lipid homeostasis and improves hypertriglyceridemia. Pemafibrate is a novel selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. Here, we computationally constructed the structure of the human PPARα in a complex with pemafibrate, along with that of hPPARα complexed with the classical fenofibrate, and studied their interactions quantitatively by using the first-principles calculations-based fragment molecular orbital (FMO) method...
March 19, 2018: Biochemical and Biophysical Research Communications
Boris Waldman, Jean-Claude Ansquer, David R Sullivan, Alicia J Jenkins, Neil McGill, Luke Buizen, Timothy M E Davis, James D Best, Liping Li, Michael D Feher, Christelle Foucher, Y Antero Kesaniemi, Jeffrey Flack, Michael C d'Emden, Russell S Scott, John Hedley, Val Gebski, Anthony C Keech
BACKGROUND: Gout is a painful disorder and is common in type 2 diabetes. Fenofibrate lowers uric acid and reduces gout attacks in small, short-term studies. Whether fenofibrate produces sustained reductions in uric acid and gout attacks is unknown. METHODS: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, participants aged 50-75 years with type 2 diabetes were randomly assigned to receive either co-micronised fenofibrate 200 mg once per day or matching placebo for a median of 5 years follow-up...
February 26, 2018: Lancet Diabetes & Endocrinology
Michel P Hermans, Paul Valensi
PURPOSE OF REVIEW: The aim of this review is to describe in diabetic patients the determinants underlying atherogenic dyslipidemia, a complex dyslipidemia defined as the coexistence of fasting hypertriglyceridemia and low high-density lipoprotein cholesterol level. Atherogenic dyslipidemia is often comorbid with hyperglycemia in patients with the common form of type 2 diabetes mellitus (T2DM), namely that associated with obesity, insulin resistance, hyperinsulinemia and the metabolic syndrome phenotype...
April 2018: Current Opinion in Endocrinology, Diabetes, and Obesity
Charlotte Koopal, Frank L J Visseren, Jan Westerink, Yolanda van der Graaf, Henry N Ginsberg, Anthony C Keech
OBJECTIVE: In clinical trials, treatment with fenofibrate did not reduce the incidence of major cardiovascular events (MCVE) in patients with type 2 diabetes mellitus (T2DM). However, treatment effects reported by trials comprise patients who respond poorly and patients who respond well to fenofibrate. Our aim was to use statistical modeling to estimate the expected treatment effect of fenofibrate for individual patients with T2DM. RESEARCH DESIGN AND METHODS: To estimate individual risk, the FIELD risk model, with 5-year MCVE as primary outcome, was externally validated in T2DM patients from ACCORD and the SMART observational cohort...
February 22, 2018: Diabetes Care
Simone Aleandri, Monica Schönenberger, Andres Niederquell, Martin Kuentz
PURPOSE: The trial-and-error approach is still predominantly used in pharmaceutical development of nanosuspensions. Physicochemical dispersion stability is a primary focus and therefore, various analytical bulk methods are commonly employed. Clearly less attention is directed to surface changes of nanoparticles even though such interface effects can be of pharmaceutical relevance. Such potential effects in drug nanosuspensions were to be studied for temperatures of 25 and 37°C by using complementary surface analytical methods...
February 21, 2018: Pharmaceutical Research
(no author information available yet)
No abstract text is available yet for this article.
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Xin Geng, Marguerite R Irvin, Bertha Hidalgo, Stella Aslibekyan, Vinodh Srinivasasainagendra, Ping An, Alexis Frazier-Wood, Hemant K Tiwari, Tushar Dave, Kathleen Ryan, Jose M Ordovas, Robert J Straka, Mary F Feitosa, Paul N Hopkins, Ingrid Borecki, Michael A Province, Braxton D Mitchell, Donna K Arnett, Degui Zhi
Our understanding of genetic influences on the response of lipids to specific interventions is limited. In this study, we sought to elucidate effects of rare genetic variants on lipid response to a high-fat meal challenge and fenofibrate (FFB) therapy in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort using an exome-wide sequencing-based association study. Our results showed that the rare coding variants in ITGA7, SIPA1L2, and CEP72 are significantly associated with fasting low-density lipoprotein cholesterol (LDL-C) response to FFB (P=1...
February 20, 2018: Journal of Lipid Research
Yongnan Li, Shuodong Wu
This study aims to explore the effect of epigallocatechin gallate (EGCG) on blood lipids, liver lipids, and cholesterol synthesis in hyperlipidemic rats. SREBP-2 transgenic rats were used to investigate the transcriptional level of SREBP-2 regulated by SIRT-1/FOXO1 and the molecular mechanism of rate-limiting enzyme HMGCR that affects cholesterol synthesis. Rat models of hyperlipidemia were established and administered EGCG. Cholesterol synthesis was observed. Enzyme linked immunosorbent assay was used to determine serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), free fatty acid (FFA), superoxide dismutase (SOD), malondialdehyde (MDA), and T-AOC contents...
February 14, 2018: Molecular and Cellular Biochemistry
K Forner, I Hidalgo, J Lin, M Ackermann, P Langguth
The evaluation of formulation strategies in early drug development requires in vitro methods that correctly predict oral drug absorption. The present study aimed to define key parameters for the predictability of dissolution/permeation experiments. Dissolution/permeation experiments were performed in various setups. The IDAS1 chamber, Ussing chamber, and transwells were used as Caco-2 cell based dissolution/permeation models to study the impact of chamber volumes and vertical or horizontal membrane orientation...
October 1, 2017: Die Pharmazie
Bhavesh D Kevadiya, Manish Barvaliya, Lu Zhang, Ashish Anovadiya, Harshad Brahmbhatt, Parimal Paul, Chandrabhanu Tripathi
The aim of the present study was to make a fenofibrate (FNB) nanocrystal (NC) by wet media milling, characterizations and formulates into oral strip-films (OSFs). Mechanical properties, redispersion study, and solid-state characterizations results suggested that reduction of drug crystal size at nanoscale and incorporation into OSFs does not affect the solid-state properties of the drug. In vitro dissolution kinetics showed enhanced dissolution rate was easily manipulated by changing the thickness of the OSF...
February 13, 2018: Bioengineering
Kausik K Ray, Lawrence A Leiter, Dirk Müller-Wieland, Bertrand Cariou, Helen M Colhoun, Robert R Henry, Francisco J Tinahones, Maja Bujas-Bobanovic, Catherine Domenger, Alexia Letierce, Rita Samuel, Stefano Del Prato
AIMS: Individuals with type 2 diabetes (T2DM) and mixed dyslipidaemia represent a high-risk and difficult-to-treat population. ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) compared alirocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, with usual care (UC) in individuals with T2DM and mixed dyslipidaemia not optimally managed by maximally-tolerated statins. MATERIALS AND METHODS: UC options (no additional lipid-lowering therapy; fenofibrate; ezetimibe; omega-3 fatty acid; nicotinic acid) were selected prior to stratified randomization to open-label alirocumab 75 mg every 2 weeks (Q2W; with increase to 150 mg Q2W at Week [W]12 if W8 non-high-density lipoprotein cholesterol [non-HDL-C] was ≥2...
February 13, 2018: Diabetes, Obesity & Metabolism
Habib Yaribeygi, Mohammad Taghi Mohammadi, Amirhossein Sahebkar
BACKGROUND: Diabetes-induced oxidative stress has an essential role in pancreatic cells dysfunction. The present study aimed to evaluate whether peroxisome proliferator activated receptor- alpha (PPAR-α) induction by fenofibrate counterbalances oxidative stress in pancreatic cells. METHODS: In this in vivo study, male Wistar rats were randomly divided into four groups as normal, normal treated, diabetic and diabetic treated groups (n=6 in each group). Diabetes was induced by a single intravenous injection of streptozotocin (45 mg/kg)...
February 12, 2018: Drug Research
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