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Pharmacological inertness

Aparajita Banerjee, Björn Hamberger
Catalyzing stereo- and regio-specific oxidation of inert hydrocarbon backbones, and a range of more exotic reactions inherently difficult in formal chemical synthesis, cytochromes P450 (P450s) offer outstanding potential for biotechnological engineering. Plants and their dazzling diversity of specialized metabolites have emerged as rich repository for functional P450s with the advances of deep transcriptomics and genome wide discovery. P450s are of outstanding interest for understanding chemical diversification throughout evolution, for gaining mechanistic insights through the study of their structure-function relationship, and for exploitation in Synthetic Biology...
2018: Phytochemistry Reviews: Proceedings of the Phytochemical Society of Europe
Sarah Theiner, Márkó Grabarics, Luis Galvez, Hristo P Varbanov, Nadine S Sommerfeld, Markus Galanski, Bernhard K Keppler, Gunda Koellensperger
The potential advantage of platinum(iv) complexes as alternatives to classical platinum(ii)-based drugs relies on their kinetic stability in the body before reaching the tumor site and on their activation by reduction inside cancer cells. In this study, an analytical workflow has been developed to investigate the reductive biotransformation and kinetic inertness of platinum(iv) prodrugs comprising different ligand coordination spheres (respectively, lipophilicity and redox behavior) in whole human blood. The distribution of platinum(iv) complexes in blood pellets and plasma was determined by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave digestion...
March 21, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Mark A Burbridge, Richard A Jaffe
Medications used in anesthesiology contain both pharmacologically active compounds and additional additives that are usually regarded as being pharmacologically inactive. These additives, called excipients, serve diverse functions. Despite being labeled inert, excipients are not necessarily benign substances. Anesthesiologists should have a clear understanding of their chemical properties and the potential for adverse reactions. This report catalogs the excipients found in drugs commonly used in anesthesiology, provides a brief description of their function, and documents examples from the literature regarding their adverse effects...
March 1, 2018: Anesthesia and Analgesia
Daniel F Manvich, Kevin A Webster, Stephanie L Foster, Martilias S Farrell, James C Ritchie, Joseph H Porter, David Weinshenker
Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice...
March 1, 2018: Scientific Reports
Jieni Xu, Jingjing Sun, Pengcheng Wang, Xiaochao Ma, Song Li
Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI) approved by FDA for the treatment of cutaneous T cell lymphoma, is a promising anticancer drug for various cancers with a unique mode of action. However, it demonstrates limited clinical benefits in solid tumors as a single drug. In order to achieve enhanced and synergistic co-delivery of SAHA and Doxorubicin (DOX), a cleavable SAHA-based prodrug polymer (POEG-b-PSAHA), consisting of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) blocks and hydrophobic SAHA segments, has been developed...
December 18, 2017: Journal of Drug Targeting
Sophie Layé, Agnès Nadjar, Corinne Joffre, Richard P Bazinet
Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior...
January 2018: Pharmacological Reviews
Scott M Schafer, Stephan Geuter, Tor D Wager
Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive expectations both play important roles in placebo responses, however we are just beginning to understand how interactions between these processes lead to powerful effects. Here, we review the psychological principles underlying placebo effects and our current understanding of their brain bases, focusing on studies demonstrating both the importance of cognitive expectations and those that demonstrate expectancy-independent associative learning...
January 2018: Progress in Neurobiology
Bernd Gesslbauer, Valery Bochkov
Acute or chronic oxidative stress plays an important role in many pathologies. Two opposite approaches are typically used to prevent the damage induced by reactive oxygen and nitrogen species (RONS), namely treatment either with antioxidants or with weak oxidants that up-regulate endogenous antioxidant mechanisms. This review discusses options for the third pharmacological approach, namely amelioration of oxidative stress by 'redox-inert' compounds, which do not inactivate RONS but either inhibit the basic mechanisms leading to their formation (i...
November 3, 2017: Biochemical Society Transactions
Kennett Sprogøe, Eva Mortensen, David B Karpf, Jonathan A Leff
The fundamental challenge of developing a long-acting growth hormone (LAGH) is to create a more convenient growth hormone (GH) dosing profile while retaining the excellent safety, efficacy and tolerability of daily GH. With GH receptors on virtually all cells, replacement therapy should achieve the same tissue distribution and effects of daily (and endogenous) GH while maintaining levels of GH and resulting IGF-1 within the physiologic range. To date, only two LAGHs have gained the approval of either the Food and Drug Administration (FDA) or the European Medicines Agency (EMA); both released unmodified GH, thus presumably replicating distribution and pharmacological actions of daily GH...
November 2017: Endocrine Connections
Carmen Walter, Bruno G Oertel, Lisa Felden, Ulrike Nöth, Johannes Vermehren, Ralf Deichmann, Jörn Lötsch
BACKGROUND: Considering the increasing acknowledgment of the human sense of smell as a significant component of the quality of life, olfactory drug effects gain potential clinical importance. A recent observation in a human experimental context indicated that Δ(9)-tetrahydrocannabinol (THC) impaired the subject's performance in olfactory tests. To further analyze the role of THC in human olfaction, the present report addresses its effects on the central processing of olfactory stimuli...
December 2017: European Journal of Clinical Pharmacology
Jingwei Jiang, Huxing Cui, Kamal Rahmouni
Remote and selective spatiotemporal control of the activity of neurons to regulate behavior and physiological functions has been a long-sought goal in system neuroscience. Identification and subsequent bioengineering of light-sensitive ion channels (e.g., channelrhodopsins, halorhodopsin, and archaerhodopsins) from the bacteria have made it possible to use light to artificially modulate neuronal activity, namely optogenetics. Recent advance in genetics has also allowed development of novel pharmacological tools to selectively and remotely control neuronal activity using engineered G protein-coupled receptors, which can be activated by otherwise inert drug-like small molecules such as the designer receptors exclusively activated by designer drug, a form of chemogenetics...
December 1, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Robabeh Soleimani, Maryam Kousha, Homa Zarrabi, Seyede Mahnaz Tavafzadeh-Haghi, Mir Mohammad Jalali
BACKGROUND: Children with attention deficit hyperactivity disorder/developmental coordination disorder (ADHD/DCD) suffer from problems associated with gross and fine motor skills. There is no effective pharmacological therapy for such patients. We aimed to assess the impact of methylphenidate (MPH) on motor performance of children with ADHD/DCD. METHODS: In this double-blind placebo-controlled, 17 children (12 boys) with ADHD/DCD with a mean age of 7 years 6 months were recruited in Shafa Hospital, Rasht, Iran...
July 2017: Iranian Journal of Medical Sciences
Laxmaiah Manchikanti, Mark V Boswell, Alan D Kaye, Standiford Helm Ii, Joshua A Hirsch
Research into interventional techniques in managing chronic spinal pain continues to be challenging, mystifying, confusing, and biased. Insight, or lack thereof, into placebo and nocebo phenomena contributes mightily to these difficulties. Unfortunately, placebo-nocebo responses are the subject of numerous controversies and challenges from not only a research perspective, but also clinical perspective. While interventionalists consider the biggest threat to interventional pain management research is inappropriate and outdated interpretation of the data, a greater problem is the misuse of the placebo response in research, with the declaration that all and everything as a placebo effect: with a misinterpretation of the nature of the placebo the, associated conclusions can be inaccurate...
July 2017: Pain Physician
William F S Sellers
BACKGROUND: Current pressurised metered dose asthma inhaler (pMDI) propellants are not inert pharmacologically as were previous chlorofluorocarbons, have smooth muscle relaxant' partial pressure effects in the lungs and inhaled hydrofluoroalkane 134a (norflurane) has anaesthetic effects. Volumes of propellant gas per actuation have never been measured. METHODS: In-vitro studies measured gas volumes produced by pMDIs on air oxygen (O2) levels in valved holding chambers (VHC) and the falls in O2% following actuation into lung ventilator delivery devices...
2017: Allergy, Asthma, and Clinical Immunology
Tracy Murray-Stewart, Elena Ferrari, Ying Xie, Fei Yu, Laurence J Marton, David Oupicky, Robert A Casero
Synthesizing polycationic polymers directly from existing drugs overcomes the drug-loading limitations often associated with pharmacologically inert nanocarriers. We recently described nanocarriers formed from a first-generation polyamine analogue, bis(ethyl)norspermine (BENSpm), that could simultaneously target polyamine metabolism while delivering therapeutic nucleic acids. In the current study, we describe the synthesis and evaluation of self-immolative nanocarriers derived from the second-generation polyamine analogue PG-11047...
2017: PloS One
Garret A Horton, Jimmy J Fraigne, Zoltan A Torontali, Matthew B Snow, Jennifer L Lapierre, Hattie Liu, Gaspard Montandon, John H Peever, Richard L Horner
Reduced tongue muscle tone precipitates obstructive sleep apnea (OSA), and activation of the tongue musculature can lessen OSA. The hypoglossal motor nucleus (HMN) innervates the tongue muscles but there is no pharmacological agent currently able to selectively manipulate a channel (e.g., Kir2.4) that is highly restricted in its expression to cranial motor pools such as the HMN. To model the effect of manipulating such a restricted target, we introduced a "designer" receptor into the HMN and selectively modulated it with a "designer" drug...
April 6, 2017: Scientific Reports
Miro Klarić, Vjekoslav Mandić, Sanjin Lovrić, Martina Krešić Ćorić, Nikolina Zovko
Most people have heard of the placebo effect, while relatively few have heard of nocebo, even within the circles of medical staff. Placebo effect means positive results by treatment via pharmacological inert substances. In contrast to placebo, by nocebo effect, due to negative beliefs and expectations, opposite results are achieved. Said in a more formal manner, what a sick person expects, unfortunately, he/she most often gets. It is a fact that a high number of medical staff is still uninterested in placebo and nocebo effects, although they would benefit from them...
February 1, 2017: Medicinski Glasnik
Sirima Soodvilai, Sunhapas Soodvilai, Varanuj Chatsudthipong, Tanasait Ngawhirunpat, Theerasak Rojanarata, Praneet Opanasopit
Increasing evidences have shown that many pharmaceutical excipients are not pharmacologically inert but instead have effects on several transport function of uptake and efflux drug transporters. Herein, we investigated whether the excipients frequently used in many drug formulations affect transport function of organic cation transporters (OCTs) that are responsible for elimination of cationic drugs. Our finding revealed that solubilizing agents, Tweens, showed the most significant effect rbOCT1/2-mediated [(3)H]-MPP(+) uptake in heterologous expressing cells...
March 30, 2017: International Journal of Pharmaceutics
Ye Ji Kim, Sun Min Kim, Chunghyeon Yu, YoungMin Yoo, Eun Jin Cho, Jung Woon Yang, Sung Wng Kim
Halogenated organic compounds are important anthropogenic chemicals widely used in chemical industry, biology, and pharmacology; however, the persistence and inertness of organic halides cause human health problems and considerable environmental pollution. Thus, the elimination or replacement of halogen atoms with organic halides has been considered a central task in synthetic chemistry. In dehalogenation reactions, the consecutive single-electron transfer from reducing agents generates the radical and corresponding carbanion and thus removes the halogen atom as the leaving group...
January 20, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
Manouchehr Teymouri, Nastaran Barati, Matteo Pirro, Amirhosein Sahebkar
Dimethoxycurcumin (DiMC) is a synthetic analog of curcumin with superior inter-related pro-oxidant and anti-cancer activity, and metabolic stability. Numerous studies have shown that DiMC reserves the biologically beneficial features, including anti-inflammatory, anti-carcinogenic, and cytoprotective properties, almost to the same extent as curcumin exhibits. DiMC lacks the phenolic-OH groups as opposed to curcumin, dimethoxycurcumin, and bis-demethoxycurcumin that all vary in the number of methoxy groups per molecule, and has drawn the attentions of researchers who attempted to discover the structure-activity relationship (SAR) of curcumin...
January 2018: Journal of Cellular Physiology
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