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Current Opinion in Pharmacology

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https://www.readbyqxmd.com/read/29145012/the-gut-brain-interaction-in-opioid-tolerance
#1
REVIEW
Hamid I Akbarali, William L Dewey
The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms...
November 13, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29136587/management-of-eosinophilic-esophagitis-and-celiac-disease
#2
REVIEW
Rok Seon Choung, Jeffrey A Alexander, David A Katzka, Joseph A Murray
Eosinophilic esophagitis (EoE) and celiac disease (CeD) are chronic immune mediated gastrointestinal disorders characterized by mucosal inflammation, both of which are related to food antigens, but with differences in clinical and histopathological features. When untreated, both diseases lead to destruction of the epithelium. While a strict gluten-free diet is the only effective therapy for CeD, several therapeutic options, such as proton pump inhibitors, topical steroids and diet elimination therapy are available for EoE...
November 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29136540/the-application-of-in-vitro-surveillance-data-for-antibacterial-dose-selection
#3
REVIEW
Robert K Flamm, Helio S Sader, Mariana Castanheira, Ronald N Jones
In vitro surveillance data, which provide key information to interpret the results of pharmacokinetic/pharmacodynamics (PK-PD) target attainment studies, are used to support dose selection decisions and recommendations for in vitro susceptibility testing criteria for antibacterial agents during drug development. Considerations for designing the in vitro surveillance database to support the development of antibacterial agents include the choice of pathogens to study, the sample size of isolate collections needed, and target patient populations from which clinical isolates should be collected...
November 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29132121/the-therapeutic-potential-of-cftr-modulators-for-copd-and-other-airway-diseases
#4
REVIEW
George M Solomon, Lianwu Fu, Steven M Rowe, James F Collawn
Airways diseases, especially chronic obstructive pulmonary disease (COPD) and asthma, are common causes of morbidity and mortality worldwide. There is an ongoing unmet need for novel and effective therapies. There is an established pathophysiological link and phenotypic similarity between the chronic bronchitis phenotype of COPD and cystic fibrosis (CF). New evidence suggests that CFTR dysfunction may play a role in other common airways diseases such as COPD, non-atopic asthma and non-CF bronchiectasis. Newly approved and investigational drugs that target both mutant and wildtype CFTR channels have provided a new treatment opportunity addressing the mucus defect in pulmonary diseases that share the same pathophysiology with CF...
November 9, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29128854/pharmacological-management-of-gastroesophageal-reflux-disease-in-infants-current-opinions
#5
REVIEW
Mohamed A El-Mahdy, Fatma A Mansoor, Sudarshan R Jadcherla
Gastroesophageal reflux disease (GERD) constitutes a troublesome symptom complex resulting from retrograde passage of gastric contents into the esophagus or extra-esophageal regions. Premature-born, high-risk infants and those with neuro-aero-digestive pathologies are at increased risk. Critical review over the last 3 years was conducted, and current opinions on pharmacological targets include agents aimed at prevention of transient lower esophageal sphincter relaxation, modification of the physico-chemical composition of gastric contents, modification of gut motility, or altering sensory thresholds to ameliorate the troublesome symptoms...
November 9, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29128853/use-of-monte-carlo-simulation-and-considerations-for-pk-pd-targets-to-support-antibacterial-dose-selection
#6
REVIEW
Michael Trang, Michael N Dudley, Sujata M Bhavnani
Monte Carlo simulation is used to generate data for pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses to assess antibacterial dosing regimens in early and late stage drug development. Careful consideration of the quality of data for pharmacokinetics, non-clinical PK-PD targets for efficacy, the choice of the bacterial reduction endpoint upon which the PK-PD target is based, variability in the PK-PD target, and effect site exposures ensures optimal dose selection. Relationships between drug exposure and efficacy and/or safety endpoints based on clinical data can also be applied to simulated data to support dose selection...
November 9, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29128743/the-suppression-of-premature-termination-codons-and-the-repair-of-splicing-mutations-in-cftr
#7
REVIEW
Yifat S Oren, Iwona M Pranke, Batsheva Kerem, Isabelle Sermet-Gaudelus
Premature termination codons (PTC) originate from nucleotide substitution introducing an in-frame PTC. They induce truncated, usually non-functional, proteins, degradation of the PTC containing transcripts by the nonsense-mediated decay (NMD) pathway and abnormal exon skipping. Readthrough compounds facilitate near cognate amino-acyl-tRNA incorporation, leading potentially to restoration of a functional full-length protein. Splicing mutations can lead to aberrantly spliced transcripts by creating a cryptic splice site or destroying a normal site...
November 9, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29121533/novel-treatments-for-chronic-hepatitis-c-closing-the-remaining-gaps
#8
REVIEW
Naim Alkhouri, Eric Lawitz, Fred Poordad
Direct acting antivirals (DAAs) have revolutionized the treatment of chronic hepatitis C virus (HCV) infection with cure rates >90% for the majority of patients and excellent safety profile. However, there remain certain unmet needs in treating HCV including treatment for patients that failed a prior DAA regimen and for those with advanced chronic kidney disease. In addition, shortening the duration of DAA regimens has the potential to increase compliance and decrease the cost of care. New regimens that were approved by the FDA in 2017 address these unmet needs and will be discussed in this concise review...
November 6, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29112883/a-new-paradigm-for-gerd-pathogenesis-not-acid-injury-but-cytokine-mediated-inflammation-driven-by-hif-2%C3%AE-a-potential-role-for-targeting-hif-2%C3%AE-to-prevent-and-treat-reflux-esophagitis
#9
REVIEW
Rhonda F Souza, Liela Bayeh, Stuart J Spechler, Uttam K Tambar, Richard K Bruick
Traditionally, reflux esophagitis was assumed to develop as a caustic, chemical injury inflicted by refluxed acid. Recently, however, studies in rats and humans suggest that reflux esophagitis develops as a cytokine-mediated inflammatory injury, with hypoxia inducible factor (HIF)-2α playing a major role. In response to the reflux of acid and bile, HIF-2α in esophageal epithelial cells becomes stabilized, thereby increasing production of pro-inflammatory cytokines that attract T lymphocytes and other inflammatory cells to damage the esophagus...
November 4, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29107872/inflammation-and-gut-brain-axis-link-obesity-to-cognitive-dysfunction-plausible-pharmacological-interventions
#10
REVIEW
Maite Solas, Fermin I Milagro, María J Ramírez, J Alfredo Martínez
Obesity prevalence is increasing steadily throughout the world's population in most countries and in parallel the prevalence of metabolic disorders including cardiovascular diseases and type 2 diabetes is also rising, but less is reported about excessive adiposity relationship with poorer cognitive performance, cognitive decline and dementia. Some human clinical studies have evidenced that obesity is related to the risk of the development of mild cognitive impairment, in the form of short-term memory and executive function deficits, as well as dementia and Alzheimer's disease...
November 3, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29107871/an-appetite-for-life-brain-regulation-of-hunger-and-satiety
#11
REVIEW
Lora K Heisler, Daniel D Lam
Obesity results from the consumption of food in excess of bodily energy requirements, with the excess energy stored as adipose tissue. Sequelae of obesity, such as heart disease and type 2 diabetes, consistently rank among the top causes of death worldwide. The global prevalence of obesity highlights the urgency of understanding the mechanisms regulating hunger and satiety. Appetite, defined as the motivational drive to obtain food, is regulated by a complex neurocircuitry which integrates a variety of interoceptive signals to gauge nutritional state and guide appropriate levels of food-seeking...
November 3, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29107808/genetic-therapies-for-cystic-fibrosis-lung-disease
#12
REVIEW
Stephen L Hart, Patrick T Harrison
Gene therapy for cystic fibrosis (CF) has been the subject of intense research over the last twenty-five years or more, using both viral and liposomal delivery methods, but so far without the emergence of a clinical therapy. New approaches to CF gene therapy involving recent improvements to vector systems, both viral and non-viral, as well as new nucleic acid technologies have led to renewed interest in the field. The field of therapeutic gene editing is rapidly developing with the emergence of CRISPR/Cas9 as well as chemically modified mRNA therapeutics...
November 3, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29102744/modulating-bile-acid-pathways-and-tgr5-receptors-for-treating-liver-and-gi-diseases
#13
REVIEW
Harmeet Malhi, Michael Camilleri
Bile acids are central signals in enterohepatic communication and also integrate microbiota-derived signals into this signaling axis. Discovery of the tissue distribution and signaling pathways activated by the natural receptors for bile acids, farnesoid X receptor and G protein-coupled bile acid receptor 1 (GPBAR1) also known as TGR5, and bile acid transporters has led to the development of therapeutic agents that target these molecules. Obeticholic acid, a selective FXR agonist, and NGM282, a non-mitogenic FGF-19 analog, are two of the agents in this pipeline...
November 2, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29096277/the-implications-of-cftr-structural-studies-for-cystic-fibrosis-drug-development
#14
REVIEW
Isabelle Callebaut, Brice Hoffmann, Jean-Paul Mornon
Development of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators, targeting the root cause of cystic fibrosis (CF), represents a challenge in the era of personalized medicine, as CFTR mutations lead to a variety of phenotypes, which likely require different, specific treatments. CF drug development is also complicated by the need to preserve the right balance between stability and flexibility, required for optimal function of the CFTR protein. In this review, we highlight how structural data can be exploited in this context to understand the molecular mechanisms of disease-associated mutations, to characterize the mechanisms of action of known modulators and to rationalize the search for novel, specific compounds...
October 30, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29096171/considerations-for-effect-site-pharmacokinetics-to-estimate-drug-exposure-concentrations-of-antibiotics-in-the-lung
#15
REVIEW
Keith A Rodvold, William W Hope, Sara E Boyd
Bronchoalveolar lavage (BAL) and microdialysis have become the most reliable and relevant methods for measuring lung concentrations of antibiotics, with the majority of BAL studies involving either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Emphasis on the amount of drug that reaches the site of infection is increasingly recognized as necessary to determine whether a dose selection will translate to good clinical outcomes in the treatment of patients with pneumonia. Observed concentrations and/or parameters of exposure (e...
October 30, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29096172/%C3%AE-lactamase-inhibitors-what-you-really-need-to-know
#16
REVIEW
Paul G Ambrose, Olga Lomovskaya, David C Griffith, Michael N Dudley, Brian VanScoy
The world is awash in antibiotic-resistant bacteria. The usefulness of nearly every antibacterial agent available in our hospital pharmacies has been compromised. About half of the recently approved antimicrobial agents for gram-negative pathogens, those pending approval, and those entering clinical development are β-lactam-β-lactamase inhibitor combinations. Thus, we are betting heavily on the efficacy and durability of these agents. However, one needs to be cognizant that poor dose regimen design can result in suboptimal efficacy, on-therapy resistance development, and resistance selection that may harm the activity of all β-lactam-β-lactamase inhibitor combinations...
October 27, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29102743/novel-designs-and-paradigms-to-study-the-placebo-response-in-gastroenterology
#17
REVIEW
Paul Enck, Younbyoung Chae, Sigrid Elsenbruch
The investigation of the placebo and the nocebo effect and their mechanisms has a rather short history of less than 20 years, especially in gastroenterology, and only the last 5 years have resulted in substantial improvement of understanding. Placebo refers to symptom improvement following a treatment, nocebo to the opposite, symptom worsening. Among the factors driving this progress are traditional psychological models derived from learning (conditioning) theory bridging into clinical science, new animal models to investigate the pharmacology of placebo analgesia, and novel study designs to overcome limitations of traditional randomized and placebo-controlled study designs in drug testing...
October 26, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29080476/corrector-combination-therapies-for-f508del-cftr
#18
REVIEW
John W Hanrahan, Elizabeth Matthes, Graeme Carlile, David Y Thomas
These are exciting times in the development of therapeutics for cystic fibrosis (CF). New correctors and potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) are being developed in academic laboratories and pharmaceutical companies, and the field is just beginning to understand their mechanisms of action. Studies of CFTR modulators are also yielding insight into the general principles and strategies that can be used when developing pharmacological chaperones, a new class of drugs. Combining two or even three correctors with a potentiator is an especially promising approach which should may lead to further improvements in efficacy and clinical benefit for patients...
October 25, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29073476/cftr-potentiators-from-bench-to-bedside
#19
REVIEW
Kang-Yang Jih, Wen-Ying Lin, Yoshiro Sohma, Tzyh-Chang Hwang
One major breakthrough in cystic fibrosis research in the past decade is the development of drugs that target the root cause of the disease-dysfunctional CFTR protein. One of the compounds, Ivacaftor or Kalydeco, which has been approved for clinical use since 2012, acts by promoting the gating function of CFTR. Our recent studies have led to a gating model that features an energetic coupling between NBD dimerization and gate opening/closing in CFTR's TMDs. Based on this model, we showed that ATP analogs can enhance CFTR gating by facilitating NBD dimerization, whereas Ivacaftor works by stabilizing the open channel conformation of the TMDs...
October 23, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29065356/bypassing-cftr-dysfunction-in-cystic-fibrosis-with-alternative-pathways-for-anion-transport
#20
REVIEW
Hongyu Li, Johanna J Salomon, David N Sheppard, Marcus A Mall, Luis Jv Galietta
One therapeutic strategy for cystic fibrosis (CF) seeks to restore anion transport to affected epithelia by targeting other apical membrane Cl(-) channels to bypass dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. The properties and regulation of the Ca(2+)-activated Cl(-) channel TMEM16A argue that long-acting small molecules which target directly TMEM16A are required to overcome CFTR loss. Through genetic studies of lung diseases, SLC26A9, a member of the solute carrier 26 family of anion transporters, has emerged as a promising target to bypass CFTR dysfunction...
October 21, 2017: Current Opinion in Pharmacology
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