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Current Opinion in Pharmacology

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https://www.readbyqxmd.com/read/28807483/the-potential-efficacy-of-gabab-antagonists-in-depression
#1
REVIEW
Robert C Alexander
Evidence for the potential utility of GABAB antagonists has been assembled from a variety of sources, including clinical experience with the GABAB agonist baclofen, murine genetic GABAB knock-outs, rodent studies of GABAB receptor expression and function following treatment with antidepressant therapies, animal models of depression, and some functional and post mortem data from human subjects. Definitive testing of GABAB antagonists in depression, however, still awaits the development of potent, selective and brain-penetrant compounds for human testing...
August 11, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28806581/engineered-systems-for-therapeutic-angiogenesis
#2
REVIEW
Shane Browne, Abhay Pandit
Ischemic disease caused by insufficient blood supply leads to a lack of oxygen and nutrients and a build-up of waste products in the affected tissue. Therapeutic angiogenesis, as a means to enhance perfusion of tissues with an inadequate blood supply, holds great promise for the treatment of ischemic disease. A wide range of factors that play a key role in physiological angiogenesis have been identified and trialed as pro-angiogenic agents. However, as yet pro-angiogenic treatments have failed to be translated clinically, owing to both lack of efficacy and safety concerns regarding the use of doses considerably larger than is typical present under physiological conditions...
August 11, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28803835/receptor-distribution-studies
#3
REVIEW
Renzo Carletti, Stefano Tacconi, Manolo Mugnaini, Philip Gerrard
Receptor distribution studies have played a key role in the characterization of receptor systems (e.g. GABAB, NMDA (GluNRs), and Neurokinin 1) and in generating hypotheses to exploit these systems as potential therapeutic targets. Distribution studies can provide important information on the potential role of candidate receptors in normal physiology/disease and alert for possible adverse effects of targeting the receptors. Moreover, they can provide valuable information relating to quantitative target engagement (e...
August 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28802874/targeting-gastrointestinal-nutrient-sensing-mechanisms-to-treat-obesity
#4
REVIEW
Mariana Norton, Kevin G Murphy
Gut hormones have important roles in the regulation of appetite and glucose homeostasis. Understanding how macronutrient sensing in the gastrointestinal tract modulates gut hormone release may reveal novel pharmacological or dietary approaches to metabolic disease. In this short review we discuss the mechanisms by which the gut senses macronutrients and the products of macronutrient digestion, and their putative utility in treating obesity and related conditions.
August 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28802873/gut-check-on-diabesity-leveraging-gut-mechanisms-for-the-treatment-of-type-2-diabetes-and-obesity
#5
REVIEW
Sarah Will, David C Hornigold, David J Baker, Matthew P Coghlan, Malcolm Mesquita, James L Trevaskis, Jacqueline Naylor
Gut hormones have long been understood to regulate food intake and metabolism. Bariatric surgery significantly elevates circulating gut hormone levels and is proven to affect acute remission of type 2 diabetes before any weight loss is observed. Subsequent weight loss is accrued over weeks to months but is sustained into the long term. Hence, there exists great enthusiasm to recapitulate these changes in gut hormones in the form of novel combination drugs for type 2 diabetes and obesity.
August 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28802779/pharmacological-aspects-of-closed-loop-insulin-delivery-for-type-1-diabetes
#6
REVIEW
Chukwuma Uduku, Nick Oliver
Insulin deficiency and impaired glucose homeostasis are hallmarks of type 1 diabetes. Since the discovery of insulin, pharmacological and clinical developments have endeavoured to replicate its endogenous pharmacokinetics (PK) and pharmacodynamics (PD). Closed loop insulin delivery systems operate as an artificial pancreas by making automated insulin dose adjustments based on real time continuous glucose monitoring. The increasing adoption of continuous insulin pump therapy and evolving technological advances have seen significant progress in the development of closed loop insulin delivery systems...
August 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28800417/buccal-delivery-of-small-molecules-and-biologics-of-mucoadhesive-polymers-films-and-nanoparticles
#7
REVIEW
Javier O Morales, David J Brayden
Buccal delivery of macromolecules (biologics) sets a great challenge for researchers. Although several niche small molecule products have been approved as simple sprays, tablets and oral films, it is not simply a case of adapting existing technologies to biologics. Buccal delivery of insulin has reached clinical trials with two approaches: oromucosal sprays of the peptide with permeation enhancers, and embedded gold nanoparticles in a dissolvable film. However, neither of these approaches have led to FDA approvals likely due to poor efficacy, submaximal peptide loading in the dosage form, and to wide intra-subject variability in pharmacokinetics and pharmacodynamics...
August 8, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28800407/human-brown-adipose-tissue-function-and-therapeutic-potential-in-metabolic-disease
#8
REVIEW
Padmanabh Shrikant Bhatt, Waljit S Dhillo, Victoria Salem
There has been a resurgence of interest in brown adipose tissue (BAT) over the last decade. Key to this has been our ability to accurately image it, which has improved significantly. The role of BAT in regulating energy expenditure is important, and its pharmacological manipulation may hold therapeutic potential in metabolic disease. There is ample evidence of BAT activation by cold exposure, and pharmacological utilisation of similar pathways, using B3 receptor agonists holds promise since the development of selective agonists with limited cross-reactivity has rekindled interest...
August 8, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28781107/epileptogenesis-meets-occam-s-razor
#9
REVIEW
Robert S Sloviter
Pharmacological treatment to prevent brain injury-induced temporal lobe epileptogenesis has been generally unsuccessful, raising the issues of exactly when the conversion process to an epileptic brain state occurs and reaches completion, and which cellular or network processes might be the most promising therapeutic targets. The time course of epileptogenesis is a central issue, with recent results suggesting that injury-induced epileptogenesis can be a much more rapid process than previously thought, and may be inconsistent with a delayed epileptogenic mechanism...
August 3, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28780407/microneedles-for-enhanced-transdermal-and-intraocular-drug-delivery
#10
REVIEW
Kurtis Moffatt, Yujing Wang, Thakur Raghu Raj Singh, Ryan F Donnelly
Microneedle mediated delivery based research has garnered great interest in recent years. In the past, the initial focus was delivery of macromolecules of biological origin, however the field has now broadened its scope to include transdermal delivery of conventional low molecular weight drug molecules. Great success has been demonstrated utilising this approach, particularly in the field of vaccine delivery. Current technological advances have permitted an enhancement in design formulation, allowing delivery of therapeutic doses of small molecule drugs and biomolecules, aided by larger patch sizes and scalable manufacture...
August 3, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28779684/oral-delivery-of-biologics-using-drug-device-combinations
#11
REVIEW
Ester Caffarel-Salvador, Alex Abramson, Robert Langer, Giovanni Traverso
Orally administered devices could enable the systemic uptake of biologic therapeutics by engineering around the physiological barriers present in the gastrointestinal (GI) tract. Such devices aim to shield cargo from degradative enzymes and increase the diffusion rate of medication through the GI mucosa. In order to achieve clinical relevance, these designs must significantly increase systemic drug bioavailability, deliver a clinically relevant dose and remain safe when taken frequently. Such an achievement stands to reduce our dependence on needle injections, potentially increasing patient adherence and reducing needle-associated complications...
August 2, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28743034/therapeutic-advances-in-musculoskeletal-aav-targeting-approaches
#12
REVIEW
Karen Bulaklak, Xiao Xiao
The use of recombinant adeno-associated viruses (rAAVs) is highly prevalent in musculoskeletal gene therapies due to their versatility, high transduction efficiency, natural tropism and vector genome persistence for years. As the largest organ in the body, treatment of skeletal muscle for widespread and sufficient therapeutic gene expression is highly challenging. In addition to disease-specific hurdles, vector genome loss, off-target gene transfer and immune responses to treatment can diminish the overall benefit of rAAV therapies...
July 22, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28734136/the-good-and-bad-of-targeting-cancer-associated-extracellular-matrix
#13
REVIEW
Sabina Sangaletti, Claudia Chiodoni, Claudio Tripodo, Mario P Colombo
The maintenance of tissue homeostasis requires extracellular matrix (ECM) remodeling. Immune cells actively participate in regenerating damaged tissues contributing to ECM deposition and shaping. Dysregulated ECM deposition characterizes fibrotic diseases and cancer stromatogenesis, where a chronic inflammatory state sustains the ECM increase. In cancer, the ECM fosters several steps of tumor progression, providing pro-survival and proliferative signals, promoting tumor cell dissemination via collagen fibers or acting as a barrier to impede drug diffusion...
July 19, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28688237/antibacterial-drug-development-program-successes-and-failures-a-pharmacometric-explanation
#14
REVIEW
Paul G Ambrose
My thesis is a simple one. We have not been doing a good enough job selecting dose regimens for serious infections during the drug development process. If we are to do a better job in the future, we need to revisit some uncomfortable places. That is, some notable program failures. To be clear, we are not revisiting program failures to make anyone uncomfortable or cast aspersions - but rather so that we sow the seeds for a better future. To that end, we will examine program failures and successes through a pharmacometric lens...
July 5, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28623714/can-the-co-dependence-of-the-immune-system-and-angiogenesis-facilitate-pharmacological-targeting-of-tumours
#15
REVIEW
Lorenzo Mortara, Andrew V Benest, David O Bates, Douglas M Noonan
Tumours elicit a number of mechanisms to induce a reprogramming of innate and adaptive immune cells to their advantage, inducing a pro-angiogenic phenotype. Investigation of these events is now leading to the identification of specific myeloid and lymphoid cell-targeted therapies, as well as of unexplored off-target activities of clinically relevant chemotherapeutic and metabolic drugs. It is also leading to an enhanced understanding of the interplay between angiogenesis and the immune system, and the value of novel co-targeting approaches using both immunotherapy and anti-angiogenic therapy...
June 14, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28618326/inflammation-as-target-in-cancer-therapy
#16
REVIEW
Giulia Marelli, Antonio Sica, Luca Vannucci, Paola Allavena
Cells of the innate immunity infiltrating tumour tissues promote, rather than halt, cancer cell proliferation and distant spreading. Tumour-Associated Macrophages (TAMs) are abundantly present in the tumour milieu and here trigger and perpetrate a state of chronic inflammation which ultimately supports disease development and contributes to an immune-suppressive environment. Therapeutic strategies to limit inflammatory cells and their products have been successful in pre-clinical tumour models. Early clinical trials with specific cytokine and chemokine inhibitors, or with strategies designed to target TAMs, are on their way in different solid malignancies...
June 12, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28609681/epigenetic-modulation-in-cancer-immunotherapy
#17
REVIEW
Stuart J Gallagher, Elena Shklovskaya, Peter Hersey
The success of immune checkpoint inhibitors in cancer immunotherapy has been widely heralded. However many cancer patients do not respond to immune checkpoint therapy and some relapse due to acquired tumor resistance. Epigenetic targeting may be beneficial in cancer immunotherapy by reversing immune avoidance and escape mechanisms employed by cancer cells, as well as by modulating immune cell differentiation and function. In this manuscript we review recent findings suggesting how epigenetics may be used to improve cancer immunotherapy...
June 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28605657/muscle-as-a-paracrine-and-endocrine-organ
#18
REVIEW
Jimena Giudice, Joan M Taylor
Skeletal muscle cells are highly abundant and metabolically active and are known to 'communicate' their energy demands to other organs through active secretion. Muscle-derived secretory proteins include a variety of cytokines and peptides collectively referred to as 'myokines' that exert autocrine, paracrine or endocrine effects. Analyses of the skeletal muscle secretome revealed that numerous myokines are secreted in response to contraction or strength training, and that these factors not only regulate energy demand but also contribute to the broad beneficial effects of exercise on cardiovascular, metabolic, and mental health...
June 9, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28577499/leukocyte-trafficking-in-tumor-microenvironment
#19
REVIEW
Annalisa Del Prete, Tiziana Schioppa, Laura Tiberio, Helena Stabile, Silvano Sozzani
The tumor microenvironment consists of both malignant and non-malignant cells and a plethora of soluble mediators. Different types of tumors have specific tumor microenvironments characterized by distinct chemokines and chemotactic factors that influence leukocyte recruitment. The immune cell infiltrate continuously interacts with stroma cells and influence tumor growth. Emerging evidence suggests that the regulation of the composition and the metabolic state of tumor-associated leukocytes may represent a new promising intervention strategy...
May 31, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28554057/the-immune-regulation-in-cancer-by-the-amino-acid-metabolizing-enzymes-arg-and-ido
#20
REVIEW
Giada Mondanelli, Stefano Ugel, Ursula Grohmann, Vincenzo Bronte
Some enzymes degrading amino acids have evolved in mammals to dampen immune responses and maintain peripheral tolerance. The enzymes metabolizing l-arginine and l-tryptophan are particularly powerful, contributing to restrain immunity towards fetal tissues and establish neonatal tolerance. Solid tumors can hijack these formidable pathways to construct a microenvironment highly unfavorable to anti-tumor T lymphocytes able to recognize them, one of mechanisms for their immune evasion. In this review, we analyze emerging concepts in the cross-talk between cells expressing these enzymes, their immune regulatory functions and pharmacological approaches that can target them to enhance cancer immunotherapy...
May 26, 2017: Current Opinion in Pharmacology
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