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Handbook of Experimental Pharmacology

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https://www.readbyqxmd.com/read/28332049/molecular-and-pharmacological-mechanisms-of-drug-resistance-an-evolving-paradigm
#1
Benedetta Colmegna, Lavinia Morosi, Maurizio D'Incalci
The high heterogeneity and genomic instability of malignant tumors explains why even responsive tumors contain cell clones that are resistant for many possible mechanisms involving intracellular drug inactivation, low uptake or high efflux of anticancer drugs from cancer cells, qualitative or quantitative changes in the drug target. Many tumors, however, are resistant because of insufficient exposure to anticancer drugs, due to pharmacokinetic reasons and inefficient and heterogeneous tumor drug distribution, related to a deficient vascularization and high interstitial pressure...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28332048/histamine-release-from-mast-cells-and-basophils
#2
Francesco Borriello, Raffaella Iannone, Gianni Marone
Mast cells and basophils represent the most relevant source of histamine in the immune system. Histamine is stored in cytoplasmic granules along with other amines (e.g., serotonin), proteases, proteoglycans, cytokines/chemokines, and angiogenic factors and rapidly released upon triggering with a variety of stimuli. Moreover, mast cell and basophil histamine release is regulated by several activating and inhibitory receptors. The engagement of different receptors can trigger different modalities of histamine release and degranulation...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28332047/mechanisms-of-resistance-to-target-therapies-in-non-small-cell-lung-cancer
#3
Francesco Facchinetti, Claudia Proto, Roberta Minari, Marina Garassino, Marcello Tiseo
Targeted therapies are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements, has changed the treatment landscape while improving the prognosis of lung cancer patients. Inevitably, virtually all patients initially treated with targeted therapies develop resistance because of the emergence of an insensitive cellular population, selected by pharmacologic pressure. Diverse mechanisms of resistance, in particular to EGFR, ALK and ROS1 tyrosine-kinase inhibitors (TKIs), have now been discovered and may be classified in three different groups: (1) alterations in the target (such as EGFR T790M and ALK or ROS1 mutations); (2) activation of alternative pathways (i...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28321587/analytical-methods-for-the-quantification-of-histamine-and-histamine-metabolites
#4
Heike Bähre, Volkhard Kaever
The endogenous metabolite histamine (HA) is synthesized in various mammalian cells but can also be ingested from exogenous sources. It is involved in a plethora of physiological and pathophysiological processes. So far, four different HA receptors (H1R-H4R) have been described and numerous HAR antagonists have been developed. Contemporary investigations regarding the various roles of HA and its main metabolites have been hampered by the lack of highly specific and sensitive analytic methods for all of these analytes...
March 21, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28315073/mechanisms-of-resistance-to-immune-checkpoint-antibodies
#5
Rodrigo N Ramos, Eliane Piaggio, Emanuela Romano
Immunotherapy using checkpoint inhibitors has changed the way we treat several aggressive cancers such as melanoma, non-small cell lung and head & neck cancers, among others, with durable responses achieved in the metastatic setting. However, unfortunately, the vast majority of patients do not respond to checkpoint inhibition therapy and a minority of patients, who do respond to treatment, develop secondary resistance and experience relapse by mechanisms still inadequately understood. Emerging evidence shows that alterations in multiple signaling pathways are involved in primary and/or secondary resistance to checkpoint inhibition...
March 18, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28315072/direct-myosin-activation-by-omecamtiv-mecarbil-for-heart-failure-with-reduced-ejection-fraction
#6
Mitchell A Psotka, John R Teerlink
Myosin is the indispensable molecular motor that utilizes chemical energy to produce force for contraction within the cardiac myocyte. Myosin activity is gated by intracellular calcium levels which are regulated by multiple upstream signaling cascades that can be altered for clinical utility using inotropic medications. In contrast to clinically available cardiac inotropes, omecamtiv mecarbil is a novel direct myosin activator developed to augment left ventricular systolic function without the undesirable secondary effects of altered calcium homeostasis...
March 18, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28315071/delta-opioid-receptor-and-peptide-a-dynamic-therapy-for-stroke-and-other-neurological-disorders
#7
M Grant Liska, Marci G Crowley, Trenton Lippert, Sydney Corey, Cesar V Borlongan
Research of the opioid system and its composite receptors and ligands has revealed its promise as a potential therapy for neurodegenerative diseases such as stroke and Parkinson's Disease. In particular, delta opioid receptors (DORs) have been elucidated as a therapeutically distinguished subset of opioid receptors and a compelling target for novel intervention techniques. Research is progressively shedding light on the underlying mechanism of DORs and has revealed two mechanisms of DOR neuroprotection; DORs function to maintain ionic homeostasis and also to trigger endogenous neuroprotective pathways...
March 18, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28315070/mechanisms-of-resistance-in-multiple-myeloma
#8
Athanasios Papadas, Fotis Asimakopoulos
Multiple myeloma (MM) is an incurable hematopoietic cancer that is characterized by malignant plasma cell infiltration of the bone marrow and/or extramedullary sites. Multi-modality approaches including "novel agents," traditional chemotherapy, and/or stem cell transplantation are used in MM therapy. Drug resistance, however, ultimately develops and the disease remains incurable for the vast majority of patients. In this chapter, we review both tumor cell-autonomous and non-autonomous (microenvironment-dependent) mechanisms of drug resistance...
March 18, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28275913/sigma-1-receptor-and-pain
#9
Manuel Merlos, Luz Romero, Daniel Zamanillo, Carlos Plata-Salamán, José Miguel Vela
There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy respect to existing therapies and/or reduce their unwanted effects. Current preclinical evidence supports the modulatory role of the sigma-1 receptor (σ1R) in nociception, mainly based on the pain-attenuated phenotype of σ1R knockout mice and on the antinociceptive effect exerted by σ1R antagonists on pain of different etiology, very consistently in neuropathic pain, but also in nociceptive, inflammatory, and visceral pain...
March 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28275912/mechanisms-of-resistance-to-targeted-therapies-in-chronic-lymphocytic-leukemia
#10
Francesca Arruga, Silvia Deaglio
Even if treatment options for Chronic Lymphocytic Leukemia (CLL) patients have changed dramatically in the past few years, with the approval of targeted therapeutic agents, the disease remains incurable. Beside intrinsic genetic features characterizing the leukemic cell, signals coming from the microenvironment have a key role in promoting cell survival and in protecting CLL cells from the action of drugs. Consequently, the identification of previously unrecognized genetic lesions is important in risk-stratification of CLL patients and is progressively becoming a critical tool for choosing the best therapeutic strategy...
March 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28275911/sigma-1-%C3%AF-1-receptor-in-memory-and-neurodegenerative-diseases
#11
Tangui Maurice, Nino Goguadze
The sigma-1 (σ1) receptor has been associated with regulation of intracellular Ca(2+) homeostasis, several cellular signaling pathways, and inter-organelle communication, in part through its chaperone activity. In vivo, agonists of the σ1 receptor enhance brain plasticity, with particularly well-described impact on learning and memory. Under pathological conditions, σ1 receptor agonists can induce cytoprotective responses. These protective responses comprise various complementary pathways that appear to be differentially engaged according to pathological mechanism...
March 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28275910/mechanisms-of-drug-resistance-in-melanoma
#12
Matthew Winder, Amaya Virós
Metastatic melanoma is associated with poor outcome and is largely refractory to the historic standard of care. In recent years, the development of targeted small-molecule inhibitors and immunotherapy has revolutionised the care and improved the overall survival of these patients. Therapies targeting BRAF and MEK to block the mitogen-activated protein kinase (MAPK) pathway were the first to show unprecedented clinical responses. Following these encouraging results, antibodies targeting immune checkpoint inhibition molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD)-1, and PD-ligand1(PD-L1) demonstrated sustained tumour regression in a significant subset of patients by enabling an anti-tumour immunologic response...
March 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28275909/sigma-1-receptor-and-neuronal-excitability
#13
Saïd Kourrich
The sigma-1 receptor (Sig-1R), via interaction with various proteins, including voltage-gated and ligand-gated ion channels (VGICs and LGICs), is involved in a plethora of neuronal functions. This capability to regulate a variety of ion channel targets endows the Sig-1R with a powerful capability to fine tune neuronal excitability, and thereby the transmission of information within brain circuits. This versatility may also explain why the Sig-1R is associated to numerous diseases at both peripheral and central levels...
March 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28251365/mitochondria-in-alzheimer-s-disease-and-diabetes-associated-neurodegeneration-license-to-heal
#14
Susana M Cardoso, Sónia C Correia, Cristina Carvalho, Paula I Moreira
Alzheimer's disease (AD) is a difficult puzzle to solve, in part because the etiology of this devastating neurodegenerative disorder remains murky. However, diabetes has been pinpointed as a major risk factor for the sporadic forms of AD. Several overlapping neurodegenerative mechanisms have been identified between AD and diabetes, including mitochondrial malfunction. This is not surprising taking into account that neurons are cells with a complex morphology, long lifespan, and high energetic requirements which make them particularly reliant on a properly organized and dynamic mitochondrial network to sustain neuronal function and integrity...
March 2, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28238077/immunotolerance-as-a-mechanism-of-resistance-to-targeted-therapies-in-melanoma
#15
Mario Mandalà, Daniela Massi
The therapy of metastatic melanoma (MM) was radically changed by the introduction of inhibitors of BRAF, an oncogene mutated in ≈40-50% of patients. Oncogenic BRAF promotes an immune-compromised tumour microenvironment (TME). Inhibition of MAPK pathway signaling with BRAF (BRAFi) and MEK inhibitors (MEKi) attenuates immune escape and increases the melanoma immunogenicity through multiple mechanisms, including elevation of melanoma antigen expression and improved T cell infiltration and function. These changes sustain the TME for response to immunotherapy...
February 26, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28238076/delta-opioid-receptors-and-cardioprotection
#16
Louise See Hoe, Hemal H Patel, Jason N Peart
The opioid receptor family, with associated endogenous ligands, has numerous roles throughout the body. Moreover, the delta opioid receptor (DORs) has various integrated roles within the physiological systems, including the cardiovascular system. While DORs are important modulators of cardiovascular autonomic balance, they are well-established contributors to cardioprotective mechanisms. Both endogenous and exogenous opioids acting upon DORs have roles in myocardial hibernation and protection against ischaemia-reperfusion (I-R) injury...
February 26, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28236087/gastrointestinal-pharmacology
#17
Miguel Saps, Adrian Miranda
There is little evidence for most of the medications currently used to treat functional abdominal pain disorders (FAPDs) in children. Not only are there very few clinical trials, but also most have significant variability in the methods used and outcomes measured. Thus, the decision on the most appropriate pharmacological treatment is frequently based on adult studies or empirical data. In children, peppermint oil, trimebutine, and drotaverine have shown significant benefit compared with placebo, each of them in a single randomized clinical trial...
February 25, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28233185/clinical-development-of-histamine-h4-receptor-antagonists
#18
Robin L Thurmond, Jennifer Venable, Brad Savall, David La, Sandra Snook, Paul J Dunford, James P Edwards
The discovery of the histamine H4 receptor (H4R) provided a new avenue for the exploration of the physiological role of histamine, as well as providing a new drug target for the development of novel antihistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the H4R relative to other histamine receptors. The discovery of the selective H4R antagonist JNJ 7777120 was vital for showing a role for the H4R in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies...
February 24, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28233184/inflammatory-bowel-disease-pathophysiology-and-current-therapeutic-approaches
#19
Bincy P Abraham, Tasneem Ahmed, Tauseef Ali
Inflammatory bowel diseases, most commonly categorized as Crohn's disease and ulcerative colitis, are immune mediated chronic inflammatory disorders of the gastrointestinal tract. The etiopathogenesis is multifactorial with different environmental, genetic, immune mediated, and gut microbial factors playing important role. The current goals of therapy are to improve clinical symptoms, control inflammation, prevent complications, and improve quality of life. Different therapeutic agents, with their indications, mechanisms of action, and side effects are discussed in this chapter...
February 24, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28233183/leber-hereditary-optic-neuropathy-exemplar-of-an-mtdna-disease
#20
Douglas C Wallace, Marie T Lott
The report in 1988 that Leber Hereditary Optic Neuropathy (LHON) was the product of mitochondrial DNA (mtDNA) mutations provided the first demonstration of the clinical relevance of inherited mtDNA variation. From LHON studies, the medical importance was demonstrated for the mtDNA showing its coding for the most important energy genes, its maternal inheritance, its high mutation rate, its presence in hundreds to thousands of copies per cell, its quantitatively segregation of biallelic genotypes during both mitosis and meiosis, its preferential effect on the most energetic tissues including the eye and brain, its wide range of functional polymorphisms that predispose to common diseases, and its accumulation of mutations within somatic tissues providing the aging clock...
February 24, 2017: Handbook of Experimental Pharmacology
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