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1.
Targeting the Thioredoxin System as a Strategy for Cancer Therapy.
Bian, M, Fan, R, Zhao, S, Liu, W
Journal of medicinal chemistry. 2019;(16):7309-7321
Abstract
Thioredoxin reductase (TrxR) participates in the regulation of redox reactions in organisms. It works mainly via its substrate molecule, thioredoxin, to maintain the redox balance and regulate signal transduction, which controls cell proliferation, differentiation, death, and other important physiological processes. In recent years, increasing evidence has shown that the overactivation of TrxR is related to the development of tumors. The exploration of TrxR-targeted antitumor drugs has attracted wide attention and is expected to provide new therapies for cancer treatment. In this perspective, we highlight the specific relationship between TrxR and apoptotic signaling pathways. The cytoplasm and mitochondria both contain TrxR, resulting in the activation of apoptosis. TrxR activity influences reactive oxygen species (ROS) and further regulates the inflammatory signaling pathway. In addition, we discuss representative TrxR inhibitors with anticancer activity and analyze the challenges in developing TrxR inhibitors as anticancer drugs.
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2.
Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a narrative review.
Hermanns, H, Hollmann, MW, Stevens, MF, Lirk, P, Brandenburger, T, Piegeler, T, Werdehausen, R
British journal of anaesthesia. 2019;(3):335-349
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Abstract
Systemic administration of the local anaesthetic lidocaine is antinociceptive in both acute and chronic pain states, especially in acute postoperative and chronic neuropathic pain. These effects cannot be explained by its voltage-gated sodium channel blocking properties alone, but the responsible mechanisms are still elusive. This narrative review focuses on available experimental evidence of the molecular mechanisms by which systemic lidocaine exerts its clinically documented analgesic effects. These include effects on the peripheral nervous system and CNS, where lidocaine acts via silencing ectopic discharges, suppression of inflammatory processes, and modulation of inhibitory and excitatory neurotransmission. We highlight promising objectives for future research to further unravel these antinociceptive mechanisms, which subsequently may facilitate the development of new analgesic strategies and therapies for acute and chronic pain.
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3.
Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities.
Krogmann, A, Peters, L, von Hardenberg, L, Bödeker, K, Nöhles, VB, Correll, CU
CNS spectrums. 2019;(S1):38-69
Abstract
Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation. This review evaluates new/emerging pharmacological treatments for schizophrenia. Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved by U.S. Food and Drug Administration, and positive results were announced for Risperidone ISM®, each achieving therapeutic levels within 24 hours, without need for initial oral cotreatment/loading injection-strategies. Paliperidone palmitate 6-monthly intramuscularly injectable and Risperidone subcutaneously injectable TV46000 are currently under investigation. Finally, the samidorphan+olanzapine combination targets reduced weight gain liability, while maintaining olanzapine's efficacy. Most of these trial programs are still ongoing or have yielded mixed or even negative results. Thus, additional mechanisms of action and agents require study to improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, but also cognitive symptoms, negative symptoms, and treatment resistance, the areas of greatest need in schizophrenia currently.
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4.
Pharmacological plasticity-How do you hit a moving target?
Parnham, MJ, Geisslinger, G
Pharmacology research & perspectives. 2019;(6):e00532
Abstract
Paul Ehrlich's concept of the magic bullet, by which a single drug induces pharmacological effects by interacting with a single receptor has been a strong driving force in pharmacology for a century. It is continually thwarted, though, by the fact that the treated organism is highly dynamic and the target molecule(s) is (are) never static. In this article, we address some of the factors that modify and cause the mobility and plasticity of drug targets and their interactions with ligands and discuss how these can lead to unexpected (lack of) effects of drugs. These factors include genetic, epigenetic, and phenotypic variability, cellular plasticity, chronobiological rhythms, time, age and disease resolution, sex, drug metabolism, and distribution. We emphasize four existing approaches that can be taken, either singly or in combination, to try to minimize effects of pharmacological plasticity. These are firstly, to enhance specificity using target conditions close to those in diseases, secondly, by simultaneously or thirdly, sequentially aiming at multiple targets, and fourthly, in synchronization with concurrent dietary, psychological, training, and biorhythm-synchronizing procedures to optimize drug therapy.
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Pathophysiology of eosinophilic esophagitis: recent advances and their clinical implications.
Ruffner, MA, Kennedy, K, Cianferoni, A
Expert review of clinical immunology. 2019;(1):83-95
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Abstract
Introduction: Diagnostic and therapeutic strategies in eosinophilic esophagitis (EoE) are evolving. New knowledge regarding the pathophysiology of EoE has been the foundation for updated diagnostic recommendations and new therapeutic trials. Areas covered: We performed structured literature searches in Medline and PubMed, Cochrane meta-analyses, and abstracts of international congresses to review therapeutic approaches for EoE in July 2018. Additional articles were obtained by perusing the references of articles identified in the original PubMed search. Articles were excluded if they did not focus on the mechanism of disease, diagnosis, or treatment of humans with EoE. Expert commentary: Recent advances in the understanding of mechanisms underlying the pathology of EoE have resulted in significant change in the diagnostic algorithm for EoE, and are identifying promising potential targets for personalized medicine. There is a clinical need for improved targeted therapy for EoE, and better understanding the underlying pathophysiology of EoE will help to determine therapeutic targets. In this review, we highlight key mechanisms in the pathophysiology of EoE and how they are being utilized to change therapy in EoE.
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Effectiveness of ivacaftor in cystic fibrosis patients with non-G551D gating mutations.
Guimbellot, J, Solomon, GM, Baines, A, Heltshe, SL, VanDalfsen, J, Joseloff, E, Sagel, SD, Rowe, SM, ,
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2019;(1):102-109
Abstract
BACKGROUND The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator ivacaftor is approved for patients with CF with gating and residual function CFTR mutations. We report the results of an observational study investigating its effects in CF patients with non-G551D gating mutations. METHODS Patients with non-G551D gating mutations were recruited to an open-label study evaluating ivacaftor. Primary outcomes included: lung function, sweat chloride, weight gain, and quality of life scores. RESULTS Twenty-one subjects were enrolled and completed 6 months follow-up on ivacaftor; mean age was 25.6 years with 52% <18. Baseline ppFEV1 was 68% and mean sweat chloride 89.6 mEq/L. Participants experienced significant improvements in ppFEV1 (mean absolute increase of 10.9% 95% CI = [2.6,19.3], p = 0.0134), sweat chloride (-48.6 95% CI = [-67.4,-29.9], p < 0.0001), and weight (5.1 kg, 95% CI = [2.8, 7.3], p = 0.0002). CONCLUSIONS Patients with non-G551D gating mutations experienced improved lung function, nutritional status, and quality of life. This study supports ongoing use of ivacaftor for patients with these mutations.
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RNA-targeted therapeutics for lipid disorders.
Tsimikas, S
Current opinion in lipidology. 2018;(6):459-466
Abstract
PURPOSE OF REVIEW To summarize recent developments in the field of RNA-directed therapeutics targeting lipid disorders that are not effectively managed. RECENT FINDINGS Despite a number of approved therapies for lipid disorders, significant unmet needs are present in treating persistently elevated LDL-cholesterol, remnant-cholesterol, triglycerides and lipoprotein(a) [Lp(a)]. Small molecules and antibodies are effective modalities, but they are unable to adequately treat many patients with abnormal lipid parameters. Targeting mRNA with oligonucleotides to prevent protein translation is a relatively novel method to reduce circulating atherogenic lipoproteins. Small inhibiting RNA (siRNA) molecules targeting proprotein convertase subtilisin kexin type 9 to reduce LDL-C, and antisense oligonucleotides (ASO) targeting apolipoprotein C-III (apoC-III) to reduce triglycerides, angiopoietin-like 3 (ANGPTL3) to reduce LDL-C and triglycerides and apolipoprotein(a) (LPA) to reduce Lp(a) are currently in or just completed phase 1-3 trials. Fundamental differences exist in chemistry, delivery and mechanism of action of siRNA and ASOs. SUMMARY Novel RNA therapeutics are poised to provide highly potent, specific and effective therapies to reduce atherogenic lipoproteins. As these compounds are approved, clinicians will be able to choose from a broad armamentarium to treat nearly all patients to acceptable goals in order to reduce risk of cardiovascular disease and events.
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DA-9701 (Motilitone): A Multi-Targeting Botanical Drug for the Treatment of Functional Dyspepsia.
Jin, M, Son, M
International journal of molecular sciences. 2018;(12)
Abstract
Functional dyspepsia (FD) is the most common functional gastrointestinal disorder (FGID). FD is characterized by bothersome symptoms such as postprandial fullness, early satiety, and epigastric pain or burning sensations in the upper abdomen. The complexity and heterogeneity of FD pathophysiology, which involves multiple mechanisms, make both treatment and new drug development for FD difficult. Current medicines for FD targeting a single pathway have failed to show satisfactory efficacy and safety. On the other hand, multicomponent herbal medicines that act on multiple targets may be a promising alternative treatment for FD. DA-9701 (Motilitone), a botanical drug consisting of Corydalis Tuber and Pharbitidis Semen, has been prescribed for FD since it was launched in Korea in 2011. It has multiple mechanisms of action such as prokinetic effects, fundus relaxation, and visceral analgesia, which are mediated by dopamine D₂ and several serotonin receptors involved in gastrointestinal (GI) functions. In clinical studies, DA-9701 has been found to be beneficial for improvement of FD symptoms and GI functions in FD patients, while showing better safety compared to that associated with conventional medicines. In this review, we provide updated information on the pharmacological effects, safety, and clinical results of DA-9701 for the treatment of FGIDs.
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Acquired low cholesterol: diagnosis and relevance to safety of low LDL therapeutic targets.
Soran, H, Ho, JH, Durrington, PN
Current opinion in lipidology. 2018;(4):318-326
Abstract
PURPOSE OF REVIEW Acquired hypocholesterolaemia occurs more commonly than inherited hypocholesterolaemia but has received little attention in the literature. In this review, we discuss the causes and underlying mechanisms of acquired hypocholesterolaemia and its relevance to safety of therapeutically induced decreased LDL cholesterol levels. RECENT FINDINGS Hypocholesterolaemia is increasingly identified as cholesterol testing becomes more widespread in the assessment of cardiovascular risk. Lower therapeutic targets for LDL cholesterol are also being achieved more regularly with the introduction of more intensive cholesterol-lowering regimens. Acquired hypocholesterolaemia may be the presenting feature of treatable diseases. Understanding its mechanisms may also provide new treatment approaches for neoplastic disease, such as breast cancer, and infections, such as tuberculosis. SUMMARY When hypocholesterolaemia is discovered, it is important to identify its cause. Further research into the pathogenesis of hypocholesterolaemia may provide new therapies for primary diseases underlying it.
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Postprandial remnant lipoproteins as targets for the prevention of atherosclerosis.
Nakajima, K, Tanaka, A
Current opinion in endocrinology, diabetes, and obesity. 2018;(2):108-117
Abstract
PURPOSE OF REVIEW Oxidized low-density lipoprotein (Ox-LDL) and chylomicron remnants were previously proposed as the most atherogenic lipoproteins for the causal lipoproteins of atherosclerosis. However, there are still controversies on these hypothesizes. Therefore, we have proposed a new hypothesis based on our recent findings of remnant lipoproteins (RLPs) in postprandial plasma. RECENT FINDINGS Plasma RLP-C and RLP-TG increased significantly after fat load. More than 80% of the increased triglycerides after fat load consisted of the triglycerides in RLP, which contained greater amount of apoB100 than apoB48 particles as mostly very low density lipoproteins (VLDL) remnants. The majority of lipoprotein lipase (LPL) in plasma was found in RLP as RLP-LPL complex, which is released into circulation after hydrolysis. LPL activity and concentration in plasma did not increase after food intake associated with the insufficient hydrolysis of chylomicrons and VLDL and resulted in the significant increase of RLP-TG. Plasma LPL was inversely correlated with RLP particle size and number. SUMMARY VLDL remnants have been shown as the major atherogenic lipoproteins in postprandial plasma associated with LPL activity as the targets for prevention of atherosclerosis. We also proposed a new definition of RLPs, 'LPL bound TG-rich lipoproteins' based on the findings of RLP-LPL complex.