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1.
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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2.
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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3.
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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4.
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.
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5.
Novel therapeutic targets in autoimmune hepatitis.
Taubert, R, Hupa-Breier, KL, Jaeckel, E, Manns, MP
Journal of autoimmunity. 2018;:34-46
Abstract
Autoimmune hepatitis (AIH) is an orphan disease characterized by an autoimmune attack against hepatocytes. The exact sequence of events that leads to a breach of tolerance is incompletely understood. Current hypotheses suggest that environmental agents such as toxins or infectious agents like viruses cause a tissue damage that initiates autoimmunity in genetically susceptible individuals. The growing knowledge of the multi-facetted immune dysregulation, which involves Th1/Th17 polarization and the suspected inability of regulatory T cells to revert autoimmunity in the otherwise tolerogenic milieu of the liver, offers multiple new therapeutic approaches and targets. Standard of care (SOC) is treatment with corticosteroids with or without azathioprine, which is sufficient to induce remission in the majority of patients. However, it rarely cures AIH or restores intrahepatic immune tolerance. Hence, life-long therapy is required in the majority of patients. In addition, several studies suggest a weakening of immune regulation mediated by intrahepatic T cells under current therapies. Furthermore, second line therapies for non-responders, intolerant or otherwise difficult to treat patients are urgently needed as this is relevant for at least one fifth of all patients with inefficacy or intolerance to SOC. Current second line therapies are mainly based on single center retrospective experiences and none of them have been approved by regulatory authorities for AIH, yet. This article highlights new therapeutic approaches based on our growing knowledge on the pathophysiology of AIH. It focuses on cell-based therapies that strengthen or restore immune tolerance. An additional focus lies on new therapeutic agents showing promising results in non-hepatic autoimmune diseases that have a potential for treating AIH. The dynamics in the whole field of innovative therapies for non-hepatic autoimmune diseases will hopefully improve the therapeutic armamentarium for AIH patients in the future.
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6.
Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target.
Janeiro, MH, Ramírez, MJ, Milagro, FI, Martínez, JA, Solas, M
Nutrients. 2018;(10)
Abstract
Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.
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7.
Vaccines Targeting PCSK9: A Promising Alternative to Passive Immunization with Monoclonal Antibodies in the Management of Hyperlipidaemia?
Weisshaar, S, Zeitlinger, M
Drugs. 2018;(8):799-808
Abstract
Hypercholesterolaemia is frequently observed in patients with cardiovascular diseases (CVD) and is associated with increased mortality. Statin treatment has been the standard of care for reducing low-density lipoprotein cholesterol (LDL-C) to improve cardiovascular outcomes. However, statins have limited effects in some patients and may be discontinued due to adverse effects resulting in LDL-C above target levels. The proprotein convertase subtilisin kexin type 9 (PCSK9) is a pivotal regulator in the LDL-C metabolism by degrading the LDL-C receptor on hepatocytes. Inhibition of PCSK9 by monoclonal antibodies (mAb) significantly lowers LDL-C levels and is considered to reduce the likelihood of adverse cardiac events. However, such treatment regimens are not cost-effective, and require frequent administrations at high doses that may be associated with side effects and poor drug adherence. Furthermore, it has been shown that these PCSK9 medicines may trigger the formation of antidrug antibodies followed by a significant attenuation of the LDL-C-lowering effect. Active vaccination inducing high-affinity antibodies against PCSK9 with less frequent administration intervals may be a novel promising therapeutic approach to overcome the drawback of passive immunization with PCSK9 mAb. However there is a paucity of available clinical safety and efficacy data. This article discusses challenges in the development of PCSK9 vaccines and their potential therapeutic benefits by reviewing clinical studies that evaluated the safety and efficacy of PCSK9 mAb.
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8.
G protein-coupled receptors as anabolic drug targets in osteoporosis.
Diepenhorst, N, Rueda, P, Cook, AE, Pastoureau, P, Sabatini, M, Langmead, CJ
Pharmacology & therapeutics. 2018;:1-12
Abstract
Osteoporosis is a progressive bone disorder characterised by imbalance between bone building (anabolism) and resorption (catabolism). Most therapeutics target inhibition of osteoclast-mediated bone resorption, but more recent attention in early drug discovery has focussed on anabolic targets in osteoblasts or their precursors. Two marketed agents that display anabolic properties, strontium ranelate and teriparatide, mediate their actions via the G protein-coupled calcium-sensing and parathyroid hormone-1 receptors, respectively. This review explores their activity, the potential for improved therapeutics targeting these receptors and other putative anabolic GPCR targets, including Smoothened, Wnt/Frizzled, relaxin family peptide, adenosine, cannabinoid, prostaglandin and sphingosine-1-phosphate receptors.
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9.
Targeted Therapy in Thyroid Cancer: State of the Art.
Valerio, L, Pieruzzi, L, Giani, C, Agate, L, Bottici, V, Lorusso, L, Cappagli, V, Puleo, L, Matrone, A, Viola, D, et al
Clinical oncology (Royal College of Radiologists (Great Britain)). 2017;(5):316-324
Abstract
Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation for differentiated tumours and treatment with thyrotropine hormone-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Cytotoxic chemotherapy or external beam radiotherapy has a low efficacy in these patients. 'Target therapy' with tyrosine kinase inhibitors (TKIs) represent an important therapeutic option for the treatment of advanced cases of radioiodine refractory (RAI-R) differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC) and possibly for cases of poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC). In the last few years, several TKIs have been tested for the treatment of advanced, progressive and RAI-R thyroid cancers and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC; vandetanib and cabozantinib for MTC. The objective of this overview is to present the current status of the treatment of advanced DTC, MTC, PDTC and ATC with the use of TKIs by describing the benefits and the limits of their use. A comprehensive analysis and description of the molecular basis of these drugs and the new therapeutic perspectives are also reported. Some practical suggestions are also given for the management to the potential side-effects of these drugs.
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10.
Description of the EuroTARGET cohort: A European collaborative project on TArgeted therapy in renal cell cancer-GEnetic- and tumor-related biomarkers for response and toxicity.
van der Zanden, LFM, Vermeulen, SH, Oskarsdottir, A, Maurits, JSF, Diekstra, MHM, Ambert, V, Cambon-Thomsen, A, Castellano, D, Fritsch, A, Garcia Donas, J, et al
Urologic oncology. 2017;(8):529.e9-529.e16
Abstract
OBJECTIVE For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort. METHODS AND MATERIALS EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses. RESULTS In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy. CONCLUSIONS Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available.