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Protein Solvent Interaction: Transition of Protein-solvent Interaction Concept from Basic Research into Solvent Manipulation of Chromatography.
Arakawa, T, Kita, Y
Current protein & peptide science. 2019;(1):34-39
Abstract
Previously, we have reviewed in this journal (Arakawa, T., Kita, Y., Curr. Protein Pept. Sci., 15, 608-620, 2014) the interaction of arginine with proteins and various applications of this solvent additive in the area of protein formulations and downstream processes. In this special issue, we expand the concept of protein-solvent interaction into the analysis of the effects of solvent additives on various column chromatography, including mixed-mode chromatography. Earlier in our research, we have studied the interactions of such a variety of solvent additives as sugars, salts, amino acids, polymers and organic solvents with a variety of proteins, which resulted in mechanistic understanding on their protein stabilization and precipitation effects, the latter known as Hofmeister series. While such a study was then a pure academic research, rapid development of genetic engineering technologies and resultant biotechnologies made it a valuable knowledge in fully utilizing solvent additives in manipulation of protein solution, including column chromatography.
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2.
Maneuvering Clinical Pathways for Crohn's Disease.
Lu, TX, Cohen, RD
Current gastroenterology reports. 2019;(5):20
Abstract
PURPOSE OF REVIEW Crohn's disease management has changed significantly with increasing use of biologics. We review the recent literature on the clinical management of Crohn's disease and new approaches in selecting and optimizing therapy. RECENT FINDINGS Recent studies have addressed the efficacy of proactive anti-TNFα trough level monitoring, the efficacy of biosimilars, and the efficacy and immunogenicity of newer biologics including anti-integrin therapy and anti-IL12/23 therapy. Optimizing anti-TNFα therapy according to trough concentrations correlates with improved remission rates. Patients can be switched from the reference drug to a biosimilar, or vice versa, without a measurable change in efficacy, safety, or immunogenicity. Immunomodulators are effective in decreasing immunogenicity and boosting anti-TNFα drug level. The anti-integrin and anti-IL12/23 therapies are effective as induction and maintenance therapy with low immunogenicity and excellent safety profiles. Patients at high risk for post-operative recurrence should be started on a biologic therapy within 4 weeks post-op. Multiple biologic therapies are currently available for treatment of Crohn's disease including anti-TNFα therapy, anti-integrin therapy, and anti-IL12/23 therapy. The choice of first-line therapy should be based on individual risk-benefit analysis, route of administration, and patient preference. Patient with inadequate response should have their trough level checked and therapy optimized. Therapeutic prophylaxis for post-operative recurrence should be based on patient's risk factors for recurrence.
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3.
[PCSK9 inhibitors: What place in the management of dyslipidemia?].
Sabouret, P, Farnier, M, Puymirat, E
Presse medicale (Paris, France : 1983). 2019;(3 Pt 1):227-237
Abstract
PCSK9 protein is a key regulator of LDL receptor activity. Gain-of-function mutations in PCSK9 are one of the genetic causes of familial hypercholesterolemia. Conversely, loss-of-function mutations are associated with lower levels of LDL cholesterol and reduced coronary heart disease. Monoclonal antibodies targeting PCSK9 are highly efficacious in lowering LDL-C levels, with a good tolerability and safety profile. Two PCSK9 inhibitors, alirocumab and evolocumab, have demonstrated a cardiovascular benefit in addition to statin therapy in patients with established cardiovascular disease. A recent European consensus has defined the candidates for PCSK9 inhibitors, e.g., patients with established cardiovascular disease and patients with familial hypercholesterolemia in primary prevention, with substantially elevated LDL-C levels despite maximally tolerated statin with or without ezetimibe therapy.
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4.
Alirocumab for low-density lipoprotein cholesterol lowering.
Roth, EM
Future cardiology. 2019;(1):17-29
Abstract
Ischemic heart disease and stroke are the leading causes of death in the world currently. Both of these conditions are primarily caused by atherosclerosis, the underlying pathophysiology of which is the deposition of lipid, specifically low-density lipoprotein cholesterol (LDL-C) within the arterial bed. PCSK9, is a proteolytic enzyme, which indirectly increases LDL-C levels by causing the destruction of LDL receptors, the main way that humans regulate their serum LDL-C levels. Inhibitors of PCSK9 in conjunction with statins have allowed achievement of very low LDL-C levels. This review will provide an in-depth efficacy and safety review of alirocumab, a monoclonal antibody inhibitor of PCSK9, including the ODYSSEY OUTCOMES trial.
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5.
Status of PCSK9 Monoclonal Antibodies in Australia.
Scherer, DJ, Nelson, AJ, O'Brien, R, Kostner, KM, Hare, DL, Colquhoun, DM, Barter, PJ, Aylward, P, Nicholls, SJ, Watts, GF
Heart, lung & circulation. 2019;(10):1571-1579
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAb) have progressed from showing marked low density lipoprotein cholesterol lowering in early phase trials through to reducing cardiovascular events in large clinical outcome trials. Recently in Australia, the indication for evolocumab has been expanded to include both heterozygous and homozygous familial hypercholesterolaemia under the Pharmaceutical Benefits Scheme (PBS). With prices remaining high currently their use in non-familial hypercholesterolaemia in Australia remains by private prescription only at this stage. This manuscript summarises the major outcomes trials of the PCSK9 mAbs and the secondary analyses that have assessed their benefits in high risk patient groups, and describes the consensus of authors on which patients would most likely benefit from PCSK9 mAb therapy.
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6.
X-linked hypophosphatemia: Management and treatment prospects.
Lambert, AS, Zhukouskaya, V, Rothenbuhler, A, Linglart, A
Joint bone spine. 2019;(6):731-738
Abstract
X-linked hypophosphatemia (XLH), due to a PHEX gene mutation, is the most common genetic form of rickets and osteomalacia. Manifestations in children consist of rickets, lower-limb bone deformities, bone pain, failure to thrive, dental abscesses, and/or craniostenosis. Adults may present with persistent bone pain, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis. Regardless of whether the patient is an infant, child, adolescent or adult, an early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life. Treatment options include active vitamin D analogs and phosphate supplementation to correct the 1.25(OH)2 vitamin D deficiency and to compensate for the renal phosphate wasting, respectively. The recently introduced FGF23 antagonist burosumab is designed to restore renal phosphate reabsorption by the proximal tubule and to stimulate endogenous calcitriol production. In Europe, burosumab is licensed for use in pediatric patients older than 1 year who have XLH. This review discusses the diagnosis and treatment of XLH and describes the indications of the various available treatments.
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7.
Clinical guidance on the contemporary use of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies.
Ward, NC, Page, MM, Watts, GF
Diabetes, obesity & metabolism. 2019;:52-62
Abstract
There is now significant evidence for the benefits of lowering low-density lipoprotein cholesterol (LDL-c) to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Although statins are the most widely prescribed lipid-lowering therapy that effectively lower LDL-c, especially in combination with ezetimibe, some patients require adjunctive therapy to further lower LDL-c and mitigate attendant risk of ASCVD. The gap can be filled by proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies whose use is currently supported by two recent cardiovascular outcome studies and new treatment guidelines. We provide an overview of extant studies investigating PCSK9 monoclonal antibodies in various patient populations, an update of the guidelines regarding their use and a case-based discussion.
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8.
[Monoclonal antibodies in cardiovascular diseases and metabolic disorders today].
Angoulvant, D, Pathak, A
Medecine sciences : M/S. 2019;(12):1014-1016
Abstract
The use of monoclonal antibodies in cardiovascular diseases and metabolic disorders is still in its infancy. Recent development of anti-PCSK9 monoclonal antibodies for the treatment of dyslipidemia and of patients in secondary prevention is a breakthrough in the field. Anti- PCSK9 antibodies significantly improved LDL cholesterol reduction in patients with familial hypercholesterolemia. These antibodies have also demonstrated a significant reduction of clinical events in patients with previously established atherosclerotic disease such as myocardial infarction, ischemia stroke or peripheral artery disease. Other targets are under investigation such as inflammatory cells and cytokines to reduce atherosclerosis or myocardial lesions following myocardial infarction.
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9.
[The sequential therapy of romosozumab followed by denosumab for osteoporosis.].
Ono, K, Tanaka, S
Clinical calcium. 2019;(3):357-362
Abstract
Romosozumab is a bone-forming agent with a dual effect of increasing bone formation and decreasing bone resorption by inhibiting sclerostin. In the pivotal Fracture study in postmenopausal women with osteroposis(FRAME)and the extension trial, 12 months of romosozumab led to persistent fracture, especially new vertebral fracture, reduction benefit and ongoing BMD(bone mineral density)gains when follow 24 months of denosumab. The sequence therapy of romosozumab followed by denosumab may be a promising regimen for the treatment of osteoporosis.
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10.
Proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein(a)-mediated risk of atherosclerotic cardiovascular disease: more than meets the eye?
Boffa, MB, Koschinsky, ML
Current opinion in lipidology. 2019;(6):428-437
Abstract
PURPOSE OF REVIEW Evidence continues to mount for elevated lipoprotein(a) [Lp(a)] as a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease. However, the effects of existing lipid-lowering therapies on Lp(a) are comparatively modest and are not specific to Lp(a). Consequently, evidence that Lp(a)-lowering confers a cardiovascular benefit is lacking. Large-scale cardiovascular outcome trials (CVOTs) of inhibitory mAbs targeting proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may address this issue. RECENT FINDINGS Although the ability of PCSK9i to lower Lp(a) by 15-30% is now clear, the mechanisms involved continue to be debated, with in-vitro and in-vivo studies showing effects on Lp(a) clearance (through the LDL receptor or other receptors) and Lp(a)/apolipoprotein(a) biosynthesis in hepatocytes. The FOURIER CVOT showed that patients with higher baseline levels of Lp(a) derived greater benefit from evolocumab and those with the lowest combined achieved Lp(a) and LDL-cholesterol (LDL-C) had the lowest event rate. Meta-analysis of ten phase 3 trials of alirocumab came to qualitatively similar conclusions concerning achieved Lp(a) levels, although an effect independent of LDL-C lowering could not be demonstrated. SUMMARY Although it is not possible to conclude that PCSK9i specifically lower Lp(a)-attributable risk, patients with elevated Lp(a) could derive incremental benefit from PCSK9i therapy.