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A Highlight on the Inhibition of Fungal Carbonic Anhydrases as Drug Targets for the Antifungal Armamentarium.
Supuran, CT, Capasso, C
International journal of molecular sciences. 2021;(9)
Abstract
Carbon dioxide (CO2), a vital molecule of the carbon cycle, is a critical component in living organisms' metabolism, performing functions that lead to the building of compounds fundamental for the life cycle. In all living organisms, the CO2/bicarbonate (HCO3-) balancing is governed by a superfamily of enzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the pivotal physiological reaction, consisting of the reversible hydration of the CO2 to HCO3- and protons. Opportunistic and pathogenic fungi can sense the environmental CO2 levels, which influence their virulence or environmental subsistence traits. The fungal CO2-sensing is directly stimulated by HCO3- produced in a CA-dependent manner, which directly activates adenylyl cyclase (AC) involved in the fungal spore formation. The interference with CA activity may impair fungal growth and virulence, making this approach interesting for designing antifungal drugs with a novel mechanism of action: the inhibition of CAs linked to the CO2/HCO3-/pH chemosensing and signaling. This review reports that sulfonamides and their bioisosteres as well as inorganic anions can inhibit in vitro the β- and α-CAs from the fungi, suggesting how CAs may be considered as a novel "pathogen protein" target of many opportunistic, pathogenic fungi.
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Ramatroban-Based Analogues Containing Fluorine Group as Potential 18F-Labeled Positron Emission Tomography (PET) G-Protein Coupled Receptor 44 (GPR44) Tracers.
Huang, LA, Huang, KX, Tu, J, Kandeel, F, Li, J
Molecules (Basel, Switzerland). 2021;(5)
Abstract
Diabetes remains one of the fastest growing chronic diseases and is a leading source of morbidity and accelerated mortality in the world. Loss of beta cell mass (BCM) and decreased sensitivity to insulin underlie diabetes pathogenesis. Yet, the ability to safely and directly assess BCM in individuals with diabetes does not exist. Measures such as blood glucose provide only a crude indirect picture of beta cell health. PET imaging could, in theory, allow for safe, direct, and precise characterization of BCM. However, identification of beta cell-specific radiolabeled tracers remains elusive. G-protein coupled receptor 44 (GPR44) is a transmembrane protein that was characterized in 2012 as highly beta cell-specific within the insulin-positive islets of Langerhans. Accordingly, radiolabeling of existing GPR44 antagonists could be a viable method to accelerate PET tracer development. The present study aims to evaluate and summarize published analogues of the GPR44 antagonist ramatroban to develop 18F-labeled PET tracers for BCM analysis. The 77 corresponding ramatroban analogues containing a fluorine nuclide were characterized for properties including binding affinity, selectivity, and pharmacokinetic and metabolic profile, and 32 compounds with favorable properties were identified. This review illustrates the potential of GPR44 analogues for the development of PET tracers.
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How we manage adults with myelodysplastic syndrome.
Fenaux, P, Platzbecker, U, Ades, L
British journal of haematology. 2020;(6):1016-1027
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The prognosis in Myelodysplastic syndromes (MDS), although recently refined by molecular studies, remains largely based on conventional prognostic scores [International Prognostic Scoring System (IPSS), revised IPSS], classifying patients into "lower risk" MDS (LR-MDS) and "higher risk" MDS (HR-MDS). In LR-MDS, treatment mainly aims at improving cytopenias, principally anaemia, while in HR-MDS it aims at delaying disease progression and prolonging survival. In LR-MDS without deletion 5q, anaemia is generally treated first by erythropoietic stimulating factors, while second line treatments are currently not approved [lenalidomide, hypomethylating agents (HMA), luspatercept] or rarely indicated (antithymocyte globulin). Lenalidomide has major efficacy in LR-MDS with deletion 5q. Allogeneic stem cell transplantation (allo-SCT) is sometimes considered in LR-MDS, and iron chelation can be considered when multiple red blood cell transfusions are required. Allo-SCT is the only potentially curative treatment for HR-MDS; however, it is rarely applicable. It is generally preceded by intensive chemotherapy (IC) or HMA in patients with excess of marrow blasts (especially if >10%). In other patients, HMA can improve survival. The role of new drugs, including venetoclax or, in case of specific mutations, IDH1 or IDH2 inhibitors, is investigated. IC is mainly indicated as a bridge to allo-SCT, in the absence of unfavourable karyotype.
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Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies.
Taylor, PC, Kremer, JM, Emery, P, Zuckerman, SH, Ruotolo, G, Zhong, J, Chen, L, Witt, S, Saifan, C, Kurzawa, M, et al
Annals of the rheumatic diseases. 2018;(7):988-995
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Abstract
OBJECTIVES Lipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs. METHODS Lipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study. RESULTS Treatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated. CONCLUSIONS Baricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications. TRIAL REGISTRATION NUMBER NCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.
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A review of toxic epidermal necrolysis management in Japan.
Kinoshita, Y, Saeki, H
Allergology international : official journal of the Japanese Society of Allergology. 2017;(1):36-41
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Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction characterized by necrosis of the epidermis. Its incidence is approximately 1 per million a year and average mortality rate is high at 25-50%. TEN has a flu-like prodrome, followed by atypical, targetoid erythematous or purpuric macules on the skin. These macules coalesce to form flaccid blisters that slough off as areas of epidermal necrosis. Drugs such as allopurinol, sulfonamides, and carbamazepine are the most common causes. The human leukocyte antigen (HLA)-B*15:02 in Asians being administered carbamazepine and the HLA-B*58:01 antigen in patients of all ethnicities being administered allopurinol are known to be high-risk factors. Rapid diagnosis, discontinuation of the causative drug, and supportive treatment are essential for better prognosis and improvement of sequelae. Till now, systemic corticosteroids and intravenous immunoglobulins have been used as the most common active interventions; however, no gold standard has been established. In Japan, physicians follow a unique diagnostic criteria and treatment guideline to improve the diagnosis rate and streamline treatments. This may be a contributing factor for the lower mortality rate (14.3%). The efficacy of systemic corticosteroids, immunoglobulins, and plasmapheresis may have been beneficial as well. In Japan, TEN is defined as an epidermal detachment of over 10% of the body surface area (BSA), while the globally accepted definition established by Bastuji-Garin describes it as an epidermal detachment of over 30% of the BSA. In Japanese individuals, HLA-A*02:06, HLA-A*02:07, HLA-A*31:01 and HLA-B*51:01 may be linked to higher risks of TEN.
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Treatment Strategy for Standard-Dose Proton Pump Inhibitor-Resistant Reflux Esophagitis.
Iwakiri, K
Journal of Nippon Medical School = Nippon Ika Daigaku zasshi. 2017;(5):209-214
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Reflux esophagitis is characterized by excessive esophageal acid exposure. To treat reflux esophagitis, it is necessary to reduce excessive esophageal acid exposure to within the normal range. The first-line drug for the treatment of reflux esophagitis is a standard-dose proton-pump inhibitor (PPI), which is also recommended by the Evidence-based Clinical Practice Guidelines 2015 for gastroesophageal disease of the Japanese Society of Gastroenterology. It has been reported that the response to a standard dose of PPI in patients with mild reflux esophagitis is 90-100%, and that in patients with severe reflux esophagitis is 80-85%. However, PPI-resistant reflux esophagitis has been increasing. When the standard dose of PPI is not effective, modification of the lifestyle with PPI therapy, switching to another PPI, or a change in the administration method (before meals), as well as double-dose PPI (in divided doses), may be effective. In addition, vonoprazan (potassium-competitive acid blocker), which has rapid and potent acid-suppressive effects, became available in February 2015 in Japan. In the clinical trial data, vonoprazan is very effective for reflux esophagitis. However, clinical data on vonoprazan are still insufficient. The establishment of a new treatment for reflux esophagitis taking advantage of the rapid and potent acid-suppressive effects is awaited.
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Systemic Therapy for Soft Tissue Sarcoma: Proposals for the Optimal Use of Pazopanib, Trabectedin, and Eribulin.
Kawai, A, Yonemori, K, Takahashi, S, Araki, N, Ueda, T
Advances in therapy. 2017;(7):1556-1571
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UNLABELLED Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Although treatment outcomes for patients with STS have improved greatly over the past few decades owing to the adoption of a multidisciplinary approach, patients with advanced disease have a poor prognosis. The development of anticancer drugs has been directed toward improving overall survival (OS). Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. However, there is no standard therapy for second-line and later treatment at present. Since 2012, three anticancer drugs-pazopanib, trabectedin, and eribulin-have been approved in Japan for the second-line or later treatment of patients with advanced STS of any histologic subtype. However, the chemosensitivity of STS to each of these drugs varies by histologic subtype and their safety profiles differ; thus, histologic subtype and patient characteristics must be considered when determining optimal treatment. In this article, we review data from clinical studies related to the efficacy of all three drugs, including their effect on OS, and propose optimal treatment strategies for advanced STS by histologic subtype. In addition, with regard to the safety profiles, we highlight the key issues to be considered when selecting patients for treatment with pazopanib, trabectedin, or eribulin and ensuring their appropriate use, based on our combined clinical experience as specialists in the treatment of patients with STS. The proposed treatment strategies as well as treatment precautions based on clinical experience would benefit patients by maximizing the therapeutic effects and enhancing the proper use of these drugs. FUNDING Eisai Co., Ltd.
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Chemical manipulation of plant water use.
Helander, JD, Vaidya, AS, Cutler, SR
Bioorganic & medicinal chemistry. 2016;(3):493-500
Abstract
Agricultural productivity is dictated by water availability and consequently drought is the major source of crop losses worldwide. The phytohormone abscisic acid (ABA) is elevated in response to water deficit and modulates drought tolerance by reducing water consumption and inducing other drought-protective responses. The recent identification of ABA receptors, elucidation of their structures and understanding of the core ABA signaling network has created new opportunities for agrochemical development. An unusually large gene family encodes ABA receptors and, until recently, it was unclear if selective or pan-agonists would be necessary for modulating water use. The recent identification of the selective agonist quinabactin has resolved this issue and defined Pyrabactin Resistance 1 (PYR1) and its close relatives as key targets for water use control. This review provides an overview of the structure and function of ABA receptors, progress in the development of synthetic agonists, and the use of orthogonal receptors to enable agrochemical control in transgenic plants.
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Rosuvastatin Treatment for Preventing Contrast-Induced Acute Kidney Injury After Cardiac Catheterization: A Meta-Analysis of Randomized Controlled Trials.
Yang, Y, Wu, YX, Hu, YZ
Medicine. 2015;(30):e1226
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We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the protective effects of rosuvastatin on contrast-induced acute kidney injury (CI-AKI) and major adverse cardiovascular events (MACEs) in patients undergoing cardiac catherization.PubMed, MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Central RCTs were searched for RCTs from inception to May 2015, to compare rosuvastatin for preventing CI-AKI with placebo treatment in patients undergoing cardiac catherization.Five RCTs with a total of 4045 patients involving 2020 patients pretreated with rosuvastatin and 2025 control patients were identified and analyzed. Patients treated with rosuvastatin had a 51% lower risk of CI-AKI compared with the control group based on a fixed-effect model (OR = 0.49, 95% CI = 0.37-0.66, P < 0.001), and showed a trend toward a reduced risk of MACEs (OR = 0.62, 95% CI = 0.36-1.07, P = 0.08). A subgroup analysis showed that studies with Jadad score ≥3 showed a significant reduction of CI-AKI (OR = 0.53, 95% CI, 0.38-0.73, P < 0.001). However, the risk of CI-AKI did not significantly differ in the studies with Jadad score <3 (OR = 0.54, 95% CI, 0.13-2.24, P = 0.40). In addition, the rosuvastatin treatment showed no effect for preventing CI-AKI in patients with chronic kidney disease (CKD) undergoing elective cardiac catherization (I = 0%, OR = 0.81, 95% CI = 0.41-1.61, P = 0.55).This updated meta-analysis demonstrated that preprocedural rosuvastatin treatment could significantly reduce the incidence of CI-AKI, with a trend toward a reduced risk of MACEs in patients undergoing cardiac catheterization. However, rosuvastatin treatment did not seem to be effective for preventing CI-AKI in CKD patients undergoing elective cardiac catheterization.
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Recurrent multiple CNS hemangioblastomas with VHL disease treated with pazopanib: a case report and literature review.
Migliorini, D, Haller, S, Merkler, D, Pugliesi-Rinaldi, A, Koka, A, Schaller, K, Leemann, B, Dietrich, PY
CNS oncology. 2015;(6):387-92
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Hemangioblastoma is a rare benign neoplasm, accounting for less than 2% of all primitive brain tumors. It may arise sporadically in a solitary form, or associated with Von Hippel-Lindau (VHL) disease with multiple tumors. Surgery is the mainstay treatment, but management is challenging in case of recurrent and/or multiple tumors. VHL protein is defective in both forms of hemangioblastoma, leading to the accumulation of hypoxia-inducible factor, stimulating angiogenesis via VEGF and PDGF mainly. Here, we report a 37-year-old woman's case with recurrent and rapidly progressive VHL-associated hemangioblastomas, causing severe disability. She was treated 24 months with pazopanib, a multityrosine kinase inhibitor (TKI) targeting VEGF and PDGF-β pathways. Despite moderate radiological changes, progressive improvement in her clinical condition persisting over 3 years was observed. Inhibiting angiogenesis is a therapeutic option that may improve the quality of life and the autonomy of VHL patients disabled with multiple hemangioblastomas.