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Journal of Biomolecular Structure &... Feb 2022Schistosomiasis is a neglected disease of considerable health importance in tropical and subtropical regions. Its treatment relies on the use of praziquantel or...
Schistosomiasis is a neglected disease of considerable health importance in tropical and subtropical regions. Its treatment relies on the use of praziquantel or oxamniquine but there are reported cases of treatment failures due to resistance or tolerance. Again, derivatives of praziquantel and oxamniquine have not shown significant activities than their parent compounds. The study predicted approved drugs with possible antischistosomal activities. Four schistosomal drug targets were obtained from Protein Data Bank and six hundred and twelve (612) approved drugs including their isomers were selected based on their Molinspiration® bioscore similarities with reference compounds (praziquantel, oxamniquine, [(2S,3S,4S,5S,6S)-3,4,5-triacetyloxy-6-sulfanyloxan-2-yl] methyl acetate, [propylamino-3-hydroxy-buta-1,4-dionyl]-isoleucylproline). The selected drugs and drug targets were obtained and prepared for molecular docking simulations. The molecular docking simulations were performed using AutoDockvina-1.1.2 after validation of docking protocols while molecular dynamics simulations were performed with GROMACS-4.5.5. The binding energies were calculated using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area). Tolmetin was predicted as potential antischistosomal drug with binding energies of -231.064 ± 18.550 and -338.636 ± 36.900 KJ/mol for sulfotransferase and thioredoxin glutathione reductase (TGR) respectively. Also diflunisal was predicted as potential antischistosomal drug with binding energies of -168.641 ± 20.370 and -290.117 ± 43.800 KJ/mol for sulfotransferase and TGR respectively. Non-covalent interactions and conformational changes were responsible for molecular recognitions and specificities and average bond measurement showed that carboxylic functional groups in diflunisal and tolmetin may interact covalently with -SH group of Cys159 in TGR. Confirmation of covalent interactions and validations are recommended.Communicated by Ramaswamy H. Sarma.
Topics: Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Oxamniquine; Schistosomiasis; Schistosomicides
PubMed: 32924851
DOI: 10.1080/07391102.2020.1820382 -
Brain and Behavior Sep 2019Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant... (Review)
Review
INTRODUCTION
Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild-type ATTR) throughout the body. Two new therapies-inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy-received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR.
METHODS
A PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR.
RESULTS
Until recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early- and late-stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early-stage disease, and tafamidis, indicated for the treatment of early-stage disease in Europe, or diflunisal, a nonsteroidal anti-inflammatory drug that is used off-label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities.
CONCLUSIONS
Important differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.
Topics: Amyloid Neuropathies, Familial; Female; Humans; Oligonucleotides; RNA, Small Interfering; Treatment Outcome
PubMed: 31368669
DOI: 10.1002/brb3.1371 -
Clinical Autonomic Research : Official... Sep 2019Neurogenic orthostatic hypotension is a prominent and disabling manifestation of autonomic dysfunction in patients with hereditary transthyretin (TTR) amyloidosis... (Review)
Review
PURPOSE
Neurogenic orthostatic hypotension is a prominent and disabling manifestation of autonomic dysfunction in patients with hereditary transthyretin (TTR) amyloidosis affecting an estimated 40-60% of patients, and reducing their quality of life. We reviewed the epidemiology and pathophysiology of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis, summarize non-pharmacologic and pharmacological treatment strategies and discuss the impact of novel disease-modifying treatments such as transthyretin stabilizers (diflunisal, tafamidis) and RNA interference agents (patisiran, inotersen).
METHODS
Literature review.
RESULTS
Orthostatic hypotension in patients with hereditary transthyretin amyloidosis can be a consequence of heart failure due to amyloid cardiomyopathy or volume depletion due to diarrhea or drug effects. When none of these circumstances are apparent, orthostatic hypotension is usually neurogenic, i.e., caused by impaired norepinephrine release from sympathetic postganglionic neurons, because of neuronal amyloid fibril deposition.
CONCLUSIONS
When recognized, neurogenic orthostatic hypotension can be treated. Discontinuation of potentially aggravating medications, patient education and non-pharmacologic approaches should be applied first. Droxidopa (Northera), a synthetic norepinephrine precursor, has shown efficacy in controlled trials of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis and is now approved in the US and Asia. Although they may be useful to ameliorate autonomic dysfunction in hereditary TTR amyloidosis, the impact of disease-modifying treatments on neurogenic orthostatic hypotension is still uninvestigated.
Topics: Amyloid Neuropathies, Familial; Humans; Hypotension, Orthostatic
PubMed: 31452021
DOI: 10.1007/s10286-019-00623-x -
EMBO Reports Oct 2019Extracellular HMGB1 triggers inflammation following infection or injury and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states:...
Extracellular HMGB1 triggers inflammation following infection or injury and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of diflunisal and open the way to the rational design of functionally specific anti-inflammatory drugs.
Topics: 3T3 Cells; Animals; Chemokine CXCL12; Chemotaxis; Diflunisal; Disulfides; Glycyrrhizic Acid; HMGB1 Protein; Humans; Inflammation; Leukocytes; Macrophages; Magnetic Resonance Spectroscopy; Mice
PubMed: 31418171
DOI: 10.15252/embr.201947788 -
Transplant International : Official... 2022To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. We performed a...
To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. We performed a retrospective longitudinal study of prospectively collected data for all domino liver transplant recipients with acquired amyloid neuropathy who received diflunisal at our hospital. Neurological deterioration was defined as an score increase of ≥2 points from baseline on the Neurological Impairment Scale/Neurological Impairment Scale-Lower Limbs. Twelve patients who had received compassionate use treatment with diflunisal were identified, of whom seven had follow-up data for ≥12 months. Five patients (71.4%) presented with neurological deterioration on the Neurological Impairment Scale after 12 months ( = 0.0382). The main adverse effects were cardiovascular and renal, leading to diflunisal being stopped in five patients and the dose being reduced in two patients. Our study suggests that most domino liver transplant recipients with acquired amyloid neuropathy will develop neurological deterioration by 12 months of treatment with diflunisal. This therapy was also associated with a high incidence of adverse effects and low treatment retention. The low efficacy and low tolerability of diflunisal treatment encourage the search for new therapeutic options.
Topics: Amyloid Neuropathies; Diflunisal; Humans; Longitudinal Studies; Retrospective Studies; Transplant Recipients
PubMed: 35497887
DOI: 10.3389/ti.2022.10454 -
American Journal of Kidney Diseases :... Mar 2024Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive, and life-threatening disease caused by misfolded transthyretin (TTR) proteins that aggregate as... (Review)
Review
Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive, and life-threatening disease caused by misfolded transthyretin (TTR) proteins that aggregate as abnormal amyloid fibrils and accumulate throughout the body. The kidney is one of the main organs affected in amyloid light chain (AL) amyloidosis and ATTRv amyloidosis. The most common clinical presentation is proteinuria, which consists mainly of albumin; this is the first step in the natural history of ATTRv nephropathy. Not all TTR mutations are equal in terms of ATTRv kidney involvement. Kidney involvement in ATTRv itself is difficult to define, given the numerous associated confounding factors. There are several treatments available to treat ATTRv, including orthotopic liver transplant (OLT), which is the classic treatment for ATTRv. However, we should be careful regarding the use of calcineurin inhibitors in the setting of OLT because these can be nephrotoxic. New treatments for amyloidosis may have an impact on kidney function, including drugs that target specific pathways involved in the disease. Tafamidis and diflunisal, which are TTR stabilizers, patisiran (RNA interference agent), and inotersen (antisense oligonucleotide inhibitor) have been shown to reduce TTR amyloid. Tafamidis and patisiran are medications that have reduced the progression of kidney disease in amyloidosis, but inotersen and diflunisal may damage kidney function.
PubMed: 38484868
DOI: 10.1053/j.ajkd.2024.01.527 -
Journal of Clinical Medicine Apr 2022Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein builds up in the myocardium along with different organs, most commonly the peripheral and the autonomic nervous systems. Managing the cardiac complications with standard heart failure medications is difficult due to the challenge to maintain a balance between the high filling pressure associated with restricted ventricular volume and the low cardiac output. To date, tafamidis is the only agent approved for ATTR-CM treatment. Besides, several agents, including green tea, tolcapone, and diflunisal, are used off-label in ATTR-CM patients. Novel therapies using RNA interference also offer clinical promise. Patisiran and inotersen are currently approved for ATTR-polyneuropathy of hereditary origin and are under investigation for ATTR-CM. Monoclonal antibodies in the early development phases carry hope for amyloid deposit clearance. Despite several drug candidates in the clinical development pipeline, the small ATTR-CM patient population raises several challenges. This review describes current and future therapies for ATTR-CM and sheds light on the clinical development hurdles facing them.
PubMed: 35456241
DOI: 10.3390/jcm11082148 -
Antibiotics (Basel, Switzerland) May 2023Virulence factor expression is integral to pathogenicity of . We previously demonstrated that aspirin, through its major metabolite, salicylic acid (SAL), modulates...
Virulence factor expression is integral to pathogenicity of . We previously demonstrated that aspirin, through its major metabolite, salicylic acid (SAL), modulates virulence phenotypes in vitro and in vivo. We compared salicylate metabolites and a structural analogue for their ability to modulate virulence factor expression and phenotypes: (i) acetylsalicylic acid (ASA, aspirin); (ii) ASA metabolites, salicylic acid (SAL), gentisic acid (GTA) and salicyluric acid (SUA); or (iii) diflunisal (DIF), a SAL structural analogue. None of these compounds altered the growth rate of any strain tested. ASA and its metabolites SAL, GTA and SUA moderately impaired hemolysis and proteolysis phenotypes in multiple strain backgrounds and their respective deletion mutants. Only DIF significantly inhibited these virulence phenotypes in all strains. The kinetic profiles of ASA, SAL or DIF on expression of (alpha hemolysin), (V8 protease) and their regulators (, , (RNAIII)) were assessed in two prototypic strain backgrounds: SH1000 (methicillin-sensitive ; MSSA) and LAC-USA300 (methicillin-resistant ; MRSA). DIF induced expression which is coincident with the significant inhibition of RNAIII expression in both strains and precedes significant reductions in and expression. The inhibited expression of these genes within 2 h resulted in the durable suppression of hemolysis and proteolysis phenotypes. These results indicate that DIF modulates the expression of key virulence factors in via a coordinated impact on their relevant regulons and target effector genes. This strategy may hold opportunities to develop novel antivirulence strategies to address the ongoing challenge of antibiotic-resistant .
PubMed: 37237805
DOI: 10.3390/antibiotics12050902 -
Journal of Molecular Graphics &... Jul 2023An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel... (Review)
Review
An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel multitarget MAO-B/AChE agents in the treatment of Alzheimer's disease (AD). GOLD 5.3 and Glide were employed in the virtual assessments and consensus superimpositions of the obtained poses were applied to increase the reliability of the docking protocols. Furthermore, the top ranked molecules were subjected to binding free energy calculations using MM/GBSA, Induced fit docking (IFD) simulations, and a literature review. Consequently, the top four multitarget drugs were examined for their in vitro MAO-B and AChE inhibition effects. The consensus molecular docking identified Dolutegravir, Rebamipide, Loracarbef and Diflunisal as potential multitarget drugs. The biological data demonstrated that most of the docking scores were in good correlation with the in vitro experiments, however the theoretical simulations in the active site of MAO-B identified two false-positives - Rebamipide and Diflunisal. Dolutegravir and Loracarbef were accessed as active MAO-B inhibitors, while Dolutegravir, Rebamapide and Diflunisal as potential AChE inhibitors. The antiretroviral agent Dolutegravir exhibited the most potent multitarget activity - 41% inhibition of MAO-B (1 μM) and 68% inhibition of AChE (10 μM). Visualizations of the intermolecular interactions of Dolutegravir in the active sites of MAO-B and AChE revealed the formation of several stable hydrogen bonds. Overall, Dolutegravir was identified as a potential anti-AD drug, however further in vivo evaluations should be considered.
Topics: Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Alzheimer Disease; Molecular Docking Simulation; Diflunisal; Drug Repositioning; Reproducibility of Results; Cholinesterase Inhibitors; Acetylcholinesterase
PubMed: 37087882
DOI: 10.1016/j.jmgm.2023.108471 -
Amyloid : the International Journal of... Jun 2023Transthyretin (TTR) dissociation is the rate limiting step for both aggregation and subunit exchange. Kinetic stabilisers, small molecules that bind to the native...
Transthyretin (TTR) dissociation is the rate limiting step for both aggregation and subunit exchange. Kinetic stabilisers, small molecules that bind to the native tetrameric structure of TTR, slow TTR dissociation and inhibit aggregation. One such stabiliser is the non-steroidal anti-inflammatory drug (NSAID), diflunisal, which has been repurposed to treat TTR polyneuropathy. Previously, we compared the efficacy of diflunisal, tafamidis, tolcapone, and AG10 as kinetic stabilisers for transthyretin. However, we could not meaningfully compare diflunisal because we were unsure of its plasma concentration after long-term oral dosing. Herein, we report the diflunisal plasma concentrations measured by extraction, reversed phase HPLC separation, and fluorescence detection after long-term 250 mg BID oral dosing in two groups: a placebo-controlled diflunisal clinical trial group and an open-label Japanese polyneuropathy treatment cohort. The measured mean diflunisal plasma concentration from both groups was 282.2 M 143.7 M (mean standard deviation). Thus, quantification of TTR kinetic stabilisation using subunit exchange was carried out at 100, 200, 300, and 400 concentrations, all observed in patients after 250 mg BID oral dosing. A 250 M diflunisal plasma concentration reduced the wild-type TTR dissociation rate in plasma by 95%, which is sufficient to stop transthyretin aggregation, consistent with the clinical efficacy of diflunisal for ameliorating transthyretin polyneuropathy.
Topics: Humans; Diflunisal; Prealbumin; Anti-Inflammatory Agents, Non-Steroidal; Excipients; Polyneuropathies; Amyloid Neuropathies, Familial
PubMed: 36444793
DOI: 10.1080/13506129.2022.2148094