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Orphanet Journal of Rare Diseases May 2024There are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers....
BACKGROUND
There are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers. While many patients may be on both classes of medications, there is no data available on the safety and efficacy of combination therapy.
OBJECTIVES
To describe ATTRv patient and TTR-targeted therapy characteristics in a US cohort, and compare outcomes with combination therapy versus monotherapy.
METHODS
We performed a retrospective cohort study with electronic health record data of patients with ATTRv seen at a single institution between January 2018 and December 2022. We collected data on symptomatology, gene mutation, disease severity, ATTRv treatment, hospitalizations, and mortality.
RESULTS
One hundred sixty-two patients with ATTRv were identified. The average age at diagnosis was 65 years. 86 patients (53%) had the V122I variant. 119 patients were symptomatic, of whom 103 were started on ATTRv-specific treatment. 41 patients (40%) had cardiomyopathy only, and 53 (51%) had a mixed phenotype of cardiomyopathy and neuropathy. 38 patients (37%) received therapy with both a gene silencer and protein stabilizer. 9 patients (15%) in the monotherapy group had two or more cardiac hospitalizations after starting treatment, compared to 3 patients (9%) on combination therapy (p=0.26). The adjusted hazard ratio of all-cause mortality for the patients on combination therapy compared to monotherapy was 0.37 (0.08-1.8, p=0.21).
CONCLUSIONS
While the efficacy is unproven, over one-third of patients with ATTRv are on both a stabilizer and a silencer. There were no safety issues for combination therapy. There was a trend towards improved hospitalizations and survival in patients in the combination group but this was not statistically significant. Larger studies with longer follow-up are necessary to determine benefit of combination therapy.
Topics: Humans; Amyloid Neuropathies, Familial; Male; Female; Retrospective Studies; Aged; Middle Aged; Cohort Studies; Prealbumin; Aged, 80 and over; Adult
PubMed: 38720335
DOI: 10.1186/s13023-024-03198-7 -
Revista Espanola de Cardiologia... May 2024
Topics: Humans; Amyloid Neuropathies, Familial; Diflunisal; Male; Cardiomyopathies; Female; Aged; Treatment Outcome; Middle Aged
PubMed: 38325700
DOI: 10.1016/j.rec.2023.10.016 -
Molecules (Basel, Switzerland) Jan 2024The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of...
The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer's Disease (AD)-like pathology in mice, although the mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques. In this work, we report an isotopic exchange reaction to obtain IDIF radiolabeled with F. [F/F]exchange reaction over IDIF in dimethyl sulfoxide at 160 °C resulted in the formation of [F]IDIF in 7 ± 3% radiochemical yield in a 20 min reaction time, with a final radiochemical purity of >99%. Biodistribution studies after intravenous administration of [F]IDIF in wild-type mice using positron emission tomography (PET) imaging showed capacity to cross the blood-brain barrier (ca. 1% of injected dose per gram of tissue in the brain at t > 10 min post administration), rapid accumulation in the liver, long circulation time, and progressive elimination via urine. Our results open opportunities for future studies in larger animal species or human subjects.
Topics: Humans; Animals; Mice; Pharmaceutical Preparations; Tissue Distribution; Alzheimer Disease; Prealbumin; Amyloid beta-Peptides; Excipients; Diflunisal
PubMed: 38257401
DOI: 10.3390/molecules29020488 -
ESC Heart Failure Feb 2024We conducted a presentation on an 84-year-old male patient who has been diagnosed with TTRA81V (p. TTRA101V) hereditary transthyretin cardiac amyloidosis (hATTR-CM). In...
AIMS
We conducted a presentation on an 84-year-old male patient who has been diagnosed with TTRA81V (p. TTRA101V) hereditary transthyretin cardiac amyloidosis (hATTR-CM). In order to establish its pathogenicity, we extensively investigated the biochemical and biophysical properties of the condition.
METHODS AND RESULTS
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly acknowledged progressive infiltrative cardiomyopathy that leads to heart failure and potentially fatal arrhythmias. Gaining a comprehensive understanding of the biochemical and biophysical characteristics of genetically mutated TTR proteins serves as the fundamental cornerstone for delivering precise medical care to individuals affected by ATTR. Laboratory assessments indicated a brain natriuretic peptide of 200.12 ng/L (normal range: 0-100 ng/L) and high-sensitivity cardiac troponin I of 0.189 μg/L (normal range: 0-0.1 μg/L). Echocardiography identified left atrial enlargement, symmetrical left ventricular hypertrophy (16 mm septal and 16 mm posterior wall), and a left ventricular ejection fraction of 56%. Cardiac-enhanced magnetic resonance imaging revealed subendocardial late gadolinium enhancement. Tc-99m-PYP nuclear scintigraphy confirmed grade 3 myocardial uptake, showing an increased heart-to-contralateral ratio (H/CL = 2.33). Genetic testing revealed a heterozygous missense mutation in the TTR gene (c.302C>T), resulting in an alanine-to-valine residue change (p. Ala81Val, following the first 20 residues of signal sequence nomenclature). Biochemical analysis of this variant displayed compromised kinetic stability in both the TTRA81V:WT (wild-type) heterozygote protein (half-life, t = 21 h) and the TTRA81V homozygote protein (t = 17.5 h). The kinetic stability fell between that of the TTRWT (t = 42 h) and the early-onset TTRL55P mutation (t = 4.4 h), indicating the patient's late-onset condition. Kinetic stabilizers (Tafamidis, Diflunisal, and AG10) all exhibited the capacity to inhibit TTRA81V acid- and mechanical force-induced fibril formation, albeit less effectively than with TTRWT. Chromatographic assessment of the patient's serum TTR tetramers indicated a slightly lower concentration (3.0 μM) before oral administration of Tafamidis compared with the normal range (3.6-7.2 μM).
CONCLUSIONS
We identified a patient with hATTR-CM who possesses a rare TTRA81V mutation solely associated with cardiac complications. The slightly reduced kinetic stability of this mutation indicates its late-onset nature and contributes to the gradual progression of the disease.
Topics: Male; Humans; Aged, 80 and over; Prealbumin; Contrast Media; Stroke Volume; Gadolinium; Ventricular Function, Left; Amyloid Neuropathies, Familial; Cardiomyopathies; Mutation
PubMed: 37827496
DOI: 10.1002/ehf2.14543 -
Antibiotics (Basel, Switzerland) Jul 2023Invasive methicillin-resistant (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional...
Invasive methicillin-resistant (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional antibiotics. Thus, minimizing virulence and enhancing antibiotic efficacy against MRSA is a public health imperative. We originally demonstrated that diflunisal (DIF; [2-hydroxy-5-(2,4-difluorophenyl) benzoic acid]) inhibits virulence factor expression. To investigate pharmacophores that are active in this function, we evaluated a library of structural analogues for their efficacy to modulate virulence phenotypes in a panel of clinically relevant isolates in vitro. Overall, the positions of the phenyl, hydroxyl, and carboxylic moieties and the presence or type of halogen (F vs. Cl) influenced the efficacy of compounds in suppressing hemolysis, proteolysis, and biofilm virulence phenotypes. Analogues lacking halogens inhibited proteolysis to an extent similar to DIF but were ineffective at reducing hemolysis or biofilm production. In contrast, most analogues lacking the hydroxyl or carboxylic acid groups did not suppress proteolysis but did mitigate hemolysis and biofilm production to an extent similar to DIF. Interestingly, chirality and the substitution of fluorine with chlorine resulted in a differential reduction in virulence phenotypes. Together, this pattern of data suggests virulence-suppressing pharmacophores of DIF and structural analogues integrate halogen, hydroxyl, and carboxylic acid moiety stereochemistry. The anti-virulence effects of DIF were achieved using concentrations that are safe in humans, do not impair platelet antimicrobial functions, do not affect growth, and do not alter the efficacy of conventional antibiotics. These results offer proof of concept for using novel anti-virulence strategies as adjuvants to antibiotic therapy to address the challenge of MRSA infection.
PubMed: 37508276
DOI: 10.3390/antibiotics12071180 -
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 -
International Journal of Molecular... Mar 2023One the main research goals of bioinorganic chemists is the synthesis of novel coordination compounds possessing biological potency. Within this context, three novel...
One the main research goals of bioinorganic chemists is the synthesis of novel coordination compounds possessing biological potency. Within this context, three novel iron(III) complexes with the non-steroidal anti-inflammatory drugs diflunisal and diclofenac in the presence or absence of the nitrogen donors 1,10-phenanthroline or pyridine were isolated and characterized by diverse techniques. The complexes were evaluated for their ability to scavenge in vitro free radicals such as hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals, revealing their selective potency towards hydroxyl radicals. The in vitro inhibitory activity of the complexes towards the enzymes acetylcholinesterase and butyrylcholinesterase was evaluated, and their potential to achieve neuroprotection appeared promising. The interaction of the complexes with calf-thymus DNA was examined in vitro, revealing their ability to intercalate in-between DNA nucleobases. The affinity of the complexes for serum albumins was evaluated in vitro and revealed their tight and reversible binding.
Topics: Antioxidants; Ferric Compounds; Cholinergic Antagonists; Butyrylcholinesterase; Acetylcholinesterase; Coordination Complexes; Anti-Inflammatory Agents, Non-Steroidal; DNA
PubMed: 37047364
DOI: 10.3390/ijms24076391 -
Protein Science : a Publication of the... Apr 2023Transthyretin (TTR)-related amyloidosis (ATTR) is a syndrome of diseases characterized by the extracellular deposition of fibrillar materials containing TTR variants....
Transthyretin (TTR)-related amyloidosis (ATTR) is a syndrome of diseases characterized by the extracellular deposition of fibrillar materials containing TTR variants. Ala97Ser (A97S) is the major mutation reported in Taiwanese ATTR patients. Here, we combine atomic resolution structural information together with the biochemical data to demonstrate that substitution of polar Ser for a small hydrophobic side chain of Ala at residue 97 of TTR largely influences the local packing density of the FG-loop, thus leading to the conformational instability of native tetramer, the increased monomeric species, and thus the enhanced amyloidogenicity of apo-A97S. Based on calorimetric studies, the tetramer destabilization of A97S can be substantially altered by interacting with native stabilizers via similarly energetic patterns compared to that of wild-type (WT) TTR; however, stabilizer binding partially rearranges the networks of hydrogen bonding in TTR variants while FG-loops of tetrameric A97S still remain relatively flexible. Moreover, TTR in complexed with holo-retinol binding protein 4 is slightly influenced by the structural and dynamic changes of FG-loop caused by A97S substitution with an approximately five-fold difference in binding affinity. Collectively, our findings suggest that the amyloidogenic A97S mutation destabilizes TTR by increasing the flexibility of the FG-loop in the monomer, thus modulating the rate of amyloid fibrillization.
Topics: Humans; Amyloid; Amyloidogenic Proteins; Calorimetry; Mutation; Prealbumin
PubMed: 36851846
DOI: 10.1002/pro.4610 -
The Journal of Organic Chemistry May 2023Starting with highly fluorinated benzoates, we develop the directed photocatalytic hydrodefluorination (HDF) of fluorinated aryl benzoates and demonstrate its...
Starting with highly fluorinated benzoates, we develop the directed photocatalytic hydrodefluorination (HDF) of fluorinated aryl benzoates and demonstrate its synergistic use with other HDF strategies, along with C-H arylation, decarboxylative coupling, and decarboxylative protonation, to access most fluorination patterns found in benzoate derivatives and by extension benzene derivatives via a molecular sculpting approach. Mild reaction conditions and excellent regioselectivity make the approach ideal for synthesis. This approach provides access to 16 benzoate derivatives with different fluorination patterns from just a couple of highly fluorinated, commercially available benzoic acids. We synthesize key intermediates or the active pharmaceutical ingredient for sitagliptin, diflunisal, and other pharmaceutically important molecules. Importantly, we provide key insights into relative rates of defluorination and strategies to alter these rates. We provide demonstrations of the synergistic use of HDF and related technologies to rapidly enhance the synthetic complexity of these simple commercially available perfluoroarenes to form complex partially fluorinated molecules.
PubMed: 36656262
DOI: 10.1021/acs.joc.2c02332