-
International Journal of Molecular... Dec 2022The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion... (Review)
Review
The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion biomarkers, and a continuous flow of innovative drugs, which translated into the blooming of phase 2/3 interventional studies for light chain (AL) and transthyretin (ATTR) amyloidosis. The unprecedented availability of effective drugs ignited great interest across various medical specialties, particularly among cardiologists who are now recognizing cardiac amyloidosis at an extraordinary pace. In all amyloidosis referral centers, we are observing a substantial increase in the prevalence of wild-type transthyretin (ATTRwt) cardiomyopathy, which is now becoming the most common form of cardiac amyloidosis. This review focuses on the oral drugs that have been recently introduced for the treatment of ATTR cardiac amyloidosis, for their ease of use in the clinic. They include both old repurposed drugs or fit-for-purpose designed compounds which bind and stabilize the TTR tetramer, thus reducing the formation of new amyloid fibrils, such as tafamidis, diflunisal, and acoramidis, as well as fibril disruptors which have the potential to promote the clearance of amyloid deposits, such as doxycycline. The development of novel therapies is based on the advances in the understanding of the molecular events underlying amyloid cardiomyopathy.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Diflunisal; Cardiomyopathies; Amyloid
PubMed: 36555787
DOI: 10.3390/ijms232416145 -
Neurology and Therapy Feb 2023Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin...
INTRODUCTION
Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study.
METHODS
Patients eligible for NEURO-TTRansform were 18-82 years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II.
RESULTS
The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8 years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0.
CONCLUSION
The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT04136184.
PubMed: 36525140
DOI: 10.1007/s40120-022-00414-z -
International Journal of Molecular... Dec 2022The unexpected dissolution behaviour of amorphous diflunisal-chitosan solid dispersions (kneading method) with respect to the crystalline co-evaporated systems is the...
The unexpected dissolution behaviour of amorphous diflunisal-chitosan solid dispersions (kneading method) with respect to the crystalline co-evaporated systems is the starting point of this research. This work is an in-depth study of the diflunisal release behaviour from either chitosan or carboxymethylchitosan dispersions. The microstructure is not usually considered when designing this type of products; however, it is essential to understand the process of solvent penetration and subsequent drug release through a polymeric system, as has been evidenced in this study. In accordance with the kinetic data analysed, it is possible to conclude that the porous structure, conditioned by the sample preparation method, can be considered the main factor involved in diflunisal release. The low mean pore size (1-2 μm), low porosity, and high tortuosity of the amorphous kneaded products are responsible for the slow drug release in comparison with the crystalline coevaporated systems, which exhibit larger pore size (8-10 μm) and lower tortuosity. Nevertheless, all diflunisal-carboxymethylchitosan products show similar porous microstructure and overlapping dissolution profiles. The drug release mechanisms obtained can also be related to the porous structure. Fickian diffusion was the main mechanism involved in drug release from chitosan, whereas an important contribution of erosion was detected for carboxymethylchitosan systems, probably due to its high solubility.
Topics: Drug Liberation; Chitosan; Solubility; Diflunisal; Polymers
PubMed: 36499692
DOI: 10.3390/ijms232315367 -
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 -
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 -
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) Apr 2022The bacterial cell wall is essential for protecting bacteria from the surrounding environment and maintaining the integrity of bacteria cells. The MurA enzyme, which is...
The bacterial cell wall is essential for protecting bacteria from the surrounding environment and maintaining the integrity of bacteria cells. The MurA enzyme, which is an essential enzyme involved in bacterial cell wall synthesis, could be a good drug target for antibiotics. Although fosfomycin is used clinically as a MurA inhibitor, resistance to this antibiotic is a concern. Here we used molecular docking-based virtual screening approaches to identify potential MurA inhibitors from 1.412 million compounds from three databases. Thirty-three top compounds from virtual screening were experimentally tested in (Gram-positive bacterium) and (Gram-negative bacterium). Compound 2-Amino-5-bromobenzimidazole (S17) showed growth inhibition effect in both and , with the same Minimum Inhibitory Concentration (MIC) value of 0.5 mg/mL. Compound 2-[4-(dimethylamino)benzylidene]--nitrohydrazinecarboximidamide (C1) had growth inhibition effect only in , with a MIC value of 0.5 mg/mL. Two FDA-approved drugs, albendazole (S4) and diflunisal (S8), had a growth inhibition effect only in , with a MIC value of 0.0625 mg/mL. The identified MurA inhibitors could be potential novel antibiotics. Furthermore, they could be potential fosfomycin substitutes for the fosfomycin-resistant strains.
PubMed: 35453279
DOI: 10.3390/antibiotics11040528 -
Medicina 2022This clinical practice guideline for treating transthyretin amyloid (ATTR) cardiomyopathy is based on the best available evidence of clinical effectiveness. The PICO...
This clinical practice guideline for treating transthyretin amyloid (ATTR) cardiomyopathy is based on the best available evidence of clinical effectiveness. The PICO format was used to generate a list of questions focused on the effectiveness and safety of the specific treatment of patients with ATTR cardiomyopathy. The search was conducted in PubMed, Cochrane and Epistemokus, between July-August 2020, and selected articles between 2000-2020, in English and Spanish. The level of evidence and recommendations were analyzed and classified by the GRADE system. The following drugs were included in the analysis: tafamidis, diflunisal, inotersen, patisiran y doxycycline and ursodeoxycholic acid. The expert panel had an agreement that tafamidis 80mg/daily is the only available drug with moderate evidence and weak recommendation for the reduction of total mortality, cardiovascular morbidity, heart failure hospitalization and progression of the disease in patients with ATTR cardiomyopathy and NYHA class = 3. In contrast, tafamidis 20 mg/daily had low-quality evidence in this group of patients. The expert panel did not recommend inotersen, patisiran and diflunisal in patients with ATTR cardiomyopathy due to the lack of supporting evidence, local drug availability, and the potential risk of toxicity. When patients did not have access to tafamidis, the expert panel stated a weak recommendation to use doxycycline and ursodeoxycholic acid in patients with ATTR cardiomyopathy.
Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Diflunisal; Doxycycline; Humans; Prealbumin; Ursodeoxycholic Acid
PubMed: 35417392
DOI: No ID Found -
Medicina 2022This clinical practice guideline for the treatment of familial amyloid polyneuropathy is based on the best available evidence of clinical effectiveness. A list of...
This clinical practice guideline for the treatment of familial amyloid polyneuropathy is based on the best available evidence of clinical effectiveness. A list of questions was generated with a PICO format focused on the effectiveness and safety of the treatment of familial amyloid polyneuropathy. The search was carried out in PubMed, Cochrane and Epistemonikos. The levels of evidence and grades of recommendation were based on the GRADE system. Recommendations were graded according to their direction and their strength and were evaluated with the GLIA tool for their implementation. In patients with familial amyloid polyneuropathy and stage I and II neuropathy, it is suggested: inotersen 300 mg subcutaneous weekly or patisirán 0.3 mg/kg intravenously once every 3 weeks, since they probably stabilize or slow the progression of neuropathy and worsening quality of life (moderate quality of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and stage I neuropathy, treatment with tafamidis 20 mg orally, once a day, is suggested, as it could slow the progression of neuropathy and worsen quality of life (low quality of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and symptomatic neuropathy and in the absence of other treatments with approved efficacy, treatment with oral diflunisal 250 mg twice daily is suggested, as it could prevent the progression of neuropathy (quality evidence low; strength of recommendation weak).
Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Humans; Prealbumin; Quality of Life; Treatment Outcome
PubMed: 35417391
DOI: No ID Found -
Internal Medicine (Tokyo, Japan) Aug 2022We herein report a 44-year-old Japanese man with hereditary transthyretin amyloidosis (ATTRv amyloidosis) harboring the variant Leu58Arg (p.Leu78Arg) in TTR in whom we... (Observational Study)
Observational Study
We herein report a 44-year-old Japanese man with hereditary transthyretin amyloidosis (ATTRv amyloidosis) harboring the variant Leu58Arg (p.Leu78Arg) in TTR in whom we conducted an observational study with liver transplantation (LT) and transthyretin (TTR) stabilizers (tafamidis and diflunisal) for 9 years. This patient showed gradual deterioration of sensory, motor, and autonomic neuropathy symptoms after LT. Furthermore, cardiac amyloidosis gradually developed. Although the present case showed deterioration of the symptoms after disease-modifying treatments, LT might be suitable in patients with the same variant if they are young and in good condition due to a long survival after LT.
Topics: Adult; Amyloid Neuropathies, Familial; Humans; Liver Transplantation; Male; Nervous System Diseases; Prealbumin
PubMed: 35283385
DOI: 10.2169/internalmedicine.8945-21