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1.
Front Endocrinol (Lausanne) ; 15: 1329294, 2024.
Article in English | MEDLINE | ID: mdl-38828415

ABSTRACT

Aim: Short-term use of pemafibrate (PEM), a selective modulator of peroxisome proliferator-activated receptor alpha, has been reported to improve abnormal liver function in patients with nonalcoholic fatty liver disease with hypertriglyceridemia (HTG-NAFLD). This study aimed to clarify the effects and predictive factors of long-term 72-week PEM administration on body composition, and laboratory tests in HTG-NAFLD patients. Methods: Fifty-three HTG-NAFLD patients receiving a 72-week PEM regimen were retrospectively enrolled. Routine blood and body composition results were analyzed immediately before and at the end of the study period. Results: PEM treatment significantly improved liver enzyme levels such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and gamma-glutamyl transferase, along with lipid profiles including triglyceride, total cholesterol, and low-density lipoprotein cholesterol. PEM did not have any detectable impact on body composition parameters. The factors of female, higher AST (≥ 46 U/L) and fat mass (≥ 31.9%), as well as lower soft lean mass (< 61.6%), skeletal muscle mass (< 36%), and skeletal muscle mass index (< 6.9 kg/m2) were significantly associated with the treatment response status of a > 30% decrease in ALT. All patients completed the treatment without any adverse effects. Conclusions: Long-term PEM treatment had a positive impact on liver enzymes and lipid profiles, but it did not result in significant changes in body composition among HTG-NAFLD patients. In predicting the response to PEM treatment, the evaluation of AST and body composition may be useful.


Subject(s)
Body Composition , Hypertriglyceridemia , Non-alcoholic Fatty Liver Disease , Humans , Female , Male , Middle Aged , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/complications , Hypertriglyceridemia/blood , Retrospective Studies , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/blood , Body Composition/drug effects , Benzoxazoles/therapeutic use , Benzoxazoles/administration & dosage , Adult , Butyrates/therapeutic use , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Adipose Tissue/pathology , Aged , Hypolipidemic Agents/therapeutic use , Hypolipidemic Agents/administration & dosage
2.
Heart Fail Clin ; 20(3): 333-341, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38844304

ABSTRACT

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the myocardial extracellular deposition of amyloid fibrils formed from the dissociation of TTR tetramer into monomers. The rate-limiting step in TTR amyloidogenesis is the dissociation of the TTR tetramer into monomers: Tafamidis is an effective TTR-stabilizer in its native homotetrameric structure. Tafamidis is a safe and effective drug in reducing symptoms, hospitalization and mortality in accurately selected patients affected by hereditary and wild-type transthyretin amyloid cardiomyopathy.


Subject(s)
Amyloid Neuropathies, Familial , Benzoxazoles , Cardiomyopathies , Humans , Benzoxazoles/therapeutic use , Benzoxazoles/pharmacology , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/complications , Amyloid Neuropathies, Familial/genetics , Cardiomyopathies/drug therapy , Cardiomyopathies/metabolism , Prealbumin/genetics , Prealbumin/metabolism
3.
Heart Fail Clin ; 20(3): 343-352, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38844305

ABSTRACT

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a relatively prevalent cause of morbidity and mortality. Over the recent years, development of disease-modifying treatments has enabled stabilization of the circulating transthyretin tetramer and suppression of its hepatic production, resulting in a remarkable improvement in survival of patients with ATTR-CM. Second-generation drugs for silencing are currently under investigation in randomized clinical trials. In vivo gene editing of transthyretin has been achieving unanticipated suppression of hepatic production in ATTR-CM. Trials of antibodies inducing the active removal of transthyretin amyloid deposits in the heart are ongoing, and evidence has gathered for exceptional spontaneous regression of ATTR-CM.


Subject(s)
Amyloid Neuropathies, Familial , Benzoxazoles , Cardiomyopathies , Prealbumin , Humans , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/metabolism , Cardiomyopathies/drug therapy , Cardiomyopathies/metabolism , Benzoxazoles/therapeutic use , Prealbumin/metabolism , Prealbumin/genetics
4.
J Am Heart Assoc ; 13(10): e034518, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38761073

ABSTRACT

BACKGROUND: Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic effect remains unclear. This study investigated the association between changes in cardiac biomarkers, high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) during the first year after tafamidis treatment and clinical outcomes. METHODS AND RESULTS: In 101 patients with wild-type transthyretin amyloid cardiomyopathy receiving tafamidis at our institution, change in cardiac biomarkers from baseline to 1 year after tafamidis administration and its association with composite outcomes (composite of all-cause death and hospitalization attributable to heart failure) was assessed. During the follow-up period (median, 17 months), 16 (16%) patients experienced composite outcomes. The hs-cTnT level significantly decreased at 1 year after tafamidis treatment, unlike the BNP level. The frequencies of increased hs-cTnT and BNP levels were significantly higher in those with composite outcomes than in those without (44% versus 15%; P=0.01). Kaplan-Meier survival analysis showed that patients in whom both hs-cTnT and BNP levels increased at 1 year after tafamidis had a higher probability of composite outcomes compared with those with decreased hs-cTnT and BNP levels (log-rank P<0.01). Cox regression analysis identified increased hs-cTnT and BNP levels at 1 year after tafamidis administration as an independent predictor of higher cumulative risk of composite outcomes. CONCLUSIONS: Deterioration in cardiac biomarkers during the first year after tafamidis treatment predicted a worse prognosis, suggesting the utility of serial assessment of cardiac biomarkers for monitoring the therapeutic response to tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy.


Subject(s)
Amyloid Neuropathies, Familial , Benzoxazoles , Biomarkers , Cardiomyopathies , Natriuretic Peptide, Brain , Troponin T , Humans , Male , Female , Biomarkers/blood , Natriuretic Peptide, Brain/blood , Aged , Amyloid Neuropathies, Familial/blood , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/mortality , Amyloid Neuropathies, Familial/diagnosis , Benzoxazoles/therapeutic use , Troponin T/blood , Cardiomyopathies/blood , Cardiomyopathies/drug therapy , Cardiomyopathies/mortality , Cardiomyopathies/diagnosis , Treatment Outcome , Time Factors , Middle Aged , Aged, 80 and over , Heart Failure/blood , Heart Failure/drug therapy , Heart Failure/mortality , Retrospective Studies , Prealbumin/metabolism
5.
Eur J Gastroenterol Hepatol ; 36(6): 793-801, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38526942

ABSTRACT

BACKGROUND/AIMS: Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. We previously reported that pemafibrate significantly improves liver function, serum triglyceride (TG) levels and liver stiffness in non-alcoholic fatty liver disease patients, however the influence of alcohol consumption was not considered. Therefore, we explored pemafibrate efficacy in patients with steatotic liver disease (SLD) and alcohol-associated liver disease (ALD). METHODS: We retrospectively evaluated pemafibrate efficacy on liver enzymes and lipids in metabolic dysfunction-associated SLD (MASLD) (n = 93), MASLD plus increased alcohol intake (MetALD; n = 23) and ALD (n = 22) patients who had taken pemafibrate for at least 48 weeks. Liver shear wave velocity (SWV, n = 75) was also evaluated. RESULTS: In MASLD group, ALT, aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and TG values were significantly decreased from baseline to week 24 and week 48 ( P  < 0.0001). ALT and TG values in MetALD group and ALT and AST values in ALD group were also significantly decreased from baseline to week 24 and week 48. Study participant SWV values decreased from baseline to week 48. We observed no significant difference in changes to ALT, AST, γ-GTP and TG (value at week 24 or week 48 minus value at baseline) among the three groups. CONCLUSION: Pemafibrate improves liver function and liver stiffness thus making it a promising therapeutic agent for SLD, even in patients with excess alcohol consumption (MetALD and ALD groups).


Subject(s)
Alanine Transaminase , Alcohol Drinking , Aspartate Aminotransferases , Benzoxazoles , Butyrates , Liver , Triglycerides , gamma-Glutamyltransferase , Humans , Male , Female , Middle Aged , Retrospective Studies , gamma-Glutamyltransferase/blood , Alcohol Drinking/adverse effects , Treatment Outcome , Butyrates/therapeutic use , Benzoxazoles/therapeutic use , Alanine Transaminase/blood , Triglycerides/blood , Aspartate Aminotransferases/blood , Aged , Liver/drug effects , Liver/pathology , Elasticity Imaging Techniques , Adult , Non-alcoholic Fatty Liver Disease/drug therapy , Time Factors , Biomarkers/blood , Fatty Liver/drug therapy , Fatty Liver, Alcoholic/drug therapy
6.
Eur J Heart Fail ; 26(3): 612-615, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38439606

ABSTRACT

AIMS: To evaluate the effect of long-term tafamidis treatment on health-related quality of life (HRQoL) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension (LTE) study. METHODS AND RESULTS: We examined change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) and clinical summary (KCCQ-CS) scores in patients who received tafamidis meglumine 80 mg for 30 months in ATTR-ACT and tafamidis (meglumine 80 mg or bioequivalent free acid 61 mg) for 30 months in the LTE study, and in patients who received placebo for 30 months in ATTR-ACT and tafamidis for 30 months in the LTE study. In ATTR-ACT, 176 and 177 patients were randomized to tafamidis 80 mg and placebo, respectively. Patients who continuously received tafamidis had a 6- to 7-point reduction in least squares (LS) mean (standard error) KCCQ-OS and KCCQ-CS scores at month 30 (-6.25 [1.53] and -7.48 [1.39]), with little or no further decline over the next 30 months (-5.92 [1.77] and -9.21 [1.88] at month 60). Patients who received placebo in ATTR-ACT had a 20-point reduction in LS mean KCCQ-OS and KCCQ-CS scores at month 30 (-19.60 [1.94] and -19.90 [2.01]), but the decline slowed after initiating tafamidis (-24.70 [3.04] and -25.30 [3.36] at month 60). CONCLUSION: Tafamidis reduced HRQoL decline in patients with ATTR-CM. Patients continuously treated with tafamidis for 60 months demonstrated stabilized HRQoL. In patients who initially received placebo in ATTR-ACT, tafamidis reduced the decline in HRQoL during the LTE study.


Subject(s)
Amyloid Neuropathies, Familial , Benzoxazoles , Cardiomyopathies , Quality of Life , Humans , Male , Female , Benzoxazoles/therapeutic use , Amyloid Neuropathies, Familial/drug therapy , Aged , Cardiomyopathies/drug therapy , Middle Aged , Double-Blind Method , Treatment Outcome , Surveys and Questionnaires , Time Factors
7.
Med Clin (Barc) ; 162(9): e27-e32, 2024 05 17.
Article in English, Spanish | MEDLINE | ID: mdl-38556397

ABSTRACT

INTRODUCTION: Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain. METHODS: This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed. RESULTS: 100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability. CONCLUSIONS: Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment.


Subject(s)
Amyloid Neuropathies, Familial , Benzoxazoles , Polyneuropathies , Humans , Male , Female , Benzoxazoles/therapeutic use , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/complications , Spain , Aged , Middle Aged , Polyneuropathies/drug therapy , Polyneuropathies/etiology , Treatment Outcome , Prealbumin/genetics , Aged, 80 and over , Peptide Fragments/blood
8.
Curr Opin Cardiol ; 39(4): 286-291, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38482842

ABSTRACT

PURPOSE OF REVIEW: Although high triglycerides are consistently associated with elevated risk of cardiovascular disease (CVD), therapies that reduce triglyceride levels have inconsistently translated into reduced CVD risk. RECENT FINDINGS: To date, three clinical trials have tested triglyceride-lowering therapies in patients with hypertriglyceridemia (HTG) and elevated risk of incident/recurrent CVD. In REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), assignment to IPE, a highly purified eicosapentanoic acid (EPA), resulted in a 25% reduction in nonfatal myocardial infarction), nonfatal stroke, cardiovascular death, coronary revascularization and hospitalization for unstable angina. By contrast, the combination of EPA and docosahexanoic acid (DHA) carboxylic fatty acids used in the STRENGTH trial (Statin Residual Risk With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia) failed to reduce CVD risk. Most recently, PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) also failed to demonstrate reduction in CVD events despite use of a potent triglyceride-lowering, fibric-acid derivative. However, improvement in HTG-associated metabolic complications (e.g. nonalcoholic fatty liver disease) was observed with pemafibrate as well as with another potent triglyceride-lowering therapy (i.e. pegozafermin). Moreover, trials are underway evaluating whether the most fatal metabolic complication of HTG, pancreatitis, may be reduced with highly potent triglyceride-lowering therapies (e.g. apolipoprotein C3 inhibitors). SUMMARY: Taken together, HTG is associated with increased risk of CVD and attendant adverse metabolic sequalae. To this end, a potentially promising and evidence-based landscape is emerging for treating a clinical phenotype that in the past has been insufficiently addressed.


Subject(s)
Benzoxazoles , Butyrates , Cardiovascular Diseases , Hypertriglyceridemia , Hypolipidemic Agents , Humans , Cardiovascular Diseases/prevention & control , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/complications , Hypolipidemic Agents/therapeutic use , Benzoxazoles/therapeutic use , Butyrates/therapeutic use , Butyrates/pharmacology , Triglycerides/blood , Metabolic Diseases/prevention & control
9.
Heart Vessels ; 39(6): 486-495, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38393377

ABSTRACT

This study examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α agonist, on the serum biochemical parameters of male patients with coronary artery disease and metabolic syndrome (MetS). This was a post hoc analysis of a randomized, crossover study that treated hypertriglyceridemia with pemafibrate or bezafibrate for 24 weeks, followed by a crossover of another 24 weeks. Of the 60 patients enrolled in the study, 55 were male. Forty-one of 55 male patients were found to have MetS. In this sub-analysis, male patients with MetS (MetS group, n = 41) and those without MetS (non-MetS group, n = 14) were compared. The primary endpoint was a change in fasting serum triglyceride (TG) levels during pemafibrate therapy, and the secondary endpoints were changes in insulin resistance-related markers and liver function parameters. Serum TG levels significantly decreased (MetS group, from 266.6 to 148.0 mg/dL, p < 0.001; non-MetS group, from 203.9 to 97.6 mg/dL, p < 0.001); however, a percent change (%Change) was not significantly different between the groups (- 44.1% vs. - 51.6%, p = 0.084). Serum insulin levels and homeostasis model assessment of insulin resistance significantly decreased in the MetS group but not in the non-MetS group. %Change in liver enzyme levels was markedly decreased in the MetS group compared with that in the non-MetS group (alanine aminotransferase, - 25.1% vs. - 11.3%, p = 0.027; gamma-glutamyl transferase, - 45.8% vs. - 36.2%, p = 0.020). In conclusion, pemafibrate can effectively decrease TG levels in patients with MetS, and it may be a more efficient drug for improving insulin resistance and liver function in such patients.


Subject(s)
Benzoxazoles , Butyrates , Coronary Artery Disease , Cross-Over Studies , Hypertriglyceridemia , Insulin Resistance , Metabolic Syndrome , Humans , Male , Metabolic Syndrome/blood , Metabolic Syndrome/drug therapy , Metabolic Syndrome/complications , Metabolic Syndrome/diagnosis , Hypertriglyceridemia/blood , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/complications , Hypertriglyceridemia/diagnosis , Middle Aged , Coronary Artery Disease/blood , Coronary Artery Disease/drug therapy , Benzoxazoles/therapeutic use , Benzoxazoles/pharmacology , Butyrates/therapeutic use , Butyrates/pharmacology , Treatment Outcome , Aged , Triglycerides/blood , Hypolipidemic Agents/therapeutic use , Hypolipidemic Agents/pharmacology , Biomarkers/blood , PPAR alpha/agonists , Bezafibrate/therapeutic use , Bezafibrate/pharmacology
10.
Diabetes Metab J ; 48(3): 473-481, 2024 May.
Article in English | MEDLINE | ID: mdl-38419467

ABSTRACT

BACKGRUOUND: Fibrates have renal toxicity limiting their use in subjects with chronic kidney disease (CKD). However, pemafibrate has fewer toxic effects on renal function. In the present analysis, we evaluated the effects of pemafibrate on the renal function of diabetic subjects with or without CKD in a real-world clinical setting. METHODS: We performed a sub-analysis of data collected during a multi-center, prospective, observational study of the effects of pemafibrate on lipid metabolism in subjects with type 2 diabetes mellitus complicated by hypertriglyceridemia (the PARM-T2D study). The participants were allocated to add pemafibrate to their existing regimen (ADD-ON), switch from their existing fibrate to pemafibrate (SWITCH), or continue conventional therapy (CTRL). The changes in estimated glomerular filtration rate (eGFR) over 52 weeks were compared among these groups as well as among subgroups created according to CKD status. RESULTS: Data for 520 participants (ADD-ON, n=166; SWITCH, n=96; CTRL, n=258) were analyzed. Of them, 56.7% had CKD. The eGFR increased only in the SWITCH group, and this trend was also present in the CKD subgroup (P<0.001). On the other hand, eGFR was not affected by switching in participants with severe renal dysfunction (G3b or G4) and/or macroalbuminuria. Multivariate analysis showed that being older and a switch from fenofibrate were associated with elevation in eGFR (both P<0.05). CONCLUSION: A switch to pemafibrate may be associated with an elevation in eGFR, but to a lesser extent in patients with poor renal function.


Subject(s)
Butyrates , Diabetes Mellitus, Type 2 , Glomerular Filtration Rate , Hypolipidemic Agents , Renal Insufficiency, Chronic , Humans , Male , Female , Middle Aged , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/complications , Glomerular Filtration Rate/drug effects , Aged , Prospective Studies , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Hypolipidemic Agents/therapeutic use , Butyrates/therapeutic use , Butyrates/pharmacology , Benzoxazoles/therapeutic use , Benzoxazoles/pharmacology , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/complications , Diabetic Nephropathies/drug therapy , Kidney/drug effects , Kidney/physiopathology
11.
Kurume Med J ; 69(3.4): 167-174, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38233183

ABSTRACT

OBJECTIVE: Oxidative damage is observed in the ischemic limbs of patients with arteriosclerosis obliterans. We investigated whether pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, reduced oxidative stress in ischemic limbs and consequently rescued limb damage in model mice. MATERIALS AND METHODS: We surgically induced hind-limb ischemia in mice and orally administered pemafibrate solution (P-05 group, 0.5 mg/kg/day; P-10 group, 1.0 mg/kg/day) or control solution (control group). Seven days after the surgery, differences in reactive oxygen species (ROS) contents, antioxidative enzyme and transcription factor expression, blood flow, and capillary density in ischemic limbs were assessed. RESULTS: Tissue ROS levels were lower in the P-05 and P-10 groups compared with those in the control group. Although the tissue expression levels of nuclear factor-erythroid 2-related factor 2 increased in the P-10 group compared with that in the control group, no corresponding changes were observed in the tissue expression of four antioxidative enzymes. The limb salvage rates and capillary densities in ischemic limbs were higher in the P-05 and P-10 groups than that in the control group. CONCLUSION: Pemafibrate treatment reduced oxidative stress and augmented angiogenesis in ischemic limbs, contributing to prevention of limb damage in mice.


Subject(s)
Benzoxazoles , Butyrates , Disease Models, Animal , Hindlimb , Ischemia , Neovascularization, Physiologic , Oxidative Stress , Reactive Oxygen Species , Animals , Oxidative Stress/drug effects , Benzoxazoles/pharmacology , Benzoxazoles/therapeutic use , Ischemia/drug therapy , Ischemia/metabolism , Neovascularization, Physiologic/drug effects , Male , Hindlimb/blood supply , Reactive Oxygen Species/metabolism , Butyrates/pharmacology , Butyrates/therapeutic use , Mice , Antioxidants/pharmacology , NF-E2-Related Factor 2/metabolism , Regional Blood Flow/drug effects , PPAR alpha/metabolism , Limb Salvage , Angiogenesis
12.
Eur Heart J Cardiovasc Imaging ; 25(5): 678-686, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38109497

ABSTRACT

AIMS: Although tafamidis is used in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), its specific effect on cardiac function is unclear. Thus, this study aimed to investigate the effect of tafamidis on left atrial (LA) and left ventricular function using speckle-tracking echocardiography for 1 year of treatment in patients with ATTRwt-CA. METHODS AND RESULTS: We included 23 patients (mean age, 76 years) with ATTRwt-CA confirmed via biopsy. We analysed the left ventricular and LA strain using 2D speckle-tracking echocardiography and compared these parameters before and 1 year after starting treatment with tafamidis between 16 patients with sinus rhythm (SR) and 7 patients with atrial fibrillation (AF). In ATTRwt-CA patients with SR, LA reservoir strain significantly improved by 1-year tafamidis treatment (10.5 ± 5.0% to 11.9 ± 5.3%, P = 0.0307) although global longitudinal strain (GLS) did not (-10.6 ± 3.1% to -11.3 ± 3.0%, P = 0.0608). In contrast, LA reservoir strain was not significantly changed (5.4 ± 2.9% to 4.9 ± 1.7%, P = 0.4571), and GLS deteriorated (-8.4 ± 2.3% to -6.8 ± 1.4%, P = 0.0267) in ATTRwt-CA patients with AF. CONCLUSION: LA function improved with tafamidis treatment in ATTRwt-CA patients with SR but not left ventricular function. However, these cardiac functions did not improve with tafamidis treatment in ATTRwt-CA patients with AF.


Subject(s)
Amyloid Neuropathies, Familial , Benzoxazoles , Echocardiography , Aged , Female , Humans , Male , Amyloid Neuropathies, Familial/diagnostic imaging , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/complications , Atrial Fibrillation/drug therapy , Atrial Fibrillation/diagnostic imaging , Benzoxazoles/therapeutic use , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/drug therapy , Cohort Studies , Treatment Outcome , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/physiopathology
13.
Z Naturforsch C J Biosci ; 78(11-12): 433-440, 2023 Nov 27.
Article in English | MEDLINE | ID: mdl-37903727

ABSTRACT

A series of new benzoxazole-hydrazone and benzoxazole-1,3,4-oxadiazole derivatives have been designed, synthesized and evaluated as cytotoxic agents toward human A549 lung cancer cells. Compounds 3d, 3e, 5b, 5c, 5d and 5e were the most potent compounds with IC50 values of <3.9, 10.33, 11.6, 5.00, <3.9 and 4.5 µg/mL, respectively, which are higher than reference drug cisplatin (IC50 = 19.00 µg/mL). The flow cytometry-based apoptosis detection assay was performed to determine their effects on apoptosis in A549 cells. All tested compounds induced apoptosis in A549 cell line.


Subject(s)
Antineoplastic Agents , Lung Neoplasms , Humans , Benzoxazoles/pharmacology , Benzoxazoles/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Cisplatin/pharmacology , A549 Cells , Drug Screening Assays, Antitumor , Structure-Activity Relationship , Cell Proliferation , Apoptosis , Cell Line, Tumor , Molecular Structure
15.
Amyloid ; 30(3): 303-312, 2023 Sep.
Article in English | MEDLINE | ID: mdl-36795029

ABSTRACT

BACKGROUND: By stabilizing transthyretin, tafamidis delays progression of amyloidosis due to transthyretin variant (ATTRv) and replaced liver transplantation (LT) as the first-line therapy. No study compared these two therapeutic strategies. METHODS: In a monocentric retrospective cohort analysis, patients with ATTRv amyloidosis treated with either tafamidis or LT were compared using a propensity score and a competing risk analysis for three endpoints: all-cause mortality, cardiac worsening (heart failure or cardiovascular death) and neurological worsening (worsening in PolyNeuropathy Disability score). RESULTS: 345 patients treated with tafamidis (n = 129) or LT (n = 216) were analyzed, and 144 patients were matched (72 patients in each group, median age 54 years, 60% carrying the V30M mutation, 81% of stage I, 69% with cardiac involvement, median follow-up: 68 months). Patients treated with tafamidis had longer survival than LT patients (HR: 0.35; p = .032). Conversely, they also presented a 3.0-fold higher risk of cardiac worsening and a 7.1-fold higher risk of neurological worsening (p = .0071 and p < .0001 respectively). CONCLUSIONS: ATTRv amyloidosis patients treated with tafamidis would present a better survival but also a faster deterioration of their cardiac and neurological statuses as compared with LT. Further studies are needed to clarify the therapeutic strategy in ATTRv amyloidosis.


Subject(s)
Amyloid Neuropathies, Familial , Liver Transplantation , Humans , Middle Aged , Prealbumin/genetics , Retrospective Studies , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/genetics , Amyloid Neuropathies, Familial/surgery , Benzoxazoles/therapeutic use
16.
JAMA Cardiol ; 8(3): 275-280, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36723935

ABSTRACT

Importance: Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients with transthyretin (ATTR) amyloidosis. However, the clinical significance of health status changes remains unclear, particularly in patients with New York Heart Association (NYHA) class III symptoms who experienced more cardiovascular-related hospitalizations than those with NYHA class I-II symptoms. Objective: To evaluate the health status of patients taking tafamidis with baseline NYHA class III symptoms. Design, Setting, and Participants: This randomized clinical trial post hoc analysis evaluated data for patients with transthyretin (ATTR) cardiac amyloidosis and NYHA class I-III symptoms at baseline who were enrolled in ATTR-ACT, a placebo-controlled study of tafamidis held at 48 sites in 13 countries. Interventions: Tafamidis meglumine, 80 mg or 20 mg (pooled cohort), vs placebo. Main Outcomes and Measures: Established thresholds for clinical benefit on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) were used to define response groups (very large decline to very large improvement); the proportion of patients in each group was calculated within each baseline NYHA class. Results: Among 441 patients (264 tafamidis, 177 placebo), the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group and 65.9 (21.7) in the placebo group (range: 0-100, with 100 indicating the best health). There was a significant shift toward better KCCQ-OS scores in patients receiving tafamidis (odds ratio for 10-point improvement 2.4; 95% CI, 1.6-3.4; P < .001). More patients taking tafamidis were alive and not worse at all time points (37% vs 15% at month 30). These findings were similar in patients with NYHA class III symptoms. In patients with NYHA class III symptoms alive at 30 months, improvements in health status were more common (35% vs 10%) and declines were less common (38% vs 57%) with tafamidis vs placebo. Conclusions and Relevance: In ATTR-ACT, although patients with baseline NYHA class III symptoms had worse overall outcomes, treatment with tafamidis yielded better health status compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT01994889.


Subject(s)
Amyloidosis , Prealbumin , Humans , Male , Female , Aged , Benzoxazoles/therapeutic use , Health Status
17.
Future Cardiol ; 19(1): 7-17, 2023 01.
Article in English | MEDLINE | ID: mdl-36715498

ABSTRACT

WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results. WHAT DID RESEARCHERS FIND OUT?: In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study. WHAT DO THE RESULTS MEAN?: Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM. Clinical Trial Registration: NCT01994889 (ClinicalTrials.gov) Clinical Trial Registration: NCT02791230 (ClinicalTrials.gov).


Subject(s)
Amyloid Neuropathies, Familial , Cardiomyopathies , Humans , Amyloid Neuropathies, Familial/drug therapy , Prealbumin/therapeutic use , Benzoxazoles/therapeutic use
18.
J Atheroscler Thromb ; 30(5): 443-454, 2023 05 01.
Article in English | MEDLINE | ID: mdl-35768226

ABSTRACT

AIM: Pemafibrate is a highly selective agonist for peroxisome proliferator-activated receptor (PPAR)-α, a key regulator of lipid and glucose metabolism. We compared the efficacy and safety of pemafibrate with those of bezafibrate, a nonselective PPAR-α agonist. METHODS: In this randomized crossover study, 60 patients with hypertriglyceridemia (fasting triglyceride [TG] ≥ 150 mg/dL) were treated with pemafibrate of 0.2 mg/day or bezafibrate of 400 mg/day for 24 weeks. The primary endpoint was percent change (%Change) from baseline in TG levels, while the secondary endpoints were %Change in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I) levels. RESULTS: The %Change in TG and Apo A-I levels was significantly greater with pemafibrate than with bezafibrate (-46.1% vs. -34.7%, p<0.001; 9.2% vs. 5.7%, p =0.018, respectively). %Change in HDL-C levels was not significantly different between the two treatments. %Change in liver enzyme levels was markedly decreased with pemafibrate than with bezafibrate. Creatinine levels significantly increased in both treatments; however, its %Change was significantly lower with pemafibrate than with bezafibrate (5.72% vs. 15.5%, p<0.001). The incidence of adverse events (AEs) or serious AEs did not differ between the two treatments; however, the number of patients with elevated creatinine levels (≥ 0.5 mg/dL and/or 25% from baseline) was significantly higher in the bezafibrate group than in the pemafibrate group (14/60 vs. 3/60, p =0.004) [corrected]. CONCLUSION: Compared with bezafibrate, pemafibrate is more effective in decreasing TG levels and increasing Apo A-I levels and is safer regarding liver and renal function.


Subject(s)
Apolipoprotein A-I , Bezafibrate , Cholesterol, HDL , Hypertriglyceridemia , Humans , Hypertriglyceridemia/drug therapy , Bezafibrate/therapeutic use , Butyrates/therapeutic use , Benzoxazoles/therapeutic use , Cross-Over Studies , Apolipoprotein A-I/blood , Apolipoprotein A-I/drug effects , Cholesterol, HDL/blood , Cholesterol, HDL/drug effects , Treatment Outcome , Peroxisome Proliferator-Activated Receptors/metabolism , Triglycerides/metabolism , Male , Female , Adult , Middle Aged , Aged
19.
Amyloid ; 30(2): 208-219, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36399070

ABSTRACT

BACKGROUND: Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial demonstrated the efficacy of tafamidis, the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed. METHODS: We developed a model of dynamic TTR concentrations in plasma to relate TTR occupancy by tafamidis to TTR stabilisation. We then developed population pharmacokinetic-pharmacodynamic models to characterise the relationship between stabilisation and measures of disease progression. RESULTS: Modelling individual patient data of tafamidis exposure and increased plasma TTR confirmed that single-site binding provides complete tetramer stabilisation in vivo. The approved dose was estimated to reduce unbound TTR tetramer by 92%, and was associated with 53%, 56% and 49% decreases in the rate of change in NT-proBNP, KCCQ-OS, and six-minute walk test disease progression measures, respectively. Simulating complete TTR stabilisation predicted slightly greater reductions of 58%, 61% and 54%, respectively. CONCLUSIONS: These findings support the value of TTR stabilisation as a clinically beneficial treatment option in ATTR-CM and the ability of tafamidis to realise nearly the full therapeutic benefit of this mechanism. CLINICALTRIALS.GOV IDENTIFIER: NCT01994889.


Subject(s)
Amyloid Neuropathies, Familial , Cardiomyopathies , Humans , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/genetics , Amyloid Neuropathies, Familial/complications , Prealbumin/genetics , Prealbumin/metabolism , Benzoxazoles/therapeutic use , Cardiomyopathies/metabolism , Disease Progression
20.
Amyloid ; 30(1): 81-95, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36178172

ABSTRACT

BACKGROUND: TTR aggregation causes hereditary transthyretin (TTR) polyneuropathy (ATTRv-PN) in individuals with destabilised TTR variants. ATTRv-PN can be treated with ligands that bind TTR and prevent aggregation. One such ligand, tafamidis, is widely approved to treat ATTRv-PN. We explore how TTR stabilisation markers relate to clinical efficacy in 210 ATTRv-PN patients taking tafamidis. METHODS: TTR concentration in patient plasma was measured before and after tafamidis treatment using assays for native or combined native + non-native TTR. TTR tetramer dissociation kinetics, which are slowed by tafamidis binding, were also measured. RESULTS: Native TTR levels increased by 56.8% while combined native + non-native TTR levels increased by 3.1% after 24 months of tafamidis treatment, implying that non-native TTR decreased. Accordingly, the fraction of native TTR increased from 0.54 to 0.71 with tafamidis administration. Changes in native and non-native TTR levels were uncorrelated with clinical response to tafamidis. TTR tetramer dissociation generally slowed to an extent consistent with ∼40% of TTR being tafamidis-bound. Male non-responders had a lower extent of binding. CONCLUSIONS: Native and non-native TTR concentration changes cannot be used as surrogate measures for therapeutic efficacy. Also, successful tafamidis therapy requires only moderate TTR stabilisation. Male patients may benefit from higher tafamidis doses.


Subject(s)
Amyloid Neuropathies, Familial , Polyneuropathies , Humans , Male , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/genetics , Prealbumin/genetics , Prealbumin/metabolism , Polyneuropathies/drug therapy , Polyneuropathies/genetics , Benzoxazoles/pharmacology , Benzoxazoles/therapeutic use
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