Tafamidis in transthyretin amyloid cardiomyopathy

Transthyretin is primarily synthesized in the liver and transports thyroxine and vitamin A in the body. The transthyretin when dissociated into monomers can misfold and ultimately form amyloid fibrils. There are two types of ATTR amyloidosis: hereditary (caused by mutations in the TTR gene) and wild-type (also referred to as senile systemic amyloidosis). Amyloid cardiomyopathy can develop in patients with both types of ATTR amyloidosis, has a later onset and is characterized by progressive heart failure leading to death within a few years after diagnosis. Tafamidis is an oral-administered small molecule that binds to transthyretin and inhibits transthyretin tetramer dissociation, the rate-limiting step in the amyloidosis. Long-term efficacy and safety of tafamidis were shown in patients with transthyretin familial amyloid polyneuropathy. The objective of the phase 3 international, multicenter, double-blind, placebo-controlled, randomized ATTR-ACT study was to evaluate the efficacy, safety, and tolerability of tafamidis (20 or 80 mg orally QD) in comparison with placebo in 441 patients with hereditary and nonhereditary transthyretin cardiomyopathy (median age 75 years, 90% of males). At month 30, treatment with tafamidis was associated with a lower risk of all-cause mortality (by 30%) and a lower rate of cardiovascular related hospitalizations (by 32%) than placebo and resulted in a lower rate of decline in distance for the 6-minute walk test and a lower rate of decline in KCCQ-OS score. The data from extension study supports tafamidis 80 mg as the optimal dose (bioequivalent to tafamidis free acid 61 mg).

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1169Interim analysis of data from a long-term, extension trial of tafamidis meglumine in patients with transthyretin amyloid cardiomyopathy

European Heart Journal ◽

10.1093/eurheartj/ehz748.0011 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

P Elliott ◽

B M Drachman ◽

S S Gottlieb ◽

J E Hoffman ◽

S L Hummel ◽

...

Keyword(s):

Amyloid Fibrils ◽

Nyha Class ◽

Randomized Study ◽

Pooled Analysis ◽

Extension Study ◽

Class Iii ◽

Double Blind ◽

All Cause Mortality ◽

Amyloid Cardiomyopathy

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM), is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure. The Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), an international, multi-center, double-blind, placebo-controlled, randomized study, demonstrated the efficacy and safety of tafamidis treatment for patients with ATTR-CM due to variant (ATTRm) or wild-type (ATTRwt) TTR. Purpose This is a pooled analysis of data from ATTR-ACT and interim data from the ongoing, long-term, extension study to evaluate longer term data on the efficacy of tafamidis in patients with ATTR-CM. Methods Patients who completed ATTR-ACT (which had a duration of 30 months) were eligible to be enrolled in a long-term, extension study in which patients either continued to receive tafamidis meglumine at the same dose (the tafamidis/tafamidis [T/T] group) or, for patients previously treated with placebo, were randomised (in a 1:2 ratio) to tafamidis meglumine 20 mg or 80 mg (the placebo/tafamidis [P/T] group) for up to 60 months. The primary efficacy outcome was all-cause mortality. This analysis combined data from the completed ATTR-ACT with interim data from the extension study (cut-off date: 15 Feb, 2018), and included patients treated with tafamidis meglumine across the two studies with a median follow up of 36 months. Results All-cause mortality was significantly lower in the T/T group (n=264; 88 events, 33.3%) compared with the P/T group (n=177; 88 events, 50.3%); hazard ratio (95% CI), 0.64 (0.47, 0.85); P=0.001. In the subgroup of ATTRwt patients, all-cause mortality was significantly reduced in the T/T group (55/201; 27.4%) compared with the P/T group (60/134; 44.8%); 0.64 (0.44, 0.92); P=0.002. In the 106 (24.0%) ATTRm patients, there was a trend towards a reduction in all-cause mortality in the T/T group (33/63; 52.4%) compared with the P/T group (29/43; 67.4%); 0.66 (0.39, 1.09); P=0.17. In patients who were NYHA Class I or II at baseline, all-cause mortality was significantly reduced in the T/T group (38/186; 20.4%) compared with the P/T group (45/114; 39.5%); 0.49 (0.32, 0.75); P=0.001. In those patients with more severe symptoms at baseline (NYHA Class III), there were fewer deaths in the T/T group (50/78; 64.1%) compared with the P/T group (44/63; 69.8%); 0.80 (0.53, 1.21), but this difference was not statistically significant (P=0.50). Conclusions In ATTR-ACT, tafamidis was shown to significantly improve survival, functional capacity, and quality of life in patients with ATTR-CM. This pooled analysis with data from the ongoing extension study further supports the efficacy of tafamidis in patients over a longer period of time and the importance of early diagnosis and treatment. Acknowledgement/Funding This study was sponsored by Pfizer.

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Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis

Nature Communications ◽

10.1038/s41467-019-13038-z ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 20

Author(s):

Matthias Schmidt ◽

Sebastian Wiese ◽

Volkan Adak ◽

Jonas Engler ◽

Shubhangi Agarwal ◽

...

Keyword(s):

Electron Microscopy ◽

Amyloid Fibrils ◽

Amyloid Fibril ◽

The Body ◽

Systemic Amyloidosis ◽

Attr Amyloidosis ◽

Cryo Electron Microscopy ◽

Terminal Fragment ◽

Amyloid Deposits ◽

Hereditary Attr Amyloidosis

Abstract ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis. The disease is caused by the misfolding of transthyretin protein and the formation of amyloid deposits at different sites within the body. Here, we present a 2.97 Å cryo electron microscopy structure of a fibril purified from the tissue of a patient with hereditary Val30Met ATTR amyloidosis. The fibril consists of a single protofilament that is formed from an N-terminal and a C-terminal fragment of transthyretin. Our structure provides insights into the mechanism of misfolding and implies the formation of an early fibril state from unfolded transthyretin molecules, which upon proteolysis converts into mature ATTR amyloid fibrils.

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Abstract 13149: Survival Benefit With Higher Dose Tafamidis in Patients With Hereditary and Wild-type Transthyretin Amyloid Cardiomyopathy

Circulation ◽

10.1161/circ.142.suppl_3.13149 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Sanjiv J Shah ◽

Balarama Gundapaneni ◽

Marla B Sultan ◽

Giampaolo Merlini

Keyword(s):

Survival Benefit ◽

Treatment Duration ◽

Free Acid ◽

Optimal Dose ◽

Wild Type ◽

All Cause Mortality ◽

Amyloid Cardiomyopathy ◽

New Formulation

Introduction: Tafamidis was shown to be an effective treatment for patients with both hereditary/variant (ATTRv) and wild-type (ATTRwt) transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). The higher dose of tafamidis (80 mg) was shown to be the optimal dose and is approved for the treatment of ATTR-CM. We hypothesized that longer term follow up would further characterize the benefit of higher dose tafamidis. Methods: In ATTR-ACT, patients were randomized to tafamidis meglumine (80 mg or 20 mg) or placebo for 30 months. Patients who completed ATTR-ACT were eligible to enroll in a long-term extension study (LTE) in which placebo-treated patients were randomized to tafamidis 80 mg or 20 mg. As of 20 July, 2018, all patients in the LTE were transitioned to tafamidis free acid 61 mg (a new formulation bioequivalent to tafamidis 80 mg). All-cause mortality (as of 1 Aug, 2019) was assessed in patients treated with tafamidis 80 mg in ATTR-ACT and the LTE who transitioned to tafamidis free acid 61 mg (tafamidis 80/61 mg) compared with patients treated with placebo in ATTR-ACT who transitioned to tafamidis in the LTE (placebo/tafamidis). Results: There were 85 ATTRv patients (42 tafamidis 80/61 mg [median treatment duration 53.8 months]; 43 placebo/tafamidis [48.1 months]) and 268 ATTRwt patients (134 tafamidis 80/61 mg [51.7 months]; 134 placebo/tafamidis [51.6 months]).In ATTRv patients, there were 25 (59.5%) deaths with tafamidis 80/61 mg and 30 (69.8%) deaths with placebo/tafamidis; a 39.8% reduction in risk of all-cause mortality with tafamidis 80/61 mg (hazard ratio vs placebo/tafamidis [95% CI], 0.6020 [0.3473, 1.0435]; P=0.0706). In ATTRwt patients, there were 50 (37.3%) deaths with tafamidis 80/61 mg and 78 (58.2%) deaths with placebo/tafamidis; a 40.1% reduction in risk of all-cause mortality with tafamidis 80/61 mg (0.5992 [0.4186, 0.8577]; P=0.0051). Conclusions: While there were fewer ATTRv patients in the study, longer-term follow-up demonstrated similarly improved survival with higher dose tafamidis in both ATTRv and ATTRwt patients. These data further highlight the benefit of tafamidis (80 mg meglumine or 61 mg free acid) in all patients with ATTR-CM.

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Single Ingestion of Trehalose Enhances Prolonged Exercise Performance by Effective Use of Glucose and Lipid in Healthy Men

Nutrients ◽

10.3390/nu13051439 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1439

Author(s):

Naomi Hamada ◽

Tsuyoshi Wadazumi ◽

Yoko Hirata ◽

Mayumi Kuriyama ◽

Kanji Watanabe ◽

...

Keyword(s):

Exercise Performance ◽

Prolonged Exercise ◽

Insulin Response ◽

Area Under The Curve ◽

Constant Load ◽

Bicycle Ergometer ◽

The Body ◽

Water Control ◽

Double Blind ◽

Healthy Men

Trehalose increases blood glucose levels slowly and induces a slight insulin response. The present study aimed to study the effect of trehalose on prolonged exercise performance. The participants were 12 healthy men (age: 21.3 ± 0.9 y). After an overnight fast (12 h), they first exercised with a constant load (intensity: 40% V˙O2peak) for 60 min using a bicycle ergometer. They continued to exercise with a constant load (40% V˙O2peak) for 30 min between four sets of the 30-s Wingate test. After the 1st set, each participant ingested 500 mL water (control), 8% glucose, or 8% trehalose in three trials. These three trials were at least one week apart and were conducted in a double-blind and randomized crossover manner. Blood was collected for seven biochemical parameters at 12 time points during the experiment. The area under the curve of adrenaline after ingestion of trehalose was significantly lower than that for water and tended to be lower than that for glucose in the later stage of the exercise. Lower secretion of adrenaline after a single dose of 8% trehalose during prolonged exercise reflected the preservation of carbohydrates in the body in the later stage of the exercise. In conclusion, a single ingestion of trehalose helped to maintain prolonged exercise performance.

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Analysis of the Impact of a Multi-Strain Probiotic on Body Composition and Cardiorespiratory Fitness in Long-Distance Runners

Nutrients ◽

10.3390/nu12123758 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3758

Author(s):

Joanna Smarkusz-Zarzecka ◽

Lucyna Ostrowska ◽

Joanna Leszczyńska ◽

Karolina Orywal ◽

Urszula Cwalina ◽

...

Keyword(s):

Body Composition ◽

Cardiorespiratory Fitness ◽

The Body ◽

Double Blind Study ◽

Distance Runners ◽

Long Distance ◽

Double Blind ◽

Necrosis Factor Alpha ◽

Total Body ◽

The Impact

Use of probiotic supplements, the benefits of which have not been proven in sportspeople, is becoming more widespread among runners. The aim of this study was to evaluate the effect of a multi-strain probiotic on body composition, cardiorespiratory fitness and inflammation in the body. The randomised, double-blind study included 66 long-distance runners. The intervention factor was a multi-strain probiotic or placebo. At the initial and final stages of the study, evaluation of body composition and cardiorespiratory fitness was performed and the presence of inflammation determined. In the group of men using the probiotic, an increase in lean body mass (p = 0.019) and skeletal muscle mass (p = 0.022) was demonstrated, while in the group of women taking the probiotic, a decrease in the content of total body fat (p = 0.600) and visceral fat (p = 0.247) was observed. Maximum oxygen consumption (VO2max) increased in women (p = 0.140) and men (p = 0.017) using the probiotic. Concentration of tumour necrosis factor-alpha decreased in women (p = 0.003) and men (p = 0.001) using the probiotic and in women (p = 0.074) and men (p = 0.016) using the placebo. Probiotic therapy had a positive effect on selected parameters of body composition and cardiorespiratory fitness of study participants and showed a tendency to reduce inflammation.

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Embodied precision: Intranasal oxytocin modulates multisensory integration

10.1101/361261 ◽

2018 ◽

Author(s):

Laura Crucianelli ◽

Yannis Paloyelis ◽

Lucia Ricciardi ◽

Paul M Jenkinson ◽

Aikaterini Fotopoulou

Keyword(s):

Multisensory Integration ◽

Tactile Stimulation ◽

Estimation Error ◽

The Body ◽

Multisensory Perception ◽

Subjective Feeling ◽

Rubber Hand ◽

Perceptual Inference ◽

Double Blind ◽

Multisensory Input

AbstractMultisensory integration processes are fundamental to our sense of self as embodied beings. Bodily illusions, such as the rubber hand illusion (RHI) and the size-weight illusion (SWI), allow us to investigate how the brain resolves conflicting multisensory evidence during perceptual inference in relation to different facets of body representation. In the RHI, synchronous tactile stimulation of a participant’s hidden hand and a visible rubber hand creates illusory bodily ownership; in the SWI, the perceived size of the body can modulate the estimated weight of external objects. According to Bayesian models, such illusions arise as an attempt to explain the causes of multisensory perception and may reflect the attenuation of somatosensory precision, which is required to resolve perceptual hypotheses about conflicting multisensory input. Recent hypotheses propose that the precision or salience of sensorimotor representations is determined by modulators of synaptic gain, like dopamine, acetylcholine and oxytocin. However, these neuromodulatory hypotheses have not been tested in the context of embodied multisensory integration. The present, double-blind, placebo-controlled, crossed-over study (N = 41 healthy volunteers) aimed to investigate the effect of intranasal oxytocin (IN-OT) on multisensory integration processes, tested by means of the RHI and the SWI. Results showed that IN-OT enhanced the subjective feeling of ownership in the RHI, only when synchronous tactile stimulation was involved. Furthermore, IN-OT increased the embodied version of the SWI (quantified as weight estimation error). These findings suggest that oxytocin might modulate processes of visuo-tactile multisensory integration by increasing the precision of top-down signals against bottom-up sensory input.

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A randomized controlled trial of supplemental oxygen versus air in cancer patients with dyspnea

Palliative Medicine ◽

10.1191/0269216303pm826oa ◽

2003 ◽

Vol 17 (8) ◽

pp. 659-663

Author(s):

Eduardo Bruera ◽

Catherine Sweeney ◽

Jie Willey ◽

J Lynn Palmer ◽

Florian Strasser ◽

...

Keyword(s):

Controlled Trial ◽

Treatment Phase ◽

Supplemental Oxygen ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Walk Test ◽

Shortness Of Breath ◽

Double Blind ◽

6 Minute Walk Test ◽

Minute Walk

Context: The symptomatic benefits of oxygen in patients with cancer who have nonhypoxic dyspnea are not well defined. Objective: To determine whether or not oxygen is more effective than air in decreasing dyspnea and fatigue and increasing distance walked during a 6-minute walk test. Patients and methods: Patients with advanced cancer who had no severe hypoxemia (i.e., had an O2 saturation level of] / 90%) at rest and had a dyspnea intensity of] / 3 on a scale of 0–10 (03/4/no shortness of breath, 103/4/worst imaginable shortness of breath) were recruited from an outpatient thoracic clinic at a comprehensive cancer center. This was a double-blind, randomized crossover trial. Supplemental oxygen or air (5 L/min) was administered via nasal cannula during a 6-minute walk test. The outcome measures were dyspnea at 3 and 6 minutes, fatigue at 6 minutes, and distance walked. We also measured oxygen saturation levels at baseline, before second treatment phase, and at the end of study. Results: In 33 evaluable patients (31 with lung cancer), no significant differences between treatment groups were observed in dyspnea, fatigue, or distance walked (dyspnea at 3 minutes: P = 0.61; dyspnea, fatigue, and distance walked at 6 minutes: P = 0.81, 0.37, and 0.23, respectively). Conclusions: Currently, the routine use of supplemental oxygen for dyspnea during exercise in this patient population cannot be recommended.

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INTEGRATED USE OF ANIMAL AND VEGETABLE PROTEINS IN SAUSAGE PRODUCTION TECHNOLOGY

SCIENTIFIC LIFE ◽

10.35679/1991-9476-2020-15-4-535-543 ◽

2020 ◽

Vol 15 (4) ◽

pp. 535-543

Author(s):

A.L. Alekseev ◽

◽

T.V. Alekseeva ◽

Keyword(s):

Chemical Composition ◽

Dietary Fiber ◽

Production Technology ◽

Raw Materials ◽

Meat Products ◽

Optimal Dose ◽

The Body ◽

Processing Plant ◽

Protein Supplement ◽

Plant Materials

The article presents the research results obtained during the development of the technology for production of combined sausages using a vegetable-derived additive – LUPISAN lupine flour from “OOO Protein PLUS” (St. Petersburg). Under the conditions of a deteriorating environmental situation and the increase in incidence of the population of the Russian Federation, it became necessary to create biologically complete functional food products with additional functions, useful nutritional and physiological characteristics, based on the integrated use of raw materials of animal and vegetable origin. The use of plant materials in the production of meat products allows not only enriching them with functional ingredients and increasing digestibility, but also obtaining products that meet physiological nutritional standards. Having a complex chemical composition, plants have a beneficial therapeutic effect on the human body. Research was carried out at the Department of Food Technology of the Don State Agrarian University, in the testing laboratory of the Shakhty branch of the Rostov “SBBZh” and at the meat processing plant “TaVr-Zimovniki”. Basing on the conducted comprehensive studies, the effectiveness of using vegetable protein supplement based on lupine flour “LUPISAN” in the production technology of semi-smoked sausages is substantiated. It is established that in terms of quality and safety, LUPISAN meets the requirements for additives of plant origin, it is a genetically unmodified, kosher product (has the appropriate certificates). It is dispersible both in oil and in water and can be used as a natural emulsifier without labeling with the index "E". The analysis of the chemical composition and nutritional value of flour from lupine indicates that the flour contains a significant amount of complete protein is 36–40%; in addition, a rather high content of dietary fiber is noted: dietary fiber is 30–35%. It is a strong antioxidant, it does not contain gluten and cholesterol; there are no inhibitors – substances that delay the digestion process and inhibit the absorption of beneficial substances by the body, and there are glycoproteins – substances that can replace insulin. An optimal dose of introducing a protein supplement based on lupine flour into sausage stuffing is proposed, which is 10% by weight of unsalted raw materials, which makes it possible to obtain a finished product with high organoleptic quality indicators and functional properties.

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Biophysical Insight into Protein Folding, Aggregate Formation and its Inhibition Strategies

Protein and Peptide Letters ◽

10.2174/0929866528666211125114421 ◽

2021 ◽

Vol 28 ◽

Author(s):

Syed Mohammad Zakariya ◽

Aiman Zehr ◽

Rizwan Hasan Khan

Keyword(s):

Protein Folding ◽

Amyloid Fibrils ◽

Three Dimensional ◽

The Body ◽

Aggregate Formation ◽

Structural Characterisation ◽

Current Scenario ◽

Underlying Mechanisms ◽

Quality Control Mechanism ◽

Insight Into

: The failure of protein to correctly fold into its functional and unique three dimensional form leads to misfolded or partially folded protein. When these rogue proteins and polypeptides escape the quality control mechanism within the body, they result in aberrant aggregation of proteins into characteristic amyloid fibrils. This is the main cause for the number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s and Huntington’s diseases. This review aims to summarise the underlying mechanisms of protein folding, misfolding and aggregation. It also highlights the recent technologies for the structural characterisation and detection of amyloid fibrils in addition to the various factors responsible for the aggregate formation and the strategies to combat the aggregation process. Besides, the journey from origin to the current scenario of protein aggregation is also concisely discussed.

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Antidopaminergic treatment is associated with reduced chorea and irritability but impaired cognition in Huntington’s disease (Enroll-HD)

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-322038 ◽

2020 ◽

Vol 91 (6) ◽

pp. 622-630

Author(s):

Kate L Harris ◽

Wei-Li Kuan ◽

Sarah L Mason ◽

Roger A Barker

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Case Reports ◽

Controlled Trial ◽

Rate Of Change ◽

Control Group ◽

Open Label ◽

Double Blind ◽

Before And After ◽

Rate Of Decline

ObjectivesAlterations in dopamine neurotransmission underlie some of the clinical features of Huntington’s disease (HD) and as such are a target for therapeutic intervention, especially for the treatment of chorea and some behavioural problems. However, justification for such an intervention is mainly based on case reports and small open label studies and the effects these drugs have on cognition in HD remain unclear.MethodsIn this study, we used the Enroll-HD observational database to assess the effects of antidopaminergic medication on motor, psychiatric and cognitive decline, over a 3-year period. We first looked at the annual rate of decline of a group of HD patients taking antidopaminergic medication (n=466) compared with an untreated matched group (n=466). The groups were matched on specified clinical variables using propensity score matching. Next, we studied a separate group of HD patients who were prescribed such medications part way through the study (n=90) and compared their rate of change before and after the drugs were introduced and compared this to a matched control group.ResultsWe found that HD patients taking antidopaminergic medication had a slower progression in chorea and irritability compared with those not taking such medications. However, this same group of patients also displayed significantly greater rate of decline in a range of cognitive tasks.ConclusionIn conclusion we found that antidopaminergic treatment is associated with improvements in the choreic movements and irritability of HD but worsens cognition. However, further research is required to prospectively investigate this and whether these are causally linked, ideally in a double-blind placebo-controlled trial.

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