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Effect of AZD9977 and spironolactone on serum potassium in heart failure with preserved or mildly reduced ejection fraction, and renal impairment: A randomized trial.
Squire, IB, Gabrielsen, A, Greasley, PJ, Wernevik, L, Hartleib-Geschwindner, J, Holden, J, Johansson, S, Rudvik, A, Sánchez, J, Bamberg, K, et al
Clinical and translational science. 2022;(10):2493-2504
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Abstract
This phase Ib study compared the effects of AZD9977, a selective mineralocorticoid receptor modulator with predicted low hyperkalemia risk, with spironolactone on serum potassium (sK+ ) in patients with heart failure (HF) with preserved or mildly reduced ejection fraction (EF; ≥40%), and renal impairment. Patients with HF with EF greater than or equal to 40% and estimated glomerular filtration rate of 40-70 ml/min/1.73 m2 were randomized to once-daily AZD9977 100 mg or spironolactone 25 mg for 14 days, up-titrated to AZD9977 200 mg or spironolactone 50 mg for another 14 days. The primary end point was relative change (%) in sK+ for AZD9977 versus spironolactone (baseline to day 28). Serum/urinary electrolytes, fractional excretion (FE) of Na+ /K+ , plasma aldosterone, cortisol, and renin, and safety were also assessed. Sixty-eight patients were randomized (AZD9977, n = 33; spironolactone, n = 35). Mean (SD) age was 73.0 (8.5) years, 51.5% men. Mean sK+ change from baseline to day 28 was 5.7% (AZD9977) and 4.2% (spironolactone), and 1.5% and 4.2% at day 14. Relative change (95% confidence interval) in sK+ with AZD9977 versus spironolactone was -0.3% (-5.3% to 4.4%; day 28), and 3.4% (-0.8% to 7.5%; day 14). Median increase from baseline in plasma aldosterone at day 28 was 89.8 pmol/L for AZD9977 and 67.4 pmol/L for spironolactone. Median FE of K+ was 12.9% (AZD9977) and 10.1% (spironolactone). AZD9977 was well-tolerated. No discontinuations due to hyperkalemia occurred with either treatment. Evidence of target engagement for AZD9977 with a favorable safety profile, supports further evaluation of AZD9977 in patients with HF and renal impairment.
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Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study.
Whittaker, A, Kragh, ÅM, Hartleib-Geschwindner, J, Albayaty, M, Backlund, A, Greasley, PJ, Heijer, M, Kjaer, M, Forte, P, Unwin, R, et al
Clinical and translational science. 2020;(2):275-283
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Abstract
Excessive activation of the mineralocorticoid receptor (MR) underlies the pathophysiology of heart failure and chronic kidney disease. Hyperkalemia risk limits the therapeutic use of conventional MR antagonists. AZD9977 is a nonsteroidal, selective MR modulator that may protect nonepithelial tissues without disturbing electrolyte balance. This phase I study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of AZD9977 in healthy volunteers. Twenty-seven male participants aged 23-45 years were randomized 3:1 to receive oral AZD9977 or placebo for 8 days (with twice-daily dosing on days 2-7), in dose cohorts of 50, 150, and 300 mg (AZD9977, n = 6 per cohort; placebo, n = 3 per cohort). Adverse events occurred in 4 of 18 participants receiving AZD9977 (22.2%) and 6 of 9 receiving placebo (66.7%), all of mild or moderate severity; none were serious or led to withdrawal. AZD9977 was rapidly absorbed, with median time of maximum concentration of 0.50-0.84 hours across dose groups. Area under the curve and maximum concentration were approximately dose proportional but elimination and accumulation terminal half-life increased with dose. Steady-state was reached after 3-4 days, with dose-dependent accumulation of 1.2-1.7-fold. Renal clearance was 5.9-6.5 L/hour and 24-37% of AZD9977 was excreted in the urine. Serum aldosterone levels increased dose dependently from days -1 to 7 in participants receiving AZD9977, but serum potassium levels and urinary electrolyte excretion were unchanged. AZD9977 was generally well-tolerated with no safety concerns. Exploratory outcomes suggested reduced hyperkalemia risk compared with MR antagonists. These findings support further clinical development of AZD9977.
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A Khorasan Wheat-Based Replacement Diet Improves Risk Profile of Patients With Nonalcoholic Fatty Liver Disease (NAFLD): A Randomized Clinical Trial.
Dinu, M, Whittaker, A, Pagliai, G, Giangrandi, I, Colombini, B, Gori, AM, Fiorillo, C, Becatti, M, Casini, A, Benedettelli, S, et al
Journal of the American College of Nutrition. 2018;37(6):508-514
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Plain language summary
Non-alcoholic fatty liver disease (NAFLD) is prevalent, however early intervention with lifestyle modifications such as weight loss, dietary therapy and physical activity may reverse it. Previous studies have shown that the Mediterranean diet, which includes a large proportion of grains, may reduce NAFLD. However no prior studies have assessed grains in isolation on these individuals. This randomised double blind parallel arm study aimed to assess the effects of a replacement diet with ancient khorasan wheat products on patients with NAFLD. 40 people with mild- moderate NAFLD were assigned to either khorasan wheat diet or a modern wheat grain diet for three months. This comparatively small study found that a khorasan wheat based diet improved liver function and inflammation. However regardless of the diet, measures of oxidative stress, which assesses the imbalance of free radicals and antioxidants in the body, was significantly reduced and some individuals were shown to regress from moderate to mild NAFLD. Nutrition practitioners who have clients with mild-moderate NAFLD may recommend a khorasan wheat based diet in the short term to improve biochemical and inflammatory markers and to potentially reverse disease development.
Abstract
OBJECTIVE KAMUT khorasan is an ancient grain with widely acclaimed health benefits. The aim of this study was to investigate the effects of a replacement diet with ancient khorasan wheat products in patients with NAFLD, in comparison to a similar replacement diet with control products made from organic semi-whole-grain modern wheat. METHODS Forty NAFLD patients (12 M/28 F; age 55.2 ± 10.4 years) with mild to moderate liver steatosis were included. The experimental design was a randomized, double-blind, parallel-arm study with 20 participants assigned to consume either KAMUT khorasan or control wheat products (pasta, bread, crackers, biscuits) over a 3-month period. Anthropometric measurements, blood analyses, and ultrasonography examination were performed at both the beginning and end of each dietary intervention. RESULTS After the implementation of a general linear model for repeated measurements adjusted for baseline demographic details, risk factors, and medication, alanine aminotransferase (ALT) was significantly reduced by 12%, aspartate aminotransferase (AST) by 14%, alkaline phosphatase (ALP) by 8%, and cholesterol by 6% only in the khorasan group (p < 0.05 for all). Similarly, significant reductions in circulating proinflammatory tumor necrosis factor-alpha by 50%, interleukin l-receptor antagonist-alpha by 37%, interleukin-8 by 24%, and interferon gamma by 24% were evident only in participants who consumed the khorasan products (p < 0.05 for all). Finally, significant improvements in the liver steatosis grading, Doppler perfusion index values, and reactive oxygen species (ROS) production were evident after consumption of both the khorasan and control products. CONCLUSIONS This study suggests that a short-term replacement diet with ancient KAMUT khorasan products is most effective in reducing metabolic risk factors and ameliorating the liver profile in patients with NAFLD.
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The study of flavonolignan association patterns in fruits of diverging Silybum marianum (L.) Gaertn. chemotypes provides new insights into the silymarin biosynthetic pathway.
Martinelli, T, Whittaker, A, Benedettelli, S, Carboni, A, Andrzejewska, J
Phytochemistry. 2017;:9-18
Abstract
Silymarin is the phytochemical with medicinal properties extracted from Silybum marianum (L.) Gaertn. fruits. Yet, little information is available about silymarin biosynthesis. Moreover, the generally accepted pathway, formulated thus far, is not in agreement with actual experimental measurements on flavonolignan contents. The present work analyses flavonolignan and taxifolin content in 201 S. marianum samples taking into consideration a wide phenotypic variability. Two stable chemotypes were identified: one characterized by both high silychristin and silybin content (chemotype A) and another by a high silydianin content (chemotype B). Through the correlation analysis of samples divided according to chemotype, it was possible to construct a simplified silymarin biosynthetic pathway that is sufficiently versatile in explaining experimental results responding to the actually unresolved questions about this process. The proposed pathway highlights that three separate and equally sized metabolite pools exist, namely: diastereoisomers A (silybin A plus isosilybin A), diastereoisomers B (silybin B plus isosilybin B) and silychristin. In both A and B diastereoisomers pools, isosilybin A and isosilybin B always represent a given amount of the metabolite flux through the specific metabolite pool suggesting the possible involvement of dirigent protein-like enzymes. We suggest that chemotype B possesses a complete silymarin biosynthetic pathway in which silydianin biosynthesis is enzymatically controlled. On the contrary, chemotype A is probably a natural mutant unable to biosynthesize silydianin. The present simplified pathway for silymarin biosynthesis will constitute an important tool for the further understanding of the reactions that drive flavonolignan biosynthesis in S. marianum.
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A khorasan wheat-based replacement diet improves risk profile of patients with type 2 diabetes mellitus (T2DM): a randomized crossover trial.
Whittaker, A, Dinu, M, Cesari, F, Gori, AM, Fiorillo, C, Becatti, M, Casini, A, Marcucci, R, Benedettelli, S, Sofi, F
European journal of nutrition. 2017;(3):1191-1200
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Abstract
PURPOSES The aim of the present study was to examine whether a replacement diet with products made with organic ancient khorasan wheat could provide additive protective effects in reducing glucose, insulin, lipid and inflammatory risk factors, and in restoring blood redox balance in type 2 diabetes mellitus (T2DM) patients compared to diet with product made with modern organic wheat. METHODS We conducted a randomized, double-blinded crossover trial with two intervention phases on 21 T2DM patients (14 females, 7 males). The participants were assigned to consume products (bread, pasta, crackers and biscuits) made using semi-whole flour from organic wheat that was either from ancient khorasan wheat or modern control wheat for 8 weeks in a random order. An 8-week washout period was implemented between the interventions. Laboratory analyses were performed both at the beginning and at the end of each intervention phase. RESULTS The metabolic risk profile improved only after the khorasan intervention period, as measured by a reduction in total and LDL cholesterol (mean reduction: -3.7 and -3.4 %, respectively), insulin (-16.3 %) and blood glucose (-9.1 %). Similarly, there was a significant reduction in circulating levels of reactive oxygen species (ROS), vascular endothelial growth factor (VEGF) and interleukin-1ra, and a significant increase of total antioxidant capacity (+6.3 %). No significant differences from baseline were noted after the modern control wheat intervention phase. The change (from pre- to post-intervention) between the two intervention arms was significantly different (p < 0.05) for total and LDL-c, insulin and HOMA index. CONCLUSIONS A replacement diet with ancient khorasan wheat consumption provided additive protection in reducing total and LDL cholesterol, insulin, blood glucose, ROS production, and some inflammatory risk factors, which are all key factors warranting of control in secondary prevention of T2DM compared to a diet with products made with modern wheat.
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An organic khorasan wheat-based replacement diet improves risk profile of patients with acute coronary syndrome: a randomized crossover trial.
Whittaker, A, Sofi, F, Luisi, ML, Rafanelli, E, Fiorillo, C, Becatti, M, Abbate, R, Casini, A, Gensini, GF, Benedettelli, S
Nutrients. 2015;(5):3401-15
Abstract
Khorasan wheat is an ancient grain with previously reported health benefits in clinically healthy subjects. The aim of this study was to examine whether a replacement diet, thereby substituting all other cereal grains, with products made with organic khorasan wheat could provide additive protective effects in reducing lipid, oxidative and inflammatory risk factors, in patients with Acute Coronary Syndromes (ACS) in comparison to a similar replacement diet using products made from organic modern wheat. A randomized double-blinded crossover trial with two intervention phases was conducted on 22 ACS patients (9 F; 13 M). The patients were assigned to consume products (bread, pasta, biscuits and crackers) made either from organic semi-whole khorasan wheat or organic semi-whole control wheat for eight weeks in a random order. On average, patients ingested 62.0 g dry weight (DW) day-1 khorasan or control semolina; and 140.5 g DW day-1 khorasan or control flour, respectively. An eight-week washout period was implemented between the respective interventions. Blood analyses were performed both at the beginning and end of each intervention phase; thereby permitting a comparison of both the khorasan and control intervention phases, respectively, on circulatory risk factors for the same patient. Consumption of products made with khorasan wheat resulted in a significant amelioration in total cholesterol (-6.8%), low-density lipoprotein cholesterol (LDL-C) (-8.1%) glucose (-8%) and insulin (-24.6%) from baseline levels, independently of age, sex, traditional risk factors, medication and diet quality. Moreover, there was a significant reduction in reactive oxygen species (ROS), lipoperoxidation of circulating monocytes and lymphocytes, as well as in the levels of Tumor Necrosis Factor-alpha. No significant differences from baseline in the same patients were observed after the conventional control wheat intervention phase. The present results suggest that a replacement diet with cereal products made from organic khorasan wheat provides additional protection in patients with ACS. Circulating cardiovascular risk factors, including lipid parameters, and markers of both oxidative stress and inflammatory status, were reduced, irrespective of the number and combination of medicinal therapies with proven efficacy in secondary prevention.
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Effect of Triticum turgidum subsp. turanicum wheat on irritable bowel syndrome: a double-blinded randomised dietary intervention trial.
Sofi, F, Whittaker, A, Gori, AM, Cesari, F, Surrenti, E, Abbate, R, Gensini, GF, Benedettelli, S, Casini, A
The British journal of nutrition. 2014;111(11):1992-9
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Irritable bowel syndrome (IBS) is a gastrointestinal disorder in which patients experience pain and bloating, often after the intake of wheat products. Increasing interest has grown around the potential of ancient wheat grain varieties in improving the inflammatory profile through its rich source of health-promoting substances. The aim of this study was to examine the effect of replacing modern wheat with an ancient variety on symptoms and inflammatory parameters in 20 patients with IBS. A randomised crossover trial was performed and participants received wheat products made either from ancient or modern wheat for six weeks with a six-week washout period. Symptoms were recorded through questionnaires and blood analyses were conducted at the beginning and end of each intervention period.
Abstract
The aim of the present study was to examine the effect of a replacement diet with organic, semi-whole-grain products derived from Triticum turgidum subsp. turanicum (ancient) wheat on irritable bowel syndrome (IBS) symptoms and inflammatory/biochemical parameters. A double-blinded randomised cross-over trial was performed using twenty participants (thirteen females and seven males, aged 18-59 years) classified as having moderate IBS. Participants received products (bread, pasta, biscuits and crackers) made either from ancient or modern wheat for 6 weeks in a random order. Symptoms due to IBS were evaluated using two questionnaires, which were compiled both at baseline and on a weekly basis during the intervention period. Blood analyses were carried out at the beginning and end of each respective intervention period. During the intervention period with ancient wheat products, patients experienced a significant decrease in the severity of IBS symptoms, such as abdominal pain (P< 0·0001), bloating (P= 0·004), satisfaction with stool consistency (P< 0·001) and tiredness (P< 0·0001). No significant difference was observed after the intervention period with modern wheat products. Similarly, patients reported significant amelioration in the severity of gastrointestinal symptoms only after the ancient wheat intervention period, as measured by the intensity of pain (P= 0·001), the frequency of pain (P< 0·0001), bloating (P< 0·0001), abdominal distension (P< 0·001) and the quality of life (P< 0·0001). Interestingly, the inflammatory profile showed a significant reduction in the circulating levels of pro-inflammatory cytokines, including IL-6, IL-17, interferon-γ, monocyte chemotactic protein-1 and vascular endothelial growth factor after the intervention period with ancient wheat products, but not after the control period. In conclusion, significant improvements in both IBS symptoms and the inflammatory profile were reported after the ingestion of ancient wheat products.
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Characterization of Khorasan wheat (Kamut) and impact of a replacement diet on cardiovascular risk factors: cross-over dietary intervention study.
Sofi, F, Whittaker, A, Cesari, F, Gori, AM, Fiorillo, C, Becatti, M, Marotti, I, Dinelli, G, Casini, A, Abbate, R, et al
European journal of clinical nutrition. 2013;(2):190-5
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Abstract
BACKGROUND/OBJECTIVES Khorasan wheat (Kamut) is an ancient grain with widely acclaimed beneficial effects on human health. The objective was to characterise Kamut and to examine the effect of a replacement diet with their products on cardiovascular risk parameters. SUBJECTS/METHODS We conducted a randomized, single-blinded cross-over trial with two intervention phases on 22 healthy subjects (14 females; 8 males). The participants were assigned to consume products (bread, pasta and crackers) made either from Kamut or control semi-whole-grain wheat for 8 weeks in a random order. An 8-week washout period was implemented between the interventions. Laboratory analyses were performed both at the beginning and at the end of each intervention phase. RESULTS At a general linear model for repeated measurements adjusted for several confounders, consumption of Kamut products showed a significant reduction of metabolic risk factors such as total cholesterol (mean reduction: -8.46 mg/dl; -4%), low-density lipoprotein cholesterol (-9.82 mg/dl; -7.8%) and blood glucose. Similarly, redox status was significantly improved only after the Kamut intervention phase, as measured by a reduction in both thiobarbituric acid reactive substances (-0.17 nmol/ml; -21.5%;) and carbonyl levels (-0.16 nmol/ml; -17.6%). The replacement diet with Kamut products also resulted in a significant increase of serum potassium and magnesium. Circulating levels of key pro-inflammatory cytokines (interleukin (IL)-6, IL-12, tumour necrosis factor-α and vascular endothelial growth factor) were significantly reduced after the consumption of Kamut products. CONCLUSIONS The present results suggest that a replacement diet with Kamut products could be effective in reducing metabolic risk factors, markers of both oxidative stress and inflammatory status.