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Palus S.,University of Gottingen | von Haehling S.,University of Gottingen | von Haehling S.,Applied Cachexia Research | Springer J.,University of Gottingen
Journal of Cachexia, Sarcopenia and Muscle | Year: 2014

The syndrome of cachexia, i.e., involuntary weight loss in patients with underlying diseases, sarcopenia, i.e., loss of muscle mass due to aging, and general muscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients, and therefore, they represent a major socio-economic burden for the society today. This mini-review looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last 3 years on the causes and effects of muscle wasting, new targets for therapy development, and potential biomarkers for assessing skeletal muscle mass. The targets include the following: (1) E-3 ligases TRIM32, SOCS1, and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72), and the mitochondrial Mul1; (2) the kinase MST1; and (3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time. In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new target and biomarker muscles, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades. © 2014 Springer-Verlag Berlin Heidelberg.


Pitt B.,University of Michigan | Anker S.D.,Applied Cachexia Research | Anker S.D.,Center for Clinical and Basic Research | Bushinsky D.A.,University of Rochester | And 3 more authors.
European Heart Journal | Year: 2011

Aims To evaluate efficacy and safety of RLY5016 (a non-absorbed, orally administered, potassium [K +]-binding polymer) on serum K + levels in patients with chronic heart failure (HF) receiving standard therapy and spironolactone. Methods and resultsOne hundred and five patients with HF and a history of hyperkalaemia resulting in discontinuation of a reninangiotensinaldosterone system inhibitor/blocker and/or beta-adrenergic blocking agent or chronic kidney disease (CKD) with an estimated glomerular filtration rate of <60 mL/min were randomized to double-blind treatment with 30 g/day RLY5016 or placebo for 4 weeks. Spironolactone, initiated at 25 mg/day, was increased to 50 mg/day on Day 15 if K + was ≤5.1 mEq/L. Endpoints included the change from baseline in serum K + at the end of treatment (primary); the proportion of patients with hyperkalaemia (K + >5.5 mEq/L); and the proportion titrated to spironolactone 50 mg/day. Safety assessments included adverse events (AEs) and clinical laboratory tests. RLY5016 (n 55) and placebo (n 49) patients had similar baseline characteristics. At the end of treatment, compared with placebo, RLY5016 had significantly lowered serum K + levels with a difference between groups of -0.45 mEq/L (P < 0.001); a lower incidence of hyperkalaemia (7.3 RLY5016 vs. 24.5 placebo, P 0.015); and a higher proportion of patients on spironolactone 50 mg/day (91 RLY5016 vs. 74 placebo, P 0.019). In patients with CKD (n 66), the difference in K + between groups was -0.52 mEq/L (P 0.031), and the incidence of hyperkalaemia was 6.7 RLY5016 vs. 38.5 placebo (P 0.041). Adverse events were mainly gastrointestinal, and mild or moderate in severity. Adverse events resulting in study withdrawal were similar (7 RLY5016, 6 placebo). There were no drug-related serious AEs. Hypokalaemia (K + <3.5 mEq/L) occurred in 6 of RLY5016 patients vs. 0 of placebo patients (P 0.094). ConclusionRLY5016 prevented hyperkalaemia and was relatively well tolerated in patients with HF receiving standard therapy and spironolactone (2550 mg/day) (ClinicalTrials.gov registry identifier: NCT00868439). © 2011 The Author.


von Haehling S.,University of Gottingen | von Haehling S.,Applied Cachexia Research | Anker S.D.,University of Gottingen
Journal of the American Medical Directors Association | Year: 2014

Body wasting in the context of chronic illness is associated with reduced quality of life and impaired survival. Recent clinical trials have investigated different approaches to improve patients' skeletal muscle mass and strength, exercise capacity, and survival in the context of cachexia and body wasting, many of them in patients with cancer. The aim of this article was to summarize clinical trials published over the past 2years. Therapeutic approaches discussed include appetite stimulants, such as megestrol acetate, L-carnitine, or melatonin, anti-inflammatory drugs, such as thalidomide, pentoxyphylline, or a monoclonal antibody against interleukin-1α as well as ghrelin and the ghrelin agonist anamorelin; nutritional support, and anabolics, such as enobosarm and testosterone. © 2014 AMDA - The Society for Post-Acute and Long-Term Care Medicine.


Cicoira M.,University of Verona | Anker S.D.,Applied Cachexia Research | Ronco C.,International Renal Research Institute IRRIV
Journal of Cachexia, Sarcopenia and Muscle | Year: 2011

Cardio-renal syndromes (CRS) are defined as disorders of the heart and kidney whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. CRS have been classified into five categories, where types 2 and 4 represent respectively chronic cardio-renal and chronic reno-cardiac syndromes. In these conditions, the chronic disorder of either the heart or kidney has been shown to induce some degree of cachexia. At the same time, cachexia has been proposed as a possible mechanism contributing to the worsening of such pathological organ cross talk. Common pathogenetic mechanisms underlie body wasting in cachectic states of different chronic heart and kidney diseases. In these circumstances, a vicious circle could arise, in which cachexia associated with either heart failure or chronic kidney disease may contribute to further damage of the other organ. In chronic CRS, activation of the immune and neuroendocrine systems contributes to the genesis of cachexia, which in turn can negatively affect the heart and kidney function. In patients with cardiac sustained activation of the immune and neuroendocrine systems and oxidative stress, renal vascular resistance can increase and therefore impair renal perfusion, leading to worsening kidney function. Similarly, in renal cachexia, increased levels of pro-inflammatory cytokines can cause progressive left ventricular systolic dysfunction, myocardial cell death, endothelial dysfunction and increased myocardial fibrosis, with consequent impairment of the chronic reno-cardiac syndrome type 4. Thus, we speculate that the occurrence of different types of chronic CRS could represent a fundamental step in the genesis of cachexia, being renal and cardiac dysfunction closely related to the occurrence of systemic disorders leading to a final common pathway. Therefore, the heart and kidney and cachexia represent a triad causing a vicious circle that increases mortality and morbidity: In such circumstances, we may plausibly talk about cardio-renal cachexia syndrome. Complex interrelations may explain the transition from CRS to cachexia and from cachexia to CRS. Identification of the exact mechanisms occurring in these conditions could potentially help in preventing and treating this deadly combination. © 2011 The Author(s).


Palus S.,UniversityMedical Center Gottingen | Springer J.,UniversityMedical Center Gottingen | Springer J.,University of Gottingen | von Haehling S.,Applied Cachexia Research
Journal of Cachexia, Sarcopenia and Muscle | Year: 2014

The syndrome of cachexia, i.e., involuntary weight loss in patients with underlying diseases, sarcopenia, i.e., loss of muscle mass due to aging, and generalmuscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients, and therefore, they represent a major socio-economic burden for the society today. This minireview looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last 3 years on the causes and effects of muscle wasting, new targets for therapy development, and potential biomarkers for assessing skeletal muscle mass. The targets include the following: (1) E-3 ligases TRIM32, SOCS1, and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72), and the mitochondrialMul1; (2) the kinase MST1; and (3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time. In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new target and biomarker muscles, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades. © Springer-Verlag Berlin Heidelberg 2014.

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