Biochemical Markers of Musculoskeletal Health and Aging to be Assessed in Clinical Trials of Drugs Aiming at the Treatment of Sarcopenia: Consensus Paper from an Expert Group Meeting Organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the Centre Académique de Recherche et d'Expérimentation en Santé (CARES SPRL), Under the Auspices of the World Health Organization Collaborating Center for the Epidemiology of Musculoskeletal Conditions and Aging.

In clinical trials, biochemical markers provide useful information on the drug's mode of action, therapeutic response and side effect monitoring and can act as surrogate endpoints. In pharmacological intervention development for sarcopenia management, there is an urgent need to identify biomarkers to measure in clinical trials and that could be used in the future in clinical practice. The objective of the current consensus paper is to provide a clear list of biochemical markers of musculoskeletal health and aging that can be recommended to be measured in Phase II and Phase III clinical trials evaluating new chemical entities for sarcopenia treatment. A working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) proposed classifying biochemical markers into 2 series: biochemical markers evaluating musculoskeletal status and biochemical markers evaluating causal factors. For series 1, the group agreed on 4 biochemical markers that should be assessed in Phase II or Phase III trials (i.e., Myostatin-Follistatin, Brain Derived Neurotrophic Factor, N-terminal Type III Procollagen and Serum Creatinine to Serum Cystatin C Ratio - or the Sarcopenia Index). For series 2, the group agreed on 6 biochemical markers that should be assessed in Phase II trials (i.e., the hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate, and cortisol, and the inflammatory markers C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-α), and 2 in Phase III trials (i.e., IGF-I and CRP). The group also proposed optional biochemical markers that may provide insights into the mode of action of pharmacological therapies. Further research and development of new methods for biochemical marker assays may lead to the evolution of these recommendations.

Doxorubicin-mediated cardiac dysfunction: Revisiting molecular interactions, pharmacological compounds and (nano)theranostic platforms.

Although chemotherapy drugs are extensively utilized in cancer therapy, their administration for treatment of patients has faced problems that regardless of chemoresistance, increasing evidence has shown concentration-related toxicity of drugs. Doxorubicin (DOX) is a drug used in treatment of solid and hematological tumors, and its function is based on topoisomerase suppression to impair cancer progression. However, DOX can also affect the other organs of body and after chemotherapy, life quality of cancer patients decreases due to the side effects. Heart is one of the vital organs of body that is significantly affected by DOX during cancer chemotherapy, and this can lead to cardiac dysfunction and predispose to development of cardiovascular diseases and atherosclerosis, among others. The exposure to DOX can stimulate apoptosis and sometimes, pro-survival autophagy stimulation can ameliorate this condition. Moreover, DOX-mediated ferroptosis impairs proper function of heart and by increasing oxidative stress and inflammation, DOX causes cardiac dysfunction. The function of DOX in mediating cardiac toxicity is mediated by several pathways that some of them demonstrate protective function including Nrf2. Therefore, if expression level of such protective mechanisms increases, they can alleviate DOX-mediated cardiac toxicity. For this purpose, pharmacological compounds and therapeutic drugs in preventing DOX-mediated cardiotoxicity have been utilized and they can reduce side effects of DOX to prevent development of cardiovascular diseases in patients underwent chemotherapy. Furthermore, (nano)platforms are used comprehensively in treatment of cardiovascular diseases and using them for DOX delivery can reduce side effects by decreasing concentration of drug. Moreover, when DOX is loaded on nanoparticles, it is delivered into cells in a targeted way and its accumulation in healthy organs is prevented to diminish its adverse impacts. Hence, current paper provides a comprehensive discussion of DOX-mediated toxicity and subsequent alleviation by drugs and nanotherapeutics in treatment of cardiovascular diseases.

An Expert Overview on Therapies in Non-Transfusion-Dependent Thalassemia: Classical to Cutting Edge in Treatment.

The thalassemia issue is a growing worldwide health concern that anticipates the number of patients suffering from the disease will soon increase significantly. Patients with ß-thalassemia intermedia (ß-TI) manifest mild to intermediate levels of anemia, which is a reason for it to be clinically located between thalassemia minor and ß-thalassemia major (ß-TM). Notably, the determination of the actual rate of ß-TI is more complicated than ß-TM. The leading cause of this illness could be partial repression of ß-globin protein production; accordingly, the rate of ß-globin gene repression is different in patients, and the gene repression intensity creates a different clinical status. This review article provides an overview of functional mechanisms, advantages, and disadvantages of the classic to latest new treatments for this group of patients, depending on the disease severity divided into the typical management strategies for patients with ß-TI such as fetal hemoglobin (Hb) induction, splenectomy, bone marrow transplantation (BMT), transfusion therapy, and herbal and chemical iron chelators. Recently, novel erythropoiesis-stimulating agents have been added. Novel strategies are subclassified into molecular and cellular interventions. Genome editing is one of the efficient molecular therapies for improving hemoglobinopathies, especially ß-TI. It encompasses high-fidelity DNA repair (HDR), base and prime editing, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 procedure, nuclease-free strategies, and epigenetic modulation. In cellular interventions, we mentioned the approach pattern to improve erythropoiesis impairments in translational models and patients with ß-TI that involve activin II receptor traps, Janus-associated kinase 2 (JAK2) inhibitors, and iron metabolism regulation.

Digitalis therapy in patients with ventricular tachyarrhythmias.

Objective. The study sought to assess the prognostic value of treatment with digitalis on long-term prognosis in patients with ventricular tachyarrhythmias and atrial fibrillation (AF) and/or heart failure (HF). Background. Data regarding the outcome of digitalis therapy following ventricular tachyarrhythmias is limited. Methods. A large retrospective registry was used including consecutive patients with episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2015. Patients treated with digitalis were compared to patients without. The primary prognostic endpoint was all-cause mortality at 3 years, secondary endpoints comprised a composite arrhythmic endpoint (i.e. recurrences of ventricular tachyarrhythmias, appropriate implantable cardioverter defibrillator (ICD) therapies, sudden cardiac death) and cardiac rehospitalization. Kaplan Mayer survival curves, multivariable cox regression, and time trend analyses were applied for statistics. Results. Eight hundred and thirty-one patients were included (20% treated with digitalis and 80% without). At 3 years, digitalis treatment was not associated with all-cause mortality following ventricular tachyarrhythmias (24 vs. 21%, log-rank p = .736; HR = 1.063; 95% CI 0.746-1.515; p = .736). However, digitalis therapy was associated with an increased risk of the composite arrhythmic endpoint (38 vs. 23%; log-rank p = .001; HR = 1.719; 95% CI 1.279-2.311; p = .001) and cardiac rehospitalization (31 vs. 18%; log-rank p = .001; HR = 1.829; 95% CI 1.318-2.538; p = .001), which was still evident within multivariable Cox regression analyses. Finally, digitoxin may be associated with a worse prognosis than digoxin. Conclusion. Digitalis therapy was not associated with mortality in patients with ventricular tachyarrhythmias, but with increased risk of the composite arrhythmic endpoint and cardiac rehospitalization at 3 years.

Prognostic value of beta-blocker doses in patients with ventricular tachyarrhythmias.

The study investigates the prognostic significance of beta-blocker (BB) dose in patients with ventricular tachyarrhythmias. Limited data regarding the prognostic impact of BB dose in ventricular tachyarrhythmias is available. A large retrospective registry was used including consecutive patients on BB treatment with episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2015. Discharge BB doses were grouped as > 0-12.5%, > 12.5-25%, > 25-50%, and > 50% according to doses used in randomized trials. The primary endpoint was all-cause mortality at three years. Secondary endpoints comprised of a composite arrhythmic endpoint (i.e., recurrences of ventricular tachyarrhythmias and appropriate ICD therapies) and cardiac rehospitalization. Kaplan-Meier survival curves and multivariable Cox regression analyses were applied for statistics. A total of 1313 patients with BB were included; most patients were discharged with > 25-50% of BB target dose (59%). At three years, > 12.5-25% of BB target dose was associated with improved long-term mortality as compared to the > 0-12.5% group (HR = 0.489; 95% CI 0.297-0.806; p = 0.005), whereas higher BB doses did not improve survival (> 25-50%: HR = 0.849; p = 0.434; > 50%: HR = 0.735; p = 0.285). In contrast, the composite endpoint and risk of rehospitalization were not affected by BB target dose. In conclusion, > 12.5-25% of BB target dose is associated with best long-term survival among patients with ventricular tachyarrhythmias. In contrast, risk of the composite arrhythmic endpoint and risk of cardiac rehospitalization were not affected by BB dose.

Digitalis Therapy and Risk of Recurrent Ventricular Tachyarrhythmias and ICD Therapies in Atrial Fibrillation and Heart Failure.

OBJECTIVE: This study sought to assess the impact of treatment with digitalis on recurrences of ventricular tachyarrhythmias in implantable cardioverter defibrillator (ICD) recipients with atrial fibrillation (AF) and heart failure (HF). BACKGROUND: The data regarding outcomes of digitalis therapy in ICD recipients are limited. METHODS: A large retrospective registry was used, including consecutive ICD recipients with episodes of ventricular tachyarrhythmia between 2002 and 2016. Patients treated with digitalis were compared to patients without digitalis treatment. The primary prognostic outcome was first recurrence of ventricular tachyarrhythmia at 5 years. Kaplan-Meier and multivariable Cox regression analyses were applied. RESULTS: A total of 394 ICD recipients with AF and/or HF was included (26% with digitalis treatment and 74% without). Digitalis treatment was associated with decreased freedom from recurrent ventricular tachy-arrhythmias (HR = 1.423; 95% CI 1.047-1.934; p = 0.023). Accordingly, digitalis treatment was associated with decreased freedom from appropriate ICD therapies (HR = 1.622; 95% CI 1.166-2.256; p = 0.004) and, moreover, higher rates of rehospitalization (38 vs. 21%; p = 0.001) and all-cause mortality (33 vs. 20%; p = 0.011). CONCLUSION: Among ICD recipients suffering from AF and HF, treatment with digitalis was associated with increased rates of recurrent ventricular tachyarrhythmias and ICD therapies. However, the endpoints may also have been driven by interactions between digitalis, AF, and HF.

Beta-Blockers and ACE Inhibitors Are Associated with Improved Survival Secondary to Ventricular Tachyarrhythmia.

OBJECTIVE: The study sought to assess the impact of treatment with beta-blocker (BB) or ACE inhibitor/angiotensin receptor blocker (ACEi/ARB) on secondary survival in patients presenting with ventricular tachyarrhythmia. BACKGROUND: Data regarding outcome of patients presenting with ventricular tachyarrhythmia treated with BB and ACEi/ARB is limited. METHODS: A large retrospective registry was used including consecutive patients presenting with ventricular tachycardia and fibrillation from 2002 to 2016 on admission. Applying propensity-score matching for harmonization, the impact of "BB" and "ACEi/ARB" was comparatively evaluated. The primary prognostic outcome was long-term all-cause death at 3 years. RESULTS: A total of 972 matched patients were included. Both patients with BB (long-term mortality rate 18 versus 27%; log rank p = 0.041; HR = 0.661; 95% CI = 0.443-0.986; p = 0.043) and with ACEi/ARB (long-term mortality rate 13 versus 23%; log rank p = 0.004; HR = 0.544; 95% CI = 0.359-0.824; p = 0.004) revealed better secondary survival compared to patients without after presenting with ventricular tachyarrhythmia on admission. The prognostic benefit of BB was comparable to ACEi/ARB (long-term mortality rate 21 versus 26%; log rank p = 0.539). CONCLUSION: BB and ACEi/ARB were associated with improved secondary survival in patients surviving ventricular tachyarrhythmia on admission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02982473.

Sympathetic Activation in Chronic Heart Failure: Potential Benefits of Interventional Therapies.

Heart failure (HF) is a major and growing public health problem. This condition is associated with poor prognosis, a high rate of mortality, frequent hospitalization and increasing costs to health care systems. Pharmacological approaches aimed at reducing morbidity and mortality in HF have primarily focused on inhibition of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS), both of which have been associated with disease development, progression and adverse cardiovascular (CV) outcomes. The increasing number of hospitalizations for HF decompensation suggests the failure of available treatment options, indicating the necessity for alternative therapeutic approaches. Alongside pharmacological and cardiac resynchronization therapies in selected patients with arrhythmia, recent advancements in the management of HF have been directed at inhibiting relevant neurogenic pathways underlying disease development and progression. Initial evidence regarding the safety and effectiveness of interventional procedures suggests that HF patients may benefit from novel adjunctive therapies. Here we review the critical role of sympathetic activation in HF and the rationale for therapeutic interventions including device-based and interventional approaches aimed at restoring autonomic neural balance in this condition.

The Impact of Drugs on Hydrogen Sulfide Homeostasis in Mammals.

Mammalian cells and tissues have the capacity to generate hydrogen sulfide gas (H2S) via catabolic routes involving cysteine metabolism. H2S acts on cell signaling cascades that are necessary in many biochemical and physiological roles important in the heart, brain, liver, kidney, urogenital tract, and cardiovascular and immune systems of mammals. Diminished levels of this molecule are observed in several pathophysiological conditions including heart disease, diabetes, obesity, and immune function. Interestingly, in the last two decades, it has become apparent that some commonly prescribed pharmacological drugs can impact the expression and activities of enzymes responsible for hydrogen sulfide production in cells and tissues. Therefore, the current review provides an overview of the studies that catalogue key drugs and their impact on hydrogen sulfide production in mammals.

Pharmacological hyperprolactinemia: a retrospective analysis of 501 hyperprolactinemia cases in primary care setting.

PURPOSE: To describe a series of cases with pharmacological hyperprolactinemia in primary care setting and the prolactin levels, clinical implications of different causes of pharmacological hyperprolactinemia. METHODS: A retrospective study of all patients with detected hyperprolactinemia in hormonal studies was performed between 2019 and 2020 in 20 Spanish primary care centers. Hyperprolactinemia is defined as a serum prolactin >19.4ng/ml in men and >26.5ng/ml in women. Four pharmacological causes of hyperprolactinemia were established: (i) oral contraceptives (OCPs) and other hormonal treatments; (ii) antipsychotics and antidepressants; (iii) other drugs (calcium antagonists, antiemetics, H2 antihistamines, opioids, and anabolic agents); and (iv) hyperprolactinemia due to several drugs. RESULTS: From a sample of 501 patients with elevated serum prolactin, 39.4% (n=162) had pharmacological hyperprolactinemia. The most common cause of pharmacological hyperprolactinemia in women was OCPs (n=61) while in men antipsychotics/antidepressants (n=21). In the cases of hyperprolactinemia due to antipsychotics/antidepressants, the prolactin levels were significantly higher in patients taking classical antipsychotics than in those taking second-generation antipsychotics (80.0±43.17 vs. 50.7±28.66 ng/dL, P=0.035). The antidepressant/antipsychotic group showed hyperprolactinemia-related symptoms more frequently than the group of other treatments (58.9% vs. 32%, P=0.001). The concomitant use of several drugs caused hyperprolactinemia-related symptoms more frequently than one drug alone (73% vs. 44%, P=0.031). CONCLUSION: In this series of cases, drugs represented the 39.4% of the causes of hyperprolactinemia. The most common drugs were OCPs in women and antipsychotics/antidepressants in men. Antidepressants/antipsychotics were drugs that caused the greatest elevation of the prolactin levels and showed hyperprolactinemia-related symptoms more frequently.

Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons.

Neuropathic pain, caused by a lesion or disease affecting the somatosensory system, affects between 3 and 17% of the general population. The treatment of neuropathic pain is challenging due to its heterogeneous etiologies, lack of objective diagnostic tools and resistance to classical analgesic drugs. First-line treatments recommended by the Special Interest Group on Neuropathic Pain (NeuPSIG) and European Federation of Neurological Societies (EFNS) include gabapentinoids, tricyclic antidepressants (TCAs) and selective serotonin noradrenaline reuptake inhibitors (SNRIs). Nevertheless these treatments have modest efficacy or dose limiting side effects. There is therefore a growing number of preclinical and clinical studies aim at developing new treatment strategies to treat neuropathic pain with better efficacy, selectivity, and less side effects. In this review, after a brief description of the mechanisms of action, efficacy, and limitations of current therapeutic drugs, we reviewed new preclinical and clinical targets currently under investigation, as well as promising non-pharmacological alternatives and their potential co-use with pharmacological treatments.

Carvedilol versus Metoprolol in Patients with Ventricular Tachyarrhythmias.

The study investigates the prognostic role of treatment with carvedilol as compared to metoprolol in patients with ventricular tachyarrhythmias. A large retrospective registry was used including consecutive patients on beta-blocker (BB) treatment with episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2015. Patients treated with carvedilol were compared to patients with metoprolol. The primary prognostic outcome was all-cause mortality at three years. Secondary endpoints comprised a composite arrhythmic endpoint (i.e., recurrences of ventricular tachyarrhythmias, appropriate implantable cardioverter defibrillator (ICD) therapies) and cardiac rehospitalization. Kaplan-Meier survival curves, multivariable Cox regression analyses, and propensity score matching were applied for statistics. There were 1098 patients included, 80% treated with metoprolol and 20% with carvedilol. Patients with carvedilol were older, more often presenting with VT (78% vs. 62%; p = 0.001) and with more advanced stages of heart failure. Treatment with carvedilol was associated with comparable all-cause mortality compared to metoprolol (20% vs. 16%, log rank p = 0.234; HR = 1.229; 95% CI 0.874-1.728; p = 0.235). However, secondary endpoints (i.e., composite arrhythmic endpoint: 32% vs. 17%; p = 0.001 and cardiac rehospitalization: 25% vs. 14%; p = 0.001) were more frequently observed in patients with carvedilol, which was still evident after multivariable adjustment. After propensity score matching (n = 194 patients with carvedilol and metoprolol), no further differences regarding the distribution of baseline characteristics were observed. Within the propensity-score-matched cohort, higher rates of the composite arrhythmic endpoint were still observed in patients treated with carvedilol, whereas the risk of cardiac rehospitalization was not affected by the type of beta-blocker treatment. In conclusion, carvedilol and metoprolol are associated with comparable all-cause mortality in patients with ventricular tachyarrhythmias, whereas the risk of the composite arrhythmic endpoint was increased in patients with carvedilol therapy.

Angiotensin Converting Enzyme Inhibitors versus Receptor Blockers in Patients with Ventricular Tachyarrhythmias.

Data investigating the prognostic value of treatment with angiotensin converting enzyme inhibitors (ACEi) and receptor blockers (ARB) usually focusses on patients presenting with heart failure (HF) or acute myocardial infarction (AMI). However, by preventing adverse cardiac remodeling, ACEi/ARB may also decrease the risk of ventricular tachyarrhythmias and sudden cardiac death (SCD). Although ventricular tachyarrhythmias are associated with significant mortality and morbidity, only limited data are available focusing on the prognostic role of ACEi/ARB, when prescribed for secondary prevention of SCD. Therefore, this study comprehensively investigates the role of ACEi versus ARB in patients with ventricular tachyarrhythmias. A large retrospective registry was used including consecutive patients with episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2015. The primary prognostic outcome was all-cause mortality at three years, secondary endpoints comprised a composite arrhythmic endpoint (i.e., recurrences of ventricular tachyarrhythmias, ICD therapies and sudden cardiac death) and cardiac rehospitalization. A total of 1236 patients were included (15% treated with ARB and 85% with ACEi) and followed for a median of 4.0 years. At three years, ACEi and ARB were associated with comparable long-term mortality (20% vs. 17%; log rank p = 0.287; HR = 0.965; 95% CI 0.689-1.351; p = 0.835) and comparable risk of the composite arrhythmic endpoint (HR = 1.227; 95% CI 0.841-1.790; p = 0.288). In contrast, ACEi was associated with a decreased risk of cardiac rehospitalization at three years (HR = 0.690; 95% CI 0.490-0.971; p = 0.033). Within the propensity score matched cohort (i.e., 158 patients with ACEi and ARB), ACEi and ARB were associated with comparable long-term outcomes at three years. In conclusion, ACEi and ARB are associated with comparable risk of long-term outcomes in patients presenting with ventricular tachyarrhythmias.

Roles of Gut Microbiome in Bone Homeostasis and Its Relationship with Bone-Related Diseases.

The extended microbial genome-the gut microbiome (GM)-plays a significant role in host health and disease. It is able to influence a number of physiological functions. During dysbiosis, GM is associated with the development of various chronic diseases with impaired bone quality. In general, GM is important for bone homeostasis and can affect it via several mechanisms. This review describes the roles of GM in bone homeostasis through influencing the immune and endocrine functions, short-chain fatty acids production, calcium absorption and the gut-brain axis. The relationship between GM composition and several bone-related diseases, specifically osteoporosis, osteoarthritis, rheumatoid arthritis, diabetes mellitus, obesity and bone cancer, is also highlighted and summarized. GM manipulation may become a future adjuvant therapy in the prevention of many chronic diseases. Therefore, the beneficial effects of probiotic therapy to improve the health status of individuals with aforementioned diseases are provided, but further studies are needed to clearly confirm its effectiveness. Recent evidence suggests that GM is responsible for direct and indirect effects on drug efficacy. Accordingly, various GM alterations and interactions related to the treatment of bone-related diseases are mentioned as well.

Animal Models to Study AMPK.

AMPK is an evolutionary conserved energy sensor involved in the regulation of energy metabolism. Based on biochemical studies, AMPK has brought much of interest in recent years due to its potential impact on metabolic disorders. Suitable animal models are therefore essential to promote our understanding of the molecular and functional roles of AMPK but also to bring novel information for the development of novel therapeutic strategies. The organism systems include pig (Sus scrofa), mouse (Mus musculus), fly (Drosophila melanogaster), worm (Caenorhabditis elegans), and fish (Danio rerio) models. These animal models have provided reliable experimental evidence demonstrating the crucial role of AMPK in the regulation of metabolism but also of cell polarity, autophagy, and oxidative stress. In this chapter, we update the new development in the generation and application of animal models for the study of AMPK biology. We also discuss recent breakthroughs from studies in mice, flies, and worms showing how AMPK has a primary role in initiating or promoting pathological or beneficial impact on health.