Agents targeting inflammation in heart failure

Evidence from both experimental and clinical trials indicates that inflammatory mediators are important in the pathogenesis of chronic heart failure (HF), contributing to cardiac remodelling and peripheral vascular disturbances. Several studies have shown raised levels of inflammatory cytokines such as TNF-alpha, IL-1beta and -6 in HF patients in plasma, circulating leukocytes, atherosclerotic lesions, and in the failing myocardium itself. Importantly, this rise in inflammatory mediators does not seem to be accompanied by a corresponding increase in anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta; thus resulting in an inflammatory imbalance in the cytokine network. Traditional cardiovascular drugs have little influence on the cytokine network in HF patients. Results from randomised, placebo-controlled anti-TNF studies suggest lack of effect of such therapy. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'; these studies just underscore the challenges in understanding the complex cytokine network in order to develop effective treatment modalities in HF patients. More general immunmodulating treatments, such as pentoxyfylline, intravenous immunoglobulin, thalidomide and statins, have shown promising results in smaller studies, which need to be confirmed in larger studies with hospitalisations and death as the end points. In addition, further research in this area will have to be more precise in identifying the most important 'actors' in the immunopathogenesis of chronic HF.     

Agents targeting inflammation in heart failure

Evidence from both experimental and clinical trials indicates that inflammatory mediators are important in the pathogenesis of chronic heart failure (HF), contributing to cardiac remodelling and peripheral vascular disturbances. Several studies have shown raised levels of inflammatory cytokines such as TNF-α, IL-1β and -6 in HF patients in plasma, circulating leukocytes, atherosclerotic lesions, and in the failing myocardium itself. Importantly, this rise in inflammatory mediators does not seem to be accompanied by a corresponding increase in anti-inflammatory cytokines such as IL-10 and transforming growth factor-β; thus resulting in an inflammatory imbalance in the cytokine network. Traditional cardiovascular drugs have little influence on the cytokine network in HF patients. Results from randomised, placebo-controlled anti-TNF studies suggest lack of effect of such therapy. Although somewhat disappointing, these negative results do not necessarily argue against the ‘cytokine hypothesis’; these studies just underscore the challenges in understanding the complex cytokine network in order to develop effective treatment modalities in HF patients. More general immunmodulating treatments, such as pentoxyfylline, intravenous immunoglobulin, thalidomide and statins, have shown promising results in smaller studies, which need to be confirmed in larger studies with hospitalisations and death as the end points. In addition, further research in this area will have to be more precise in identifying the most important ‘actors’ in the immunopathogenesis of chronic HF.     

Therapeutic Potential of Anticytokine Therapy in Congestive Heart Failure

Accumulating evidence indicates that inflammatory cytokines play a pathogenic role in congestive heart failure (CHF) by influencing heart contractility, inducing hypertrophy, and promoting apoptosis or fibrosis, contributing to the continuous myocardial remodeling process. While several stimuli may be operating such as heat-shock protein, microbial antigen, bacterial lipopolysaccharide, shear and oxidative stress, hypoxia and oxidized low-density lipoprotein (LDL), it seems that the inflammatory response to these stimuli may represent a common final pathogenic pathway in CHF regardless of the initial event. Traditional cardiovascular drugs seem to have little influence on the overall cytokine network, and immunomudulatory therapy has emerged as a possible new treatment modality in CHF. Several animal studies, and some clinical pilot studies, have suggested that down-regulation of inflammatory cytokines may improve cardiac performance. On the other hand, preliminary results from the placebo-controlled studies suggest no effect, or even adverse effect, of antitumor necrosis factor (TNF) therapy on mortality and hospitalization. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'. These studies just underscore the difficulties and the challenges in developing treatment modalities that can modulate the cytokine network in CHF patients resulting in anti-inflammatory and beneficial net effects. Further research in this area will have to more precisely identify the most important actors in the immunopathogenesis of CHF in order to develop more specific immunomodulating agents for this disorder. However, at present the beneficial role of anticytokine therapy in patients with CHF remains unproven.     

反应停抗肿瘤作用机制及临床应用的研究进展

目的：了解反应停抗肿瘤的作用机制及其在临床上的应用,为进一步研究提供参考。方法：回顾近年来国内外有关反应停抗肿瘤治疗的作用机制及临床试验文献资料。结果：反应停通过抑制肿瘤的血管生成、促使肿瘤细胞凋亡和免疫调节活性发挥抗肿瘤作用,现已作为抗肿瘤药广泛用于研究各种进展期恶性肿瘤的疗效观察。结论：大多数的研究证实反应停单用或联合地塞米松对多发性骨髓瘤有显著的活性。与其他的化疗药物或生物制剂联合应用时,对Kaposi＇s肉瘤、肾细胞癌和前列腺癌显示出良好的应用前景。     

Thalidomide analogues as anticancer drugs

The evolution of thalidomide as an effective treatment in several neoplasms has led to the search for compounds with increased antiangiogenic and anti-tumor effects, but decreased side-effects. The development of thalidomide analogues which retain the immunomodulatory effects of the parent compound, while minimizing the adverse reactions, brought about a class of agents termed the Immunomodulatory drugs (IMiDs). The IMiDs have undergone significant advances in recent years as evidenced by the recent FDA-approvals of one of the lead compounds, CC-5013 (lenalidomide), for 5q-myelodysplasia and for multiple myeloma (MM). Actimid (CC-4047), another IMiD lead compound, has also undergone clinical testing in MM. Apart from hematologic malignancies, these drugs are actively under investigation in solid tumor malignancies including prostate cancer, melanoma, and gliomas, in which potent activity has been demonstrated. The preclinical and clinical data relating to these analogues, as well as ENMD-0995, are reviewed herein. Encouraging results with these thalidomide analogues brought forth synthesis and screening of additional novel thalidomide analogues in the N-substituted and tetrafluorinated classes, including CPS11 and CPS49. This review also discusses the patents and preclinical findings for these agents.     

SERCA2a gene therapy in heart failure: an anti-arrhythmic positive inotrope

Therapeutic options that directly enhance cardiomyocyte contractility in chronic heart failure (HF) therapy are currently limited and do not improve prognosis. In fact, most positive inotropic agents, such as β-adrenoreceptor agonists and PDE inhibitors, which have been assessed in HF patients, cause increased mortality as a result of arrhythmia and sudden cardiac death. Cardiac sarcoplasmic reticulum Ca²⁺-ATPase2a (SERCA2a) is a key protein involved in sequestration of Ca²⁺ into the sarcoplasmic reticulum (SR) during diastole. There is a reduction of SERCA2a protein level and function in HF, which has been successfully targeted via viral transfection of the SERCA2a gene into cardiac tissue in vivo. This has enhanced cardiac contractility and reduced mortality in several preclinical models of HF. Theoretical concerns have been raised regarding the possibility of arrhythmogenic adverse effects of SERCA2a gene therapy due to enhanced SR Ca²⁺ load and induction of SR Ca²⁺ leak as a result. Contrary to these concerns, SERCA2a gene therapy in a wide variety of preclinical models, including acute ischaemia/reperfusion, chronic pressure overload and chronic myocardial infarction, has resulted in a reduction in ventricular arrhythmias. The potential mechanisms for this unexpected beneficial effect, as well as mechanisms of enhancement of cardiac contractile function, are reviewed in this article.     

Thalidomide in multiple myeloma--clinical trials and aspects of drug metabolism and toxicity

BACKGROUND: After the tragic events in the early 1960s, thalidomide has re-emerged as therapeutic for multiple myeloma (MM). It was first approved for the treatment of erythema nodosum leprosum, and is now under evaluation for hematologic and non-hematologic disorders. Its complex mechanism of action is not fully understood; however extensive preclinical studies in MM have revealed its antiangiogenic and immunomodulatory properties. OBJECTIVE: In this review, we focus on the importance and toxicity of thalidomide in today's clinical use. METHODS: Key preclinical and clinical trials available as well as data on the pharmacokinetics and pharmacodynamics of thalidomide in humans are summarized. CONCLUSIONS: Thalidomide is widely used as first-line treatment and in relapsed/refractory MM. The most common side effects are fatigue, constipation and peripheral neuropathy, and careful monitoring is required to avoid fetal exposure.     

Macrolides as immunomodulatory medications for the therapy of chronic lung diseases

Macrolide antibiotics have potent immunomodulatory activity. The spectrum of action of these antibiotics extends to regulation of leukocyte function and production of inflammatory mediators, control of mucus hypersecretion, resolution of inflammation, and modulation of host defense mechanisms. Macrolides are now being used or investigated to treat chronic lung inflammatory diseases, including diffuse panbronchiolitis (DPB), cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and asthma. Intense research is ongoing to further elucidate the targets and mechanism/s of action of macrolides in eukaryotic cells. In this paper, we review recent findings on novel effects of macrolides on epithelial barrier function and resolution of inflammation, which may shed light on the mechanisms underlying the beneficial effects of macrolides in the clinic.     

Results of an open, non-placebo controlled pilot study investigating the immunomodulatory potential of autovaccine

Autovaccines are prepared from autologous, human, non-pathogenic, "rough" variants of E. coli derived from the stool flora of individuals according to a highly standardized procedure. As a fundamental concept within microbiological therapy, these autovaccines are mainly used to treat chronic inflammatory disorders associated with impaired immune reactions resistant to standard therapeutic treatments. Generally, immunomodulatory effects of outer membrane components or cell wall fragments of gram-negative bacteria on innate or adaptive immunity are widely accepted but nevertheless mechanisms of actions of these autovaccines remained obscure, despite some recent publication about other autovaccine preparations of different origin. Hence, immunomodulating properties of autovaccine were investigated in a pilot study with 78 outpatients with variable disorders ranging from recurrent respiratory infections to diffuse gastrointestinal complaints. Patients received their autologous bacteria parenterally in increasing doses. Before application and 4 to 6 weeks after application of autovaccine, blood samples of the patients were taken to investigate a range of immunological parameters such as acute phase proteins, serum antibodies and cytokines. The results revealed that autovaccines were able to modulate significantly the release of three potent immunoregulatory cytokines e.g. interferon-gamma, granulocyte-macrophage-colony stimulating factor and interleukin-1 beta, whereas specific humoral immunity remained largely unaffected. From these results it may be concluded that the autovaccine mainly act antigen non-specifically on the cytokine level rather than inducing a specific vaccination. Further studies with more detailed kinetic measurements of cytokines will have to verify these results.     

Recent advances in the treatment of Multiple Myeloma

Multiple Myeloma (MM) remains an incurable plasma cell malignancy in the bone marrow (BM) despite conventional therapies as well as high-dose therapies with stem cell support. Therefore novel biologically-based therapeutic approaches are required. Recently, intensive laboratory and preclinical studies have identified and validated therapeutic molecular targets in MM. In particular, recognition of the biologic significance of the BM microenvironment in MM pathogenesis and as a potential target for novel therapeutics has derived several promising approaches. Novel FDA approved agents including thalidomide/thalomid, its immunomodulatory derivatives lenalidomide/Revlimid, and proteasome inhibitor bortezomib/Velcade are directed at molecular targets not only in MM cells but also in its BM milieu, and have already achieved promising results in clinical studies. Here we discuss the mechanisms of action of these novel drugs and their clinical application, alone or combined with conventional or novel drugs.     

Aptamers against interleukin-12-related cytokines as novel therapeutics in autoimmune diseases

Endogenous interleukin (IL)-12 plays a pivotal role in promoting cell-mediated immunity against intracellular pathogens. Uncontrolled cell-mediated immune responses, however, may lead to chronic inflammation and autoimmune disease. Unfortunately, treatment of either infection or autoimmunity with immunomodulating drugs always incur the danger of favouring the other form of disease. The recent discovery of the dimeric IL-12-related cytokine IL-23 adds to our understanding of the fine tuning of cellular immunity. Only recently, studies revealed IL-23, and not IL-12, to be the decisive factor in this immune deviation and a variety of autoimmune disorders have now been shown to be strikingly dependent on IL-23. Therefore, targeting of IL-23-mediated, rather than IL-12-dependent, mechanisms represent a promising therapeutic approach for autoimmune diseases. The invention of aptamers that are capable of neutralising IL-23 and/or IL-12 and their potential use as autoimmune disease therapeutics will be discussed.     

Left ventricular hypertrophy: a shift in paradigm

Observational studies have identified left ventricular hypertrophy (LVH) as a strong, independent risk factor for the development of heart failure (HF), coronary heart disease and stroke. LVH develops in response to hemodynamic overload. Classical conceptualization has it that LVH would start as an adaptive, beneficial response in order to normalize wall stress. With progression of the disease, deterioration to maladaptive hypertrophy, and further on to HF could occur. Recent experiments in animal models of pressure-overload and myocardial infarction now challenge this concept by demonstrating that blunting the hypertrophic response is actually associated with preserved cardiac function, and with improved survival. These findings may have profound therapeutical implications.     

心力衰竭治疗新靶点-Galectins．3

尽管心力衰竭（HF）的药物治疗近年来有了较大进展,但HF患者预后仍很差。针对HF发病早期行药物治疗是近年来研究的一个重点。Galectin．3（Gal-3）在心室重塑和HF病理生理发展过程中起重要作用,可作为HF治疗的靶点。Gal-3水平升高的HF患者可从醛固酮拮抗剂治疗中获益。本文简要综述以Gal-3水平为指导的HF患者个体化治疗。     

Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies

INTRODUCTION: Thalidomide and its analogs [small molecule immunomodulatory drugs (IMiDs?)] are among the most successful new therapeutic agents of recent years. Thalidomide is now an integral part of multiple myeloma (MM) therapy. Lenalidomide has been approved for the treatment of patients with relapsed MM and 5q-myelodysplastic syndromes (MDS). Currently, more than 400 clinical trials are evaluating the activity of lenalidomide, alone or in combination with other conventional or novel therapies, in newly diagnosed MM and 5q-MDS. Based on their broad range of actions within the tumor microenvironment, IMiDs are currently also evaluated in a wide variety of additional hematologic and solid malignancies. AREAS COVERED: This paper reviews the historic development of thalidomide and its derivatives and presents novel insights into their mode of action. Moreover, it discusses up-to-date clinical trials investigating IMiDs and potential future research and therapeutic perspectives in MM and other malignancies. EXPERT OPINION: Although IMiDs have emerged as powerful agents for the treatment of hematologic and solid tumors, more preclinical and clinical studies are urgently needed both to increase our knowledge of their mechanisms of action, and to optimize their clinical use, in order to further improve the patient's quality of life and survival.     

Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice

Lenalidomide is a synthetic derivative of thalidomide exhibiting multiple immunomodulatory activities beneficial in the treatment of several hematological malignancies. Murine pharmacokinetic characterization necessary for translational and further preclinical investigations has not been published. Studies herein define mouse plasma pharmacokinetics and tissue distribution after intravenous (IV) bolus administration and bioavailability after oral and intraperitoneal delivery. Range finding studies used lenalidomide concentrations up to 15 mg/kg IV, 22.5 mg/kg intraperitoneal injections (IP), and 45 mg/kg oral gavage (PO). Pharmacokinetic studies evaluated doses of 0.5, 1.5, 5, and 10 mg/kg IV and 0.5 and 10 mg/kg doses for IP and oral routes. Liquid chromatography–tandem mass spectrometry was used to quantify lenalidomide in plasma, brain, lung, liver, heart, kidney, spleen, and muscle. Pharmacokinetic parameters were estimated using noncompartmental and compartmental methods. Doses of 15 mg/kg IV, 22.5 mg/kg IP, and 45 mg/kg PO lenalidomide caused no observable toxicity up to 24 h postdose. We observed dose-dependent kinetics over the evaluated dosing range. Administration of 0.5 and 10 mg/kg resulted in systemic bioavailability ranges of 90–105% and 60–75% via IP and oral routes, respectively. Lenalidomide was detectable in the brain only after IV dosing of 5 and 10 mg/kg. Dose-dependent distribution was also observed in some tissues. High oral bioavailability of lenalidomide in mice is consistent with oral bioavailability in humans. Atypical lenalidomide tissue distribution was observed in spleen and brain. The observed dose-dependent pharmacokinetics should be taken into consideration in translational and preclinical mouse studies.     

Immunomodulatory effects of thalidomide analogs on LPS-induced plasma and hepatic cytokines in the rat

Thalidomide has shown to inhibit, selectively and mainly the cytokine tumor necrosis factor-alpha (TNF-alpha), thus, thalidomide has inhibitory consequences on other cytokines; this is ascribed as an immunomodulatory effect. Novel thalidomide analogs are reported with immunomodulatory activity. The aim of this work was to synthesize some of these analogs and to assess them as immunomodulatory agents in an acute model of LPS-induced septic challenge in rat. Animal groups received orally twice a day vehicle carboxymethylcellulose (0.9%), or thalidomide in suspension (100mg/kg), or analogs in an equimolar dose. Two hours after last dose, rats were injected with saline (NaCl, 0.9%, i.p.) or LPS (5mg/kg, i.p.). Groups were sacrificed 2h after injection and samples of blood and liver were obtained. TNF-alpha, interleukin-6, -1beta, and -10 (IL-6, IL-1beta, IL-10) were quantified by enzyme linked immunosorbent assay (ELISA) and studied in plasma and liver. After 2h of LPS-induction, different patterns of measured cytokines were observed with thalidomide analogs administration evidencing their immunomodulatory effects. Interestingly, some analogs decreased significantly plasma and hepatic levels of LPS-induced proinflammatory TNF-alpha and others increased plasma concentration of anti-inflammatory IL-10. Thalidomide analogs also showed slight effects on the remaining proinflammatory cytokines. Differences among immunomodulatory effects of analogs can be related to potency, mechanism of action, and half lives. Thalidomide analogs could be used as a pharmacological tool and in therapeutics in the future.     

Potential new drug treatments for congestive heart failure

Introduction: The prevalence of heart failure (HF) has increased globally in recent decades. Advances in our understanding of underlying pathophysiologic mechanisms have given rise to new therapies for treating the growing HF population. Nonetheless, morbidity and mortality associated with HF and its financial implications are daunting. Thus, novel therapies that can improve the natural history of HF patients are urgently needed.

Areas covered: This article reviews new investigational drugs being developed for the treatment of both acute decompensated heart failure (ADHF) and chronic heart failure with reduced ejection fraction (HFrEF). It presents the background of these drugs with a focus on their mechanism of action, their pharmacology, evidence from clinical studies and their potential role in HF management.

Expert opinion: The mortality benefit associated with serelaxin treatment in the RELAX-HF trial is being tested in RELAX-AHF II, while two other drugs, ularitide and TRV027, are also being evaluated in ADHF patients. Two new agents for the treatment of chronic HFrEF, LCZ696 and ivabradine, have been recently been approved for use by the FDA and four novel agents which have shown considerable promise in early studies, omecamtiv mecarbil, vericiguat, finerenone, and neuregulin, are currently being evaluated in late-phase clinical trials.     

Thalidomide and immunomodulatory drugs in the treatment of cancer

Thalidomide has antiangiogenic and immunomodulatory properties and has recently been used in the management of human malignancies. Multiple studies have confirmed its activity in multiple myeloma, alone or combined with dexamethasone and/or chemotherapy as first- or second-line treatment. In addition, it may reduce the need for transfusions in patients with myelofibrosis or myelodysplastic syndromes. The activity of thalidomide in solid tumours is less prominent. The most promising results have been reported in Kaposi's sarcoma, malignant melanoma and prostate cancer, especially when it is combined with chemotherapy. Recently, thalidomide analogues (immunomodulatory drugs), with higher immunomodulatory activity and different toxicity profile, have been developed. They have already shown promising activity in multiple myeloma and are currently being evaluated in clinical studies.     

Conivaptan: promise of treatment in heart failure

Conivaptan, the first vasopressin receptor antagonist approved by the FDA, is available for the treatment of hyponatremia in euvolemic and hypervolemic patients. The renin-angiotensin-aldosterone system is activated in heart failure (HF) causing clinical worsening. Arginine vasopressin levels are also elevated in HF. Conivaptan is an effective and FDA approved for the treatment of euvolemic and hypervolemic hyponatremia and may offer an extra treatment option in HF by targeting V_1a and V₂ receptors. In this article we review the physiology, preclinical studies as well as the human clinical studies on the use of conivaptan and its potential and promise in the treatment of HF.     

Intravenous immunoglobulin therapy in dermatologic disorders

Intravenous immunoglobulin (IVIG) is sterilized and purified human plasma which contains supra-physiologic levels of immunoglobulin G. IVIG is currently used in the treatment of immunodeficiency syndromes, inflammatory disorders and infectious diseases. Although numerous immunomodulatory mechanisms have been suggested, the exact mechanisms of action are poorly understood. There is also accumulating evidence that high-dose IVIG is efficacious in the treatment of some skin diseases, despite the lack of evidence from randomized, double-blind, placebo-controlled trials. Though in most cases, IVIG is only effective in combination with other immunomodulating strategies, it offers new hope for the treatment of many severe dermatologic conditions. This article focuses on the efficacy and safety of IVIG therapy in skin diseases.