Developing models for cachexia and their implications in drug discovery

Introduction: Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Systemic inflammation plays a central role in its pathophysiology. As millions of patients are in a cachectic state of chronic disease, cachexia is one of the major causes of death worldwide. Difficulties in the recruitment and follow-up of clinical trials mean that well-characterized animal models are of great importance in developing cachexia therapies. However, some of the widely used animal models have limitations in procedural reproducibility or in recapitulating in the cachectic phenotype, which has warranted the development of novel models for cachexia.

Areas covered: This review focuses on some of the currently developing rodent models designed to mimic each co-morbidity in cachexia.

Expert opinion: Through developing cancer models, researchers have been seeking more targets for intervention. In cardiac cachexia, technical issues have been overcome by transgenic models. Furthermore, the development of new animal models has enabled the elucidation of the roles of inflammation, anabolism/catabolism in muscle/fat tissue and anorexia on cachexia. As metabolic and inflammatory pathways in cachexia may compromise cardiac muscle, the analysis of cardiac function/tissue in non-cardiac cachexia may be a useful component of cachexia assessment common to different underlying diseases and pave the way for novel drug discovery.     

Clinical pharmacokinetics of drugs in cardiopulmonary associated cachexia without hepatorenal pathology: a systematic review

Cachexia not only has a dramatically harmful impact on a patient’s life, but also a poor response to therapeutic agents. The purpose of the present review is to provide updated information concerning the pharmacokinetic aspects of drugs used to treat cardiopulmonary cachexia in patients with no signs of hepatic or renal pathology. A systematic search of PubMed, the Cochrane Central Register of Control Trials, Science Direct, and Clinical Trials Registry (ClinicalTrials.gov), encompassing the period between 2000 and 2017, was conducted in accordance to PRISMA guidelines. Seven studies were identified. Collectively, these studies included a total of 196 individuals (19 healthy subjects and 177 diseased patients). This data review found no differences in bisoprolol and prothionamide absorption in cachectic patients with chronic heart failure and tuberculosis, but higher absorption of oflaxocin in the same set of patients was observed. The distribution of bisoprolol, prothionmaide, ceftazidime, and cefipirome was reduced in cardiopulmonary cachexia patients. Hepatic clearance of rifampin was equivalent in cachectic and non-cachectic patients that had normal hepatic function. Similarly in cardiopulmonary cachexia patients, renal clearance of ceftazidime was reduced by 19% but no significant differences in bisorpolol and prothionamide clearance were observed. In the case of cefipirome, both renal clearance and creatinine clearance were higher in cachectic patients with cystic fibrosis. From the limited evidence available, the main drug pharmacokinetic changes seen in cardiopulmonary cachexia patients were a reduction in the volume of distribution and impairment of clearance.     

Phase II drugs that are currently in development for the treatment of cachexia

Introduction: Cachexia is a syndrome presenting with progressive unintentional weight loss and wasting and weakness of skeletal muscle. Cachexia is prevalent in cancer and in chronic diseases including chronic obstructive pulmonary disease (COPD).

Areas covered: The authors searched trial registers for current Phase II clinical trials on cachexia. Twelve studies were found with 11 compounds, including the anti-inflammatory drugs thalidomide, OHR/AVR118, celecoxib, VT-122, omega-3 supplements, and anabolic agents such as ghrelin analogues, MT-102, BYM338 and ruxolotinib. The authors note that one of the studies related to COPD while the others were related to different cancers. Herein, the authors describe the mechanisms of action and their Phase II study design.

Expert opinion: The compounds under study affect several pathways involved in cachexia by modulating inflammatory activity, anabolic potential, digestion and direct interaction with the muscle. Due to the multifactorial aspects of cachexia syndrome, combinations of these new drugs with nutritional intervention is probably the most promising approach. Furthermore, future studies should include interventions in pre-cachetic patients, as this stage might be more responsive to treatment. Future studies will benefit from well-defined end points and improved measures of cachexia, providing new insight into the disease. This insight, in combination with the elucidation of cachexia’s underlying mechanism, will yield new treatment strategies in the near future.     

Cancer cachexia: drugs in the patent literature

Background: The therapeutic approach to the neoplastic patient with cachexia is very frustrating for the physician. Indeed, we can say that a cure for cancer cachexia does not exist. Numerous therapeutic strategies have been tested in the last few decades with discouraging or at least conflicting results. Methods: Drugs patented for the treatment of cancer cachexia are evaluated and discussed. Results: New drugs such as ghrelin splice variant, small-molecule melanocortin-4 receptor antagonists and selective androgen receptor modulators have been discovered, evaluated with promising results, and patented. It is expected that soon they will be tested in humans through adequate clinical trials in experimental studies. Other compounds such as retinoid X receptor agonists, the inhibitor of LPS-induced TNF-α factor (LIPAF) protein, novel inhibitors of TNF-α production or release and tumour cytotoxic factor II need to be tested first in experimental models of cancer cachexia. Conclusion: With the recent discovery of new, effective drugs, it seems that a new scenario is opening up in the therapy of cancer cachexia.     

Current pharmacotherapy options for cancer anorexia and cachexia

Introduction: Anorexia and cachexia syndrome represents a complex clinical picture that occurs in the late stage of several chronic inflammatory diseases, including cancer. Unless counteracted cancer-related anorexia and cachexia syndrome affects quality of life (QL) and survival. However, to date a standard effective treatment is lacking.

Areas covered: The aim of this review is to describe the current pharmacological approaches for anorexia and cachexia syndrome, focusing on cancer-related syndrome. The several pharmacological agents tested so far are discussed, distinguishing them in unproven drugs, effective drugs, and drugs under investigation. Moreover, a section is devoted to the promising use of nutritional supplements and nutraceuticals. The emerging role of a multitargeted combined treatment approach is exhaustively reviewed.

Expert opinion: Considering the complex clinical picture and the multifactorial pathogenesis of anorexia and cachexia syndrome, we believe that its clinical management requires a multidisciplinary and multipharmacological approach. In our opinion the anorexia and cachexia syndrome treatment should include drugs that target the following conditions: inflammatory status, oxidative stress, nutritional disorders, muscle catabolism, anemia, immunosuppression, and fatigue. The multidimensional therapies for anorexia and cachexia syndrome should ideally be introduced within a context of the “best supportive care,” which includes optimal symptom management and careful psychosocial counseling.     

蛋白质羰基化与大鼠心衰恶病质发生的相关性

目的 探讨蛋白质羰基化是否参与了大鼠心衰恶病质的发生、发展。方法 90只12个月龄的清洁级雄性 SD大鼠,随机分为异丙肾上腺素（ISO）组、肼苯哒嗪（HYD）+ISO组和对照组,每组各30只。分别给予ISO组和HYD+ ISO组大鼠注射异丙肾上腺素,同时HYD+ISO组大鼠用肼苯哒嗪灌胃,对照组注射生理盐水。6周后,根据大鼠的超 声心动图和体质量的变化评估大鼠造模成功率。采用全自动生化分析仪检测大鼠血清中总白蛋白、三酰甘油、胆固 醇、血糖水平;酶联免疫吸附测定试剂盒测定大鼠血清中的脑钠肽（BNP）的水平;紫外分光光度计检测心肌及骨骼肌 中蛋白质羰基水平;免疫组化染色检测心肌及骨骼肌中蛋白质羰基表达情况。结果 对照组、HYD+ISO组及ISO组 血清总白蛋白及血糖依次降低,血清三酰甘油、胆固醇、BNP、心肌和骨骼肌中蛋白质羰基浓度依次升高（P＜0.05）, 大鼠心肌和骨骼肌中蛋白质羰基化阳性细胞百分率依次增高（P＜0.05）。结论 ISO所致的心衰恶病质大鼠模型蛋 白质羰基化水平升高;HYD会抑制心衰恶病质大鼠体内蛋白质羰基化的形成,可阻止心衰恶病质的发生、发展。     

肝纤维化的动物模型及治疗药物研究

肝纤维化是肝损伤后的修复反应 ,涉及复杂的细胞及分子机制。选择与人类相似的肝纤维化动物模型不仅是深入研究肝纤维化发病机制的重要基础 ,也是筛选防治肝纤维化药物的有效手段。随着人们对肝纤维化的认识不断深入 ,有效的防治肝纤维化已成为可能。该文就肝纤维化的动物模型及抗纤维化的药物研究作一综述     

Animal models of skin disease for drug discovery

Introduction: Discovery of novel drugs, treatments, and testing of consumer products in the field of dermatology is a multi-billion dollar business. Due to the distressing nature of many dermatological diseases, and the enormous consumer demand for products to reverse the effects of skin photodamage, aging, and hair loss, this is a very active field.

Areas covered: In this paper, we will cover the use of animal models that have been reported to recapitulate to a greater or lesser extent the features of human dermatological disease. There has been a remarkable increase in the number and variety of transgenic mouse models in recent years, and the basic strategy for constructing them is outlined.

Expert opinion: Inflammatory and autoimmune skin diseases are all represented by a range of mouse models both transgenic and normal. Skin cancer is mainly studied in mice and fish. Wound healing is studied in a wider range of animal species, and skin infections such as acne and leprosy also have been studied in animal models. Moving to the more consumer-oriented area of dermatology, there are models for studying the harmful effect of sunlight on the skin, and testing of sunscreens, and several different animal models of hair loss or alopecia.     

Rolofylline: a selective adenosine 1 receptor antagonist for the treatment of heart failure

Background: Co-existent cardiac and renal dysfunction is increasingly recognized as both a predictor and mediator of poor outcomes in patients with advanced heart failure. Novel therapies, including adenosine receptor antagonists, are currently under development for the treatment of ‘cardiorenal syndrome’. Objectives: To review the pathophysiologic rationale for using rolofylline, a selective adenosine 1 receptor antagonist, in patients with cardiorenal syndrome; and to provide a critical overview of safety and efficacy data from clinical studies. Methods: We reviewed published data on the pharmacology of rolofylline, and used this to inform a comprehensive summary of preclinical and clinical trials. Cardiac and renal effects, and safety data with a particular reference to seizures, are highlighted. Results/conclusion: Rolofylline facilitates diuresis and preserves renal function in patients with acute decompensated heart failure and renal dysfunction. Pilot data also suggest beneficial effects on symptoms and short-term outcomes. The risk of seizures may be minimized by excluding high-risk patients.     

Pharmacological modulation by celecoxib of cachexia associated with experimental arthritis and atherosclerosis in rabbits

BACKGROUND AND PURPOSE

Non-steroidal anti-inflammatory drugs improve inflammatory cachexia in several conditions. Thus, we have explored inhibition of cyclooxygenase-2 (COX-2) in an experimental model of rheumatoid cachexia in rabbits.

EXPERIMENTAL APPROACH

Chronic arthritis was induced in immunized rabbits by repeated intra-articular injections of ovalbumin. To increase the degree of systemic inflammation and also to induce atherosclerotic lesions, the animals were fed a hyperlipidaemic diet (2% cholesterol and 6% peanut oil) and were given an endothelial injury of the femoral artery. Rabbits were randomized to receive the COX-2 inhibitor celecoxib (10 mg·kg⁻¹·day⁻¹) or no treatment. After 4 weeks, sera, peripheral mononuclear cells and vessel specimens were collected.

KEY RESULTS

Inhibition of COX-2 by celecoxib modulated the systemic inflammatory response and increased total cholesterol and triglyceride levels. Celecoxib also minimized weight loss and prevented serum albumin fall. At a vascular level, celecoxib reduced COX-2 protein in the femoral arterial wall, but did not modify size or the macrophage infiltration of femoral lesions nor the percentage of rabbits with spontaneous aortic plaques.

CONCLUSIONS AND IMPLICATIONS

Our animal model induced a severe inflammatory cachexia, comparable to that of persistently active rheumatoid arthritis. The inhibition of COX-2 by celecoxib improves this state, suggesting that COX products play an important role in its development, without affecting the development or the progression of vascular lesions. Overall, these results suggest that celecoxib might be considered as a new therapeutic tool for the treatment of rheumatoid cachexia.     

Animal models for anti-emphysema drug discovery

Introduction: Emphysema is characterized by an abnormal and permanent enlargement of airspaces accompanied by destruction of their walls. Up to now, there is no cure for emphysema, and animal models may be important for new drug discovery.

Areas covered: Herein, the authors review animal models of emphysema since the protease-antiprotease hypothesis as well as the results obtained with compounds tested in these models. Of particular importance are animal models of cigarette smoke exposure since it is the most important risk factor of emphysema. The authors also analyze two approaches to drug testing, that is, the approach aimed at preventing emphysema and the one aimed at reversing it.

Expert opinion: It has been suggested that early and late interventions do not have the same protective effect and that late interventions are much more likely to reveal treatments beneficial in humans. However, this is not always the case, and a compound that prevents emphysema when administered as an early intervention can also have the same protective effect when given as a late intervention. Furthermore, the fact that a compound detected by means of early intervention is now in clinical practice shows that early intervention studies can be predictive for efficacy in humans.     

动脉粥样硬化狭窄和再狭窄动物模型的实验研究

目的 :为经皮冠状动脉介入治疗(PCI)术后再狭窄研究提供理想动物模型。方法 :采用颈动脉逆行入径 ,用球囊导管对中国白兔双侧髂动脉行内膜损伤术 ,后给予高脂饮食建立双侧髂动脉粥样硬化狭窄模型 ,在此基础上行血管成形术建立再狭窄模型。结果 :(1)饲养后1 ,3,6周的血清胆固醇和甘油三酯水平显著高于饲养前 (P<0.01)。(2)血管成形术前髂动脉平均狭窄度左侧为 (50.80±14.12) %,右侧为 (51.20±13.94) % ,两者差别无统计学意义 (P>0.05),血管成形术后5周再狭窄程度模型组为 (55.20±14.47) %。 (3)病理HE染色及Masson染色示内膜显著增厚 ,主要由泡沫细胞、平滑肌细胞构成 ,内弹力膜分离断裂 ,中膜平滑肌细胞迁移入内膜层。 (4)透射电镜示膜结构破坏 ,胞浆内可见大小不等的脂质空泡沉积融合 ,多量胶原纤维束状增生。结论 :本方法成功建立了动脉粥样硬化狭窄和再狭窄动物实验模型 ,且简单、易行 ,模型稳定 ,重复性好     

老年性痴呆动物模型研究进展

老年性痴呆 (Alzheimersdisease,AD)是以老年斑和神经纤维缠结为特征的一种进行性、退行性神经系统疾病。AD动物模型的研究可大大促进AD病因、发病机制及药物筛选的研究 ,是深入开展AD研究的必要条件之一。损伤性、自然衰老动物和复合型动物模型能够复制出认知缺损等表现 ,但缺乏AD的特征性病变。SAM P/ 8是相对理想的模型。转基因小鼠是目前研究的热点 ,为在体研究AD的特定发病基因及其代谢产物提供了新的载体。随着AD治疗学由对症治疗转向对因治疗 ,AD模型也应顺应这一发展。     

多脏器微栓塞病细胞综合征动物实验模型──定义、判断标准、发生机制及其与临床的关系

利用健康杂交犬制作了多脏器微栓塞病细胞综合征（ＰＯＭＳ）模型,观察在不同时限、不同组织器官造成的病理生理改变。从中发现,钳夹腹主动脉阻断血流后,其供血器官都发生了ＲＯＭＳ,且不同器官的功能与结构损害有发生时间和程度的不同,但均有不同程度的微栓塞形成趋势,这有助对“多脏器衰竭”概念认识的深化。     

Animal models of pancreatic cancer for drug research

Background: The operative and conservative results of therapy in pancreatic ductal adenocarcinoma remain appallingly poor. This underlines the demand for further research for effective anticancer drugs. The various animal models remain the essential method for the determination of efficacy of substances during preclinical phase. Objective: Unfortunately, most of these tested substances showed a good efficacy in pancreatic carcinoma in the animal model but were not confirmed during the clinical phase. Methods: The available literature in PubMed, Medline, Ovid and secondary literature was searched regarding the available animal models for drug testing against pancreatic cancer. The models were analyzed regarding their pros and cons in anticancer drug testing. Conclusion: The different modifications of the orthotopic model (especially in mice) seem at present to be the best model for anticancer testing in pancreatic carcinoma. The value of genetically engineered animal model (GEM) and syngeneic models is on debate. A good selection of the model concerning the questions supposed to be clarified may improve the comparability of the results of animal experiments compared to clinical trials.     

沙库巴曲缬沙坦治疗慢性心肾综合征有效性和安全性的系统评价与Meta分析

目的:系统评价沙库巴曲缬沙坦治疗慢性心肾综合征(cardiorenal syndrome,CRS)的有效性和安全性。方法:在中国知网、万方、维普、中国生物医学数据库、PubMed、The Cochrane library、ClinicalTrials.gov等数据库中检索获取在慢性CRS患者中应用沙库巴曲缬沙坦的临床随机对照试验,检索时限为各数据库建库起至2022年5月17日。文献筛选、数据提取及质量评估根据Cochrane系统评价手册提供的方法进行。采用Review Manager 5.4、Stata 17.0软件对纳入文献的数据进行Meta分析。结果:最终纳入17篇文献,共计1 410例患者,其中治疗组707例,对照组703例。Meta分析结果显示:在非替代治疗患者中,治疗组改善左心室舒张末期内径(left ventricular end diastolic diameter,LVEDD)、左心室收缩期末内径(left ventricular end systolic diameter,LVESD)、左心室射血分数(left ventricular ejection fraction,LVEF)、血清N端脑钠肽前体(N-terminal pro brain natriuretic peptide,NT-proBNP)、估算的肾小球过滤率、血肌酐的效果均优于对照组(P＜0.01);而在替代治疗患者中,治疗组与对照组在改善患者LVEDD方面相比,差异无统计学意义(P=0.07),在改善患者LVESD、LVEF、NT-proBNP等方面治疗组均优于对照组(P＜0.05)。治疗组与对照组的不良反应发生率差异无统计学意义(P=0.06)。结论:沙库巴曲缬沙坦可改善非替代治疗的慢性CRS患者的心、肾功能和替代治疗的慢性CRS患者的心功能,且安全性良好。     

Medroxyprogesterone acetate in the management of cancer cachexia

Background: Medroxyprogesterone acetate (MPA) is a synthetic, orally active derivative of the natural steroid hormone progesterone, widely used in oncology both in the endocrine treatment of hormone-related cancers and as supportive therapy in the cachexia syndrome. Objective: The anticachectic mechanisms of medroxyprogesterone, beyond its endocrine activity, are described to explain its therapeutic efficacy in the treatment of cachexia. Methods: After reviewing its pathophysiology and preclinical studies, the main clinical trials on the use of medroxyprogesterone acetate in cancer cachexia, are reviewed. Results/conclusions: Progestagens, including MPA, are at present the only approved drugs in Europe for the clinical treatment of cancer-related anorexia/cachexia syndrome. Placebo-controlled trials on the effect of MPA on cachexia have generally reported an improvement of both anorexia and body weight as well as of quality-of-life parameters. However, the weight gain was due to increased body fat, while fat-free mass was not significantly influenced by MPA treatment. Moreover, very recently the combination of MPA with other new anticachectic agents has been suggested as a way of ameliorating their efficacy in the treatment of cachexia.     

Animal models of dementia

The major use of animal models for dementia is in the development of new therapeutic drugs. In contrast to other areas in psychopharmacology, where the predictive validity of animal models can be established by examining their response to known therapeutic agents, the search for antidementia drugs is hampered by the absence of recognized clinically effective reference compounds. Research scientists are therefore obliged to validate their models in terms of their similarity to the clinical condition. A second problem is the therapeutic target. Although antidementia drugs are intended to improve cognition in a general sense, the foremost therapeutic targets are the deficits in memory and attention associated with aging. The aging animal would appear to represent the best available model providing it can be shown that the cognitive deficits observed are similar to those observed in old age in humans. A logical consequence of this approach is to validate other experimental models in terms of their resemblance to naturally occurring age-related impairments. To illustrate these points, this paper reviews data obtained in aging animals in various behavioral models and the effects of drugs thereon. Comparisons are made between drug effects in aged animals with those observed in experimental models in young animals in which cognitive deficits are induced by anticholinergic drug treatment or lesions to cholinergic-rich brain regions. It is concluded that aging induces cognitive deficits mainly associated with short-term memory but that other aspects of cognition, namely attention and information processing speed, also decline with age. Putative antidementia drugs, particularly those facilitating cholinergic transmission, appear frequently to have more marked effects in experimental deficit models than in aged animals themselves. © 1995 Wiley-Liss, Inc.