Summary. Background:  Eltrombopag is an oral, non‐peptide thrombopoietin receptor agonist that has shown efficacy and safety in chronic immune thrombocytopenia (ITP). However, ethnic differences in eltrombopag exposure have been reported: area under the curve exposure to eltrombopag was 87% greater among ITP patients of East Asian descent than among ITP patients of non‐East Asian ITP descent. Objectives:  To evaluate the efficacy and safety of eltrombopag by using, in Japanese ITP patients, lower starting (12.5 mg) and maximum (50 mg) doses of eltrombopag than the standard starting (50 mg) and maximum (75 mg) doses approved in the USA and Europe. Patients:  We examined 23 Japanese patients with previously treated chronic ITP with a platelet count of < 30 000 μL−1 in a multicenter study comprising a randomized, double‐blind, placebo‐controlled phase for 6‐week evaluation (15 eltrombopag, and eight placebo) and an open‐label phase for 6‐month evaluation (23 eltrombopag). Results and Conclusions:  The response rate (platelet count of ≥ 50 000 μL−1) at week 6 of the 6‐week double‐blind phase was 60% in eltrombopag‐treated patients and 0% in placebo‐treated patients. Ten of 23 patients (43.5%) responded for ≥ 75% of predefined assessment visits during the 6‐month open‐label phase. Notably, 22% (5/23) of patients responded to 12.5 mg of eltrombopag, which was administered within the first 3 weeks of eltrombopag treatment. Bleeding decreased with eltrombopag treatment as compared with baseline. Eltrombopag was generally well tolerated; one patient experienced a transient ischemic attack on day 9. Eltrombopag (12.5–50 mg) is effective for the management of Japanese patients with chronic ITP (NCT00540423).

We recently characterized male DahlS.Z-Lepr fa /Lepr fa (Dahl salt-sensitive (DS)/obese) rats, which were established from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated cardiac pathophysiology and metabolic changes in female DS/obese rats in comparison with homozygous lean female littermates (DahlS.Z-Lepr + /Lepr + , or DS/lean, rats). Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 15 weeks of age. Systolic blood pressure was significantly higher in female DS/obese rats than in DS/lean females at 12 weeks of age and thereafter. The survival rate of DS/obese rats was significantly lower than that of DS/lean rats at 15 weeks. Body weight, as well as visceral and subcutaneous fat mass were significantly increased in DS/obese rats, which also manifested left ventricular (LV) diastolic dysfunction and marked LV hypertrophy and fibrosis. In addition, myocardial oxidative stress and inflammation were increased in DS/obese rats compared with DS/lean rats. Serum insulin and triglyceride levels as well as the ratio of low-density lipoprotein-to high-density lipoprotein-cholesterol levels were markedly elevated in DS/obese rats, whereas fasting serum glucose concentrations were similar in the two rat strains. The phenotype of female DS/obese rats is similar to that of MetS in humans. These animals also develop salt-sensitive hypertension and LV diastolic dysfunction as well as LV hypertrophy and fibrosis, and these changes are associated with increased cardiac oxidative stress and inflammation. Keywords: cardiac hypertrophy; diastolic dysfunction; metabolic syndrome; myocardial fibrosis; salt-sensitive hypertension INTRODUCTION Metabolic syndrome (MetS), a complex of highly debilitating disorders including hypertension, diabetes mellitus and dyslipidemia, is associated with the development of visceral obesity. 1 Adipocytes in visceral fat of obese humans secrete a variety of biological agents that are known as adipocytokines and include proinflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-6 as well as angiotensinogen and leptin. 2 Recent studies have revealed intricate interactions among adipocytes, the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) that contribute to the disturbed metabolic state associated with obesity. 3 Indeed, adipose tissue is thought to have an important role in the development of both hypertension and other complications related to insulin resistance. Activation of the RAAS and associated oxidative stress can result in mitochondrial abnormalities, altered bioenergetics and the accumulation of lipids in the heart, and thereby increase susceptibility to metabolic cardiomyopathy. 4

Calorie restriction (CR) can modulate the features of obesity-related metabolic and cardiovascular diseases. We have recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. DS/obese rats develop hypertension and manifest left ventricular remodeling and diastolic dysfunction, as well as increased cardiac oxidative stress and inflammation. We have now investigated the effects of CR on cardiac pathophysiology in DS/obese rats. DS/obese rats were fed either normal laboratory chow ad libitum or a calorie-restricted diet (65% of the average food intake for ad libitum) from 9 to 13 weeks. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+) or DS/lean) littermates served as controls. CR reduced body weight in both DS/obese and DS/lean rats, as well as attenuated the development of hypertension in DS/obese rats without affecting blood pressure in DS/lean rats. CR also reduced body fat content, ameliorated left ventricular hypertrophy, fibrosis, and diastolic dysfunction, and attenuated cardiac oxidative stress and inflammation in DS/obese rats. In addition, it increased serum adiponectin concentration, as well as downregulated the expression of angiotensin-converting enzyme and angiotensin II type 1A receptor genes in the heart of DS/obese rats. Our results thus show that CR attenuated obesity and hypertension, as well as left ventricular remodeling and diastolic dysfunction in DS/obese rats, with these latter effects being associated with reduced cardiac oxidative stress and inflammation.

Objective:The DahlS.Z-Leprfa/Leprfa (DS/obese) rat strain was established from a cross between Dahl salt-sensitive rats and Zucker fatty (fa/fa) rats, the latter of which harbor a missense mutation in the leptin receptor gene (Lepr). We examined whether DS/obese rats might be a suitable animal model of metabolic syndrome in humans.Methods:The systemic pathophysiological and metabolic characteristics of DS/obese rats were determined and compared with those of homozygous lean littermates, namely, DahlS.Z-Lepr+/Lepr+ (DS/lean) rats.Results:Systolic blood pressure was higher in DS/obese rats fed a normal diet than in DS/lean rats at 11 weeks of age and thereafter. The survival rate of DS/obese rats was significantly lower than that of DS/lean rats at 18 weeks. Body weight, visceral and subcutaneous fat mass, as well as heart, kidney and liver weights, were increased in DS/obese rats at 18 weeks compared with DS/lean rats. Serum low-density lipoprotein (LDL)-cholesterol, triglyceride and insulin concentrations, as well as the ratio of LDL-cholesterol to high-density lipoprotein-cholesterol levels, were increased in DS/obese rats, whereas serum glucose concentration did not differ significantly between DS/obese and DS/lean rats. Creatinine clearance was decreased and urinary protein content was increased in DS/obese rats, which also manifested lipid accumulation in the liver and elevation of serum alanine aminotransferase levels.Conclusion:These results show that the phenotype of DS/obese rats is similar to that of humans with metabolic syndrome, and that these animals may thus be an appropriate model for this condition.

BackgroundMetabolic syndrome (MetS) enhances salt sensitivity of blood pressure and is an important risk factor for cardiovascular disease. The effects of dietary salt restriction on cardiac pathology associated with metabolic syndrome remain unclear.Methods and ResultsWe investigated whether dietary salt restriction might ameliorate cardiac injury in DahlS.Z‐Leprfa/Leprfa (DS/obese) rats, which are derived from a cross between Dahl salt‐sensitive and Zucker rats and represent a model of metabolic syndrome. DS/obese rats were fed a normal‐salt (0.36% NaCl in chow) or low‐salt (0.0466% NaCl in chow) diet from 9 weeks of age and were compared with similarly treated homozygous lean littermates (DahlS.Z‐Lepr+/Lepr+, or DS/lean rats). DS/obese rats fed the normal‐salt diet progressively developed hypertension and showed left ventricular hypertrophy, fibrosis, and diastolic dysfunction at 15 weeks. Dietary salt restriction attenuated all of these changes in DS/obese rats. The levels of cardiac oxidative stress and inflammation and the expression of cardiac renin–angiotensin–aldosterone system genes were increased in DS/obese rats fed the normal‐salt diet, and dietary salt restriction downregulated these parameters in both DS/obese and DS/lean rats. In addition, dietary salt restriction attenuated the increase in visceral adipose tissue inflammation and the decrease in insulin signaling apparent in DS/obese rats without reducing body weight or visceral adipocyte size. Dietary salt restriction did not alter fasting serum glucose levels but it markedly decreased the fasting serum insulin concentration in DS/obese rats.ConclusionsDietary salt restriction not only prevents hypertension and cardiac injury but also ameliorates insulin resistance, without reducing obesity, in this model of metabolic syndrome.

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Restraint stress stimulates sympathetic nerve activity and can affect adiposity and metabolism. However, the effects of restraint stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We investigated the effects of chronic restraint stress and β-adrenergic receptor (β-AR) blockade on cardiac and adipose tissue pathology and metabolic disorders in a rat model of MetS. DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats. Rats were exposed to restraint stress (restraint cage, 2 h/day) for 4 wk from 9 wk of age with or without daily subcutaneous administration of the β-AR blocker propranolol (2 mg/kg). Age-matched homozygous lean littermates of DS/obese rats (DahlS.Z-Lepr(+)/Lepr(+) rats) served as control animals. Chronic restraint stress exacerbated hypertension as well as left ventricular hypertrophy, fibrosis, diastolic dysfunction, and oxidative stress in a manner sensitive to propranolol treatment. Restraint stress attenuated body weight gain in DS/obese rats, and this effect tended to be reversed by propranolol (P = 0.0682). Restraint stress or propranolol did not affect visceral or subcutaneous fat mass. However, restraint stress potentiated cardiac and visceral adipose tissue inflammation in DS/obese rats, and these effects were ameliorated by propranolol. Restraint stress also exacerbated glucose intolerance, insulin resistance, and abnormal lipid metabolism in a manner sensitive to propranolol. In addition, restraint stress increased urinary norepinephrine excretion, and propranolol attenuated this effect. Our results thus implicate β-ARs in the exacerbation of cardiac and adipose tissue pathology and abnormal glucose and lipid metabolism induced by restraint stress in this model of MetS.

BackgroundEltrombopag is an oral thrombopoietin receptor agonist that stimulates thrombopoiesis and shows higher exposure in East Asian patients than in non-Asian patients. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with thrombocytopenia associated with chronic liver disease (CLD).MethodsThirty-eight patients with CLD and thrombocytopenia (platelets <50,000/μL) were enrolled in this phase II, open-label, dose-ranging study that consisted of 2 parts. In the first part, 12 patients received 12.5 mg of eltrombopag once daily for 2 weeks. After the evaluation of safety, 26 patients were randomly assigned to receive either 25 or 37.5 mg of eltrombopag once daily for 2 weeks in the second part.ResultsPharmacokinetics showed that the geometric means of the maximum plasma concentration (Cmax) and the area under the curve (AUC) in the 12.5 mg group were 3,413 ng/mL and 65,236 ng h/mL, respectively. At week 2, the mean increases from baseline in platelet counts were 24,800, 54,000, and 60,000/μL in the 12.5, 25, and 37.5 mg groups, respectively. The median platelet counts increased within 2 weeks of the beginning of administration in all groups, and remained at the same level throughout the 2-week post-treatment period in the 12.5 mg group, whereas the platelet counts peaked a week after the last treatment in both the 25 and 37.5 mg groups. Most adverse events reported were grade 1 or 2; 2 patients in the 37.5 mg group had drug-related serious adverse events.ConclusionsEltrombopag ameliorated thrombocytopenia in Japanese patients with CLD and thrombocytopenia. The recommended dose for these patients is 25 mg daily for 2 weeks.