Therapeutic potential of A1 adenosine receptor ligands: a survey of recent patent literature

Background: In recent years, a number of companies, universities and other institutions have invested in research on new molecules acting as agonists, antagonists and enhancers on A₁ adenosine receptors (ARs) and in the evaluation of their new therapeutic applications. Objective: To review recent patenting activity on this topic. Methods: The first part of this article describes the compounds patented, subdivided by functional activity, and the second part the most relevant therapeutic applications or new uses for A₁ AR ligands, with a focus on compounds in or soon to be in clinical trials. Conclusion: Although a number of potential therapeutic applications are proposed in the recent literature, at present, in the authors' opinion, very few A₁ ligands are close to coming on the market, probably due to limited selectivity towards the target tissue or organ.     

Emphysema induced by elastase enhances acute inflammatory pulmonary response to intraperitoneal LPS in rats

Abnormalities in lungs caused by emphysema might alter their response to sepsis and the occurrence of acute lung injury (ALI). This study compared the extension of ALI in response to intraperitoneal lipopolysaccharide (LPS) injection in Wistar rats with and without emphysema induced by elastase. Adult male Wistar rats were randomized into four groups: control, emphysema without sepsis, normal lung with sepsis and emphysema with sepsis. Sepsis was induced, and 24 h later the rats were euthanised. The following analysis was performed: blood gas measurements, bronchoalveolar lavage (BAL), lung permeability and histology. Animals that received LPS showed significant increase in a lung injury scoring system, inflammatory cells in bronchoalveolar lavage (BAL) and IL‐6, TNF‐α and CXCL2 mRNA expression in lung tissue. Animals with emphysema and sepsis showed increased alveolocapillary membrane permeability, demonstrated by higher BAL/serum albumin ratio. In conclusion, the presence of emphysema induced by elastase increases the inflammatory response in the lungs to a systemic stimulus, represented in this model by the intraperitoneal injection of LPS.     

Transmission of Streptococcus equi Subspecies zooepidemicus Infection from Horses to Humans

Streptococcus equi subspecies zooepidemicus (S. zooepidemicus) is a zoonotic pathogen for persons in contact with horses. In horses, S. zooepidemicus is an opportunistic pathogen, but human infections associated with S. zooepidemicus are often severe. Within 6 months in 2011, 3 unrelated cases of severe, disseminated S. zooepidemicus infection occurred in men working with horses in eastern Finland. To clarify the pathogen’s epidemiology, we describe the clinical features of the infection in 3 patients and compare the S. zooepidemicus isolates from the human cases with S. zooepidemicus isolates from horses. The isolates were analyzed by using pulsed-field gel electrophoresis, multilocus sequence typing, and sequencing of the szP gene. Molecular typing methods showed that human and equine isolates were identical or closely related. These results emphasize that S. zooepidemicus transmitted from horses can lead to severe infections in humans. As leisure and professional equine sports continue to grow, this infection should be recognized as an emerging zoonosis.     

Newly discovered innate response activator B cells: crucial responders against microbial sepsis

Evaluation of: Waldmann TA, Conlon KC, Stewart DM et al. Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-β-1 mAb in patients with T-cell large granular lymphocytic leukemia. Blood 121(3), 476–484 (2013).

IL-15 is a cytokine that stimulates the proliferation of NK and T cells. Previous studies have shown that IL-15 is critical to the induction of T-cell large granular lymphocyte (T-LGL) leukemia. A Phase I trial of a humanized antibody (Hu-Mikβ1) to the IL2/IL15Rβ receptor, expressed on T-LGL, is explored in this trial to evaluate the safety, pharmacokinetics, specificity and clinical efficacy of Hu-Mikβ1. The study demonstrated no toxicity and favorable saturation of IL2/IL15Rβ receptor, but no clinical efficacy in this Phase I study.     

Pneumonia‐induced sepsis in mice: temporal study of inflammatory and cardiovascular parameters

The aim of the present work is to provide a better comprehension of the pneumonia‐induced sepsis model through temporal evaluation of several parameters, and thus identify the main factors that determine mortality in this model. Klebsiella pneumoniae was inoculated intratracheally in anesthetized Swiss male mice. Inflammatory and cardiovascular parameters were evaluated 6, 24 and 48 h after the insult. The results show that severity of infection and the mortality correlated with the amount of bacteria. Six, 24 and 48 h after inoculation, animals presented pathological changes in lungs, increase in cell number in the bronchoalveolar lavage, leukopenia, increase in TNF‐α and IL‐1β levels, hypotension and hyporesponsiveness to vasoconstrictors, the two latter characteristics of severe sepsis and septic shock. Significant numbers of bacteria in spleen and heart homogenates indicated infection spreading. Interestingly, NOS‐2 expression appeared late after bacteria inoculation, whereas levels of NOS‐1 and NOS‐3 were unchanged. The high NOS‐2 expression coincided with an exacerbated NO production in the infection focus and in plasma, as judging by nitrate + nitrite levels. This study shows that K. pneumoniae inoculation induces a systemic inflammatory response and cardiovascular alterations, which endures at least until 48 h. K. pneumoniae‐induced lung infection is a clinically relevant animal model of sepsis and a better understanding of this model may help to increase the knowledge about sepsis pathophysiology.     

黏附因子联合肾阻力指数对脓毒症相关性肾损伤的早期肾功能恢复的预测价值

目的 探讨联合应用黏附因子和肾阻力指数(renal resistace index，RRI)对脓毒症相关性急性肾损伤患者早期肾功能恢复的预测价值。 方法 选择河北医科大学第三医院重症医学科住院的脓毒症相关性肾损伤成年患者为研究对象，收集研究对象的一般资料，应用床旁超声检测患者RRI，采用酶联免疫吸附测定法测定血浆E-选择素、L-选择素和P-选择素及 内皮细胞黏附因子（intercellular cell adhesion molecule-1，ICAM-1）及血管细胞黏附分子1（vascular cell adhesion molecule-1，VCAM-1）水平,对患者进行随访1个月，将研究对象根据入组30 d是否肾功能恢复作为标准，分为肾功能恢复组和肾功能未恢复组。应用Logistics回归分析方法及接受者操作特征(receiver operating characteristic，ROC)曲线分析RRI、黏附因子、RRI联合黏附因子对脓毒症急性肾损伤患者肾功能恢复的预测价值。 结果 共纳入脓毒症相关性急性肾损伤者78例，其中男性54例，女性24例，平均年龄(70.8±23.3)岁；脓毒症急性肾损伤早期肾功能恢复组的VCAM-1表达均低于肾功能未恢复组（P=0.035 5），肾功能早期恢复组的APACHEⅡ评分及白细胞计数明显低于肾功能未恢复组（P＜0.05）。应用ROC曲线分析，VCAM-1联合RRI预测脓毒症患者早期肾功能恢复的敏感度为90.9%，特异度为32.1%，AUC=0.68。 结论 VCAM-I联合RRI对于脓毒症相关性急性肾损伤患者的早期肾功能恢复有较高的预测价值，以肾脏阻力指数的界值为0.71，VCAM-1的界值为1 233 ng/L，可以作为脓毒症相关性急性肾损伤患者的早期肾功能恢复的预测指标。     

清瘟解毒汤联合常规治疗对热毒壅滞型细菌性脓毒血症患者的临床疗效

目的考察清瘟解毒汤联合常规治疗对热毒壅滞型细菌性脓毒血症患者的临床疗效。方法94例患者随机分为对照组和观察组,每组47例,对照组给予常规治疗(抗感染、吸氧、早期体液复苏等),观察组在对照组基础上加用清瘟解毒汤,疗程2周。检测临床疗效、CKMB、Scr、ALT、TGF?β1、CHE、SOFA评分、WBC、PCT、CRP、NK细胞、PT、CD4+/CD8+、并发症发生率变化。结果观察组总有效率高于对照组(P<0.05),并发症发生率更低(P<0.05)。治疗后,2组CKMB、Scr、ALT、TGF?β1、SOFA评分、WBC、PCT、TNF?α降低(P<0.05),PT缩短(P<0.05),CHE、NK细胞、CD4+/CD8+升高(P<0.05),以观察组更明显(P<0.05)。结论清瘟解毒汤联合常规治疗可促进热毒壅滞型细菌性脓毒血症患者感染康复,减轻炎症反应,提高免疫力,保护脏器功能,降低并发症发生率。     

Current Treatment of High Grade Osteosarcoma of the Extremity: Review

Abstract

The authors review their lengthy experience in treating high grade osteosarcoma of the extremity. During the past 20 years many advances have been made in treating high grade osteosarcoma of the extremity. Twenty years ago, in spite of amputation, most patients with this tumor died, whereas today most are cured and amputation is avoided. These advances are mainly due to the development of effective adjuvant and neoadjuvant chemotherapy regimens. This review reports on the progress and controversies in the treatment of osteosarcoma.     

Additional benefit of combined therapy with melatonin and apoptotic adipose‐derived mesenchymal stem cell against sepsis‐induced kidney injury

This study tested whether combined therapy with melatonin and apoptotic adipose‐derived mesenchymal stem cells (A‐ADMSCs) offered additional benefit in ameliorating sepsis‐induced acute kidney injury. Adult male Sprague–Dawley rats (n = 65) were randomized equally into five groups: Sham controls (SC), sepsis induced by cecal‐ligation and puncture (CLP), CLP‐melatonin, CLP‐A‐ADMSC, and CLP‐melatonin‐A‐ADMSC. Circulating TNF‐α level at post‐CLP 6 hr was highest in CLP and lowest in SC groups, higher in CLP‐melatonin than in CLP‐A‐ADMSC and CLP‐melatonin‐A‐ADMSC groups (all P < 0.001). Immune reactivity as reflected in the number of splenic helper‐, cytoxic‐, and regulatory‐T cells at post‐CLP 72 hr exhibited the same pattern as that of circulating TNF‐α among all groups (P < 0.001). The histological scoring of kidney injury and the number of F4/80+ and CD14+ cells in kidney were highest in CLP and lowest in SC groups, higher in CLP‐melatonin than in CLP‐A‐ADMSC and CLP‐melatonin‐A‐ADMSC groups, and higher in CLP‐A‐ADMSC than in CLP‐melatonin‐A‐ADMSC groups (all P < 0.001). Changes in protein expressions of inflammatory (RANTES, TNF‐1α, NF‐κB, MMP‐9, MIP‐1, IL‐1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF‐β) markers, reactive‐oxygen‐species (NOX‐1, NOX‐2), and oxidative stress displayed a pattern identical to that of kidney injury score among the five groups (all P < 0.001). Expressions of antioxidants (GR+, GPx+, HO‐1, NQO‐1+) were lowest in SC group and highest in CLP‐melatonin‐A‐ADMSC group, lower in CLP than in CLP‐melatonin and CLP‐A‐ADMSC groups, and lower in CLP‐melatonin‐ than in CLP‐A‐ADMSC‐tretaed animals (all P < 0.001). In conclusion, combined treatment with melatonin and A‐ADMSC was superior to A‐ADMSC alone in protecting the kidneys from sepsis‐induced injury.     

Risk of Acute Kidney Injury after Exposure to Gadolinium-Based Contrast in Patients with Renal Impairment

Objectives: Gadolinium-based contrast media (Gd-CM) are reported to induce acute kidney injury (AKI) in a high-risk population group at the usual dose for magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) examinations. We assessed gadolinium-induced nephropathy in patients with renal impairment who underwent MRI or MRA examinations, and evaluated the risk factors. Materials and methods: In this retrospective study, 238 patients with baseline renal impairment, who received MRI or MRA examinations with Gd-CM, were recruited. After all other AKI causes—liver decompensation, severe heart failure, all kinds of shock, and severe sepsis—and patients on dialysis were excluded, 158 patients were enrolled. AKI was defined as a decrease in glomerular filtration rate (GFR) >10% of baseline data within 3 days after administration of Gd-CM. Regression analysis was used to find independent risk factors for gadolinium-induced AKI (Gd-AKI). Results: Twenty-six of the 158 patients (16.5%) developed Gd-AKI. There were no significant differences in gender, age, or baseline GFR between those who did and who did not develop AKI. Comorbid coronary artery disease, liver cirrhosis, diabetes mellitus, and hypertension were not significantly associated with the development of Gd-AKI. However, sepsis was an independent risk factor for Gd-AKI after multivariate regression analysis (adjusted odds ratio: 4.417; 95% confidence interval: 1.671–11.676, p = 0.03). Conclusions: It is potential AKI after administration of Gd-CM under sepsis condition at the dose for MRI and MRA examinations in patients with renal impairment. It is important to identify high-risk patients and closely monitor renal function after administration of Gd-CM.