Assessment of the effectiveness of golimumab 50-mg and 100-mg regimens in patients with rheumatoid arthritis in daily practice

Abstract

Objectives. To assess the effectiveness of the golimumab (GLM) 50-mg and 100-mg regimens in patients with rheumatoid arthritis (RA) in daily practice. Methods. We retrospectively analyzed RA patients who started GLM between September 2011 and July 2012. Patients were divided into three groups: a 50-mg group; a 50/100-mg group (had a dose increase to 100 mg); and a 100-mg group (started GLM at 100 mg). We assessed Disease Activity Score 28 (DAS28) and treatment continuation rate. Risk factors associated with time to discontinuation of the 50-mg regimen were determined with proportional hazards analysis. Results. We analyzed 74 patients: 43 in the 50-mg group, 23 in the 50/100-mg group, and 8 in the 100-mg group. DAS28 improved from 4.0 ± 1.0, 4.8 ± 1.0, and 4.7 ± 1.9, respectively, at baseline to 2.4 ± 1.2, 3.3 ± 1.5, and 2.5 ± 0.7, respectively, at week 52. Treatment continuation rates at week 52 were 73.7%, 60.9%, and 87.5%, respectively. In the 50/100-mg group, the mean DAS28 improved significantly from 4.4 ± 1.2 before to 3.6 ± 1.3 12 weeks after the dose increase. Oral corticosteroid therapy ≥ 5 mg/day, previous use of two biologic agents, and DAS28 > 5.1 at initiation of GLM were significantly associated with discontinuation of the 50-mg regimen. Conclusions. Both GLM 50-mg and 100-mg regimens are effective in patients with RA in daily practice.     

Comparison of polymyxin B with other antimicrobials in the treatment of ventilator-associated pneumonia and tracheobronchitis caused by Pseudomonas aeruginosa or Acinetobacter baumannii

Purpose

This study was designed to compare the efficacy of polymyxin B with other antimicrobials in the treatment of ventilator-associated pneumonia (VAP) and tracheobronchitis (VAT) by Pseudomonas aeruginosa or Acinetobacter baumannii.

Methods

A prospective cohort study was performed. Patients >18 years of age with the diagnosis of VAP or VAT who received appropriate therapy for >48 h were analyzed. The primary outcome was 30-day mortality. Clinical covariates were assessed and compared between the groups.

Results

A total of 67 episodes were analyzed: 45 (67 %) treated with polymyxin B and 22 (33 %) with comparators. The crude 30-day mortality was 53 % (24 of 45) in the polymyxin B group and 27 % (6 of 22) in the comparator group (P = 0.08). Multivariable analysis using Cox regression models indicated that polymyxin B treatment was independently associated with increased mortality.

Conclusions

Polymyxin B treatment in the currently recommended dosage may be inferior to other drugs in the treatment of VAP and VAT caused by organisms tested as susceptible in vitro to this agent.     

Effect of polymyxin B-containing regimens on renal function for the treatment of carbapenem-resistant Enterobacteriacea mediastinitis

A retrospective cohort study, were evaluated: polymyxin B plus aminoglycosides or polymyxin B plus other antibiotics. Any degree of acute kidney injury occurred in 26 (86.6%) patients. The median time to acute kidney injury was 6.0 (95% CI 3–14) days in the polymyxin-aminoglycoside containing regimen group, against 27.0 (95% CI 6–42) days in the polymyxin with other antimicrobial combinations group (p = 0.03). Polymyxin B with aminoglycosides group progressed faster to any degree of renal dysfunction.     

胺碘酮不同给药途径对阵发性心房颤动患者的疗效及安全性

目的观察胺碘酮不同给药途径对阵发性心房颤动(简称房颤)的疗效及安全性。方法128例阵发性房颤患者随机分成两组,A组:胺碘酮5mg/kg静脉注射15min,接着以1.5mg/min的速度静脉滴注6h,再以0.7～1mg/min静脉滴注24～48h,同时口服胺碘酮200mg/d。B组:胺碘酮600mg/d。给药后心电及血压监测48h。比较两组转复时间及24h,48h,7天,1个月的转复率。结果两组房颤转复率没有差别(P>0.05)。A组的房颤转复时间明显缩短(734±128minvs1428±242min,P<0.05)。给药后7天、1个月两组未转复仍保持房颤患者的心室率明显降低(P<0.05)。A组的血压在给药后24h内明显下降,而B组的血压一直保持稳定。A组有5例浅静脉炎。结论胺碘酮静脉给药可显著缩短房颤的转复时间,但增加低血压及浅静脉炎的风险。     

Effects of ketamine on proinflammatory cytokines and nuclear factor kappaB in polyrnicrobial sepsis rats

AIM: To explore the effects of ketamine on hemodynamics, plasma proinflammatory cytokine (TNF-α and IL-6) levels and nuclear factor kappa B (NF-κB) activation during polymicrobial sepsis.METHODS: Male Sprague-Dawlay rats were subjected to cecal ligation and puncture (CLP) or sham operation.The rats were randomly assigned into four equal groups:sham CLP group, CLP group, ketamine (KT)I groupand KTⅡ group. Thirty minutes before CLP, ketamine (5my/kg per hour and 10 my/kg per hour, respectively) was infused continuously through the left femoral vein cannula in KT I group or KTⅡgroup. Sham CLP group and CLP group received 0.9% saline only (5 mL/kg per hour). The right femoral artery was cannulated to monitor mean arterial pressure (MAP) and heart rates (HR),and draw blood samples. The proinflammatory cytokine (TNF-α and IL-6) levels of plasma were measured using enzyme-linked immunosorbent assays (ELISA). The hepatic NF-κB activation was determined by Western blot and HPIAS 2000 image analysis system.Twenty hours after CLP, the rats were killed by right femoral artery phlebotomization.RESULTS: CLP produced progressive hypotension,and a first increase followed by a decrease in HR. The hypotension was prevented, and the HR was slightly steady in ketamine treated rats. TNF-α levels of plasma reached a peak value at 2 h after CLP. Ketamine (KT I group or KTⅡgroup) caused a significant decrease compared with CLP group at 2, 5 and 9 h time points after CLP (14.3 ± 1.9 vs 4.3 ± 0.9, 9.7 ± 1.4 vs 4.3 ±0.9; 9.3 ± 1.5 vs 4.3 ± 0.9, 8.7 ± 1.4 vs 4.3 ± 0.9; 6.0± 1.5 vs 5.0 ± 1.7, 5.3 ± 0.8 vs 5.0 ± 1.7; P ＜ 0.01,respectively). The IL-6 levels of plasma firstly ascended and then descended in CLP group, and reached a peak value at 9 h after CLP. Ketamine (KT I group or KTⅡ group) caused a significant decrease compared with CLP group at 5, 9 or 20 h after CLP (135.0 ± 52.6 vs 60.0± 16.3, 112.5 ± 52.6 vs 60.0 ± 16.3; 410.0 ± 68.7 vs62.5 ± 12.5, 250.0 ± 28.0 vs 62.5 ± 12.5; 320.0 ± 25.9vs 52.5 ± 10.1, 215.0 ± 44.6 vs 52.5 ± 10.1; P ＜ 0.05,respectively). The IL-6 levels of plasma in KTⅡgroup were lower than those of KT I group at 9 h after CLP (250.0 ± 28.0 vs 410.0 ± 68.7; P ＜ 0.05). In addition,CLP increased hepatic NF-κB expression compared with sham CLP. Ketamine suppressed NF-κB activation in a dose-dependent manner at 4 h after CLP (237.7 ± 3.5 vs 246.9 ± 3.1; P ＜ 0.05).CONCLUSION: Ketamine stabilizes the hemodynamics,attenuates the proinflammatory cytokine responses,and inhibits hepatic NF-κB activation. These findings suggest that ketamine has protective effects against polymicrobial sepsis in rats.     

Comparative safety, tolerance, and pharmacokinetics of amphotericin B lipid complex and amphotericin B desoxycholate in healthy male volunteers.

Amphotericin B lipid complex (ABLC), a lipid complex formulation of amphotericin B, and amphotericin B desoxycholate (AB) were compared for safety, tolerance, and pharmacokinetics in two groups of eight healthy male volunteers. After a 1-mg test dose, study drug was infused at 0.1, 0.25, and 0.5 mg/kg; the 0.5-mg/kg dose was not given to subjects receiving AB. ABLC caused few acute adverse effects except for mild somnolence (drowsiness) in six volunteers. In addition, three of eight ABLC recipient had asymptomatic, transient serum transaminase elevations that resolved spontaneously. The AB recipients experienced more acute side effects, but only one had a mild shaking chill: three of eight also experienced sleepiness. No significant changes in vital signs, electrocardiogram, oximetry, pulmonary function, or clinical status were observed in either group. Due to its increased estimate volume of distribution and estimated clearance. ABLC yielded decreased amphotericin B levels and area under the serum concentration versus time curve relative to AB.     

Oral Sodium to Preserve Renal Efficiency in Acute Heart Failure: A Randomized,Placebo-Controlled,Double-Blind Study

BackgroundEvidence for modulating the sodium chloride (NaCl) intake of patients hospitalized with acute heart failure (AHF) is inconclusive. Salt restriction may not benefit; hypertonic saline may aid diuresis.ObjectiveTo compare the safety and efficacy of oral NaCl during intravenous (IV) diuretic therapy in renal function and weight.MethodsSeventy hospitalized patients with AHF who were being treated with IV furosemide infusion consented to receive, randomly, 2 grams of oral NaCl or placebo 3 times a day in a double-blind manner during diuresis. Treatment efficacy (bivariate primary endpoints of change in serum creatinine levels and change in weight) was measured at 96 hours, and adverse safety events were tracked for 90 days.ResultsSixty-five patients (34 NaCl, 31 placebo) were included for analysis after 5 withdrew. A median of 13 grams of NaCl was given compared to placebo. At 96 hours, there was no significant difference between treatment groups with respect to the primary endpoint (P = 0.33); however, the trial was underpowered, and there was greater than expected standard deviation in weight change. The mean change in creatinine levels and weight was 0.15 ± 0.44 mg/dL and 4.6 ± 4.2 kg in the placebo group compared with 0.04 ± 0.40 mg/dL and 4.0 ± 4.3 kg in the NaCl group (P = 0.30 and 0.57, respectively). Across efficacy and safety endpoints, we observed no significant difference between the 2 groups other than changes in serum sodium levels (-2.6 ± 2.7 in the placebo group and -0.3 ± 3.3 mEq/L in the NaCl group; P < 0.001) and in serum blood urea nitrogen levels (11 ± 15 in the placebo group; 3.1 ± 13 mEq/L in the NaCl group; P = 0.025).ConclusionsIn this single-center study, liberal vs restrictive oral sodium chloride intake strategies did not impact the safety and efficacy of intravenous diuretic therapy in patients with AHF. (ClinicalTrials.gov registration NCT04334668.)     

半剂量替罗非班联合替格瑞洛用于STEMI急诊冠脉介入术治疗患者的临床疗效及安全性观察

摘要 目的 分析半剂量替罗非班联合替格瑞洛用于STEMI急诊冠脉介入术治疗患者的临床疗效及安全性。方法 选取2017年5月-2018年9月到喀什地区第一人民医院行急诊PCI治疗的STEMI患者180例为研究对象。按随机数字表法分为A组、B组和C组,各60例患者,A组PCI术前、术后常规给予阿司匹林联合氯吡格雷及肝素等,术中冠脉内注射替罗非班;B、C组替换A组中氯吡格雷为替格瑞洛,再分别以微量泵按0.1μg/（kg·min）和0.05μg/（kg·min）持续静脉泵注替罗非班至术后36h。对比3组临床疗效、心肌损伤指标水平、用药安全性及主要心血管不良事件事件(MACE)。结果 B、C组临床疗效评价各指标包括术后即刻冠脉血流、心肌微循环灌注、ST段抬高回落情况及血小板聚集率均明显优于A组（P＜0.05）。治疗后,A、B、C 3组的cTnI水平分别为（3.19±0.67）ng/ml、（1.86±0.13）ng/ml和（1.73±0.48）ng/ml,CK-MB水平分别为（81.12±5.19）U/L、（68.22±5.61）U/和（62.28±7.34）U/L,3组治疗后的上述两指标水平均较治疗前下降（P＜0.05）,且B、C组较A组降低更为显著（P＜0.05）。B、C组的出血情况总发生率分别为13.33%、3.33%,均明显低于A组的25.00%（P＜0.05）,其中C组低于B组（P＜0.05）。随访期间,B、C组的MACE总发生率分别为5.00%、5.00%,均明显低于A组的16.67%（P＜0.05）。结论 替罗非班联合替格瑞洛用于STEMI急诊冠脉介入术治疗患者的临床疗效较好,使用半剂量替罗非班能减少出血风险。     

Identification of circulating microRNAs in young men with central obesity

IntroductionCentral obesity has been identified as a stronger risk factor than overall obesity for morbidity and mortality of chronic diseases. Currently, studies showed that microRNAs (miRNAs) can be found in adipose tissue and blood circulation of obese persons. Thus, miRNAs can be a potential candidate as a biomarker.ObjectivesTo determine miRNAs expression in circulating blood of central obese young men compared to non-central obese young men. Significant miRNAs will be validated individually through qPCR.MethodsSixteen young men with mean age of 32.75±5.93 years old were recruited around Selangor and Kuala Lumpur. The central obese group was comprised of subjects with mean BMI of 31.59±2.92kg/m2, mean waist circumference of 101.92±7.61cm, mean TC of 5.52±1.12mmol/L, mean TG of 1.85±0.74mmol/L, mean HDL of 0.93±0.07mmol/L and mean LDL of 3.75±1.01mmol/L. Meanwhile, the control group was comprised of subjects with mean BMI of 23.86±2.38kg/m2, mean waist circumference of 80.17±3.97cm, mean TC of 4.9±0.33mmol/L, mean TG of 0.78±0.20mmol/L, mean HDL of 1.30±0.15mmol/L and mean LDL of 3.24±0.31mmol/L. The blood was collected for qPCR-based profiling using miRCURY LNA™ Serum/Plasma Focus microRNA PCR Panel. The data were analysed by GenEx software and SPSS version 16.Results & DiscussionTwenty four significant miRNAs were found to be differentially expressed in central obese group compared to normal group (P<0.05). Twenty miRNAs were up-regulated and four miRNAs were down-regulated. Among these, miR-34a has been identified as the most up-regulated miRNA. The aberrantly elevated hepatic miR-34a was found to impair βKL/FGF19 signaling pathway in obesity by targeting directly on βKL mRNA. The role of this miRNA was found in patient with nonalcoholic liver fatty disease and insulin resistance through the FGF19 signaling.ConclusionThis study has identified miRNAs that were differentially expressed in blood circulation of central obese young men. However, these miRNAs must be validated before proceeding to exploratory downstream research.     

Nicotinamide overload may play a role in the development of type 2 diabetes

AIM: To investigate whether nicotinamide overload plays a role in type 2 diabetes.METHODS: Nicotinamide metabolic patterns of 14 diabetic and 14 non-diabetic subjects were compared using HPLC. Cumulative effects of nicotinamide and N~1-methylnicotinamide on glucose metabolism, plasma H_2O_2 levels and tissue nicotinamide adenine dinucleotide (NAD) contents of adult Sprague-Dawley rats were observed. The role of human sweat glands and rat skin in nicotinamide metabolism was investigated using sauna and burn injury, respectively.RESULTS: Diabetic subjects had significantly higher plasma N~1-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 ± 0.13 μmol/L vs 0.6 ± 0.13 μmol/L, P< 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N~1-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N~1-methylnicotinamide. Moreover, cumulative exposure to N~1-methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/ NADH ratio, and increased plasma H_2O_2 levels. Decrease in NAD/NADH ratio and increase in H_2O_2 generation were also observed in human erythrocytes after exposure to N~1-methylnicotinamide in vitro. Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load). Skin damage or aldehyde oxidase inhibition with tamoxifen or olanzapine, both being notorious for impairing glucose tolerance, delayed N~1-methylnicotinamide clearance.CONCLUSION: These findings suggest that nicotinamide overload, which induced an increase in plasma N~1-methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes.     

A low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension

BackgroundBoth obesity and hypertension are associated with endothelial dysfunction. The purpose of this study was to investigate the effects of a low-calorie diet on endothelial function in obese patients with essential hypertension.MethodsWe measured forearm blood flow (FBF) during intra-arterial infusion of acetylcholine (ACh; 7.5, 15, 30 μg/min), an index of endothelium-dependent vasodilation, and isosorbide dinitrate (ISDN; 0.75, 1.5, 3.0 μg/min), an index of endothelium-independent vasodilation, in obese patients with essential hypertension before and after 2 weeks on a low-calorie diet (800 kcal/d). The study included 11 obese hypertensive Japanese patients (mean body mass index, 30.8 ± 3.6 kg/m²). Fifteen healthy Japanese normotensive individuals were recruited as a control group.ResultsIn obese patients with hypertension, the response of FBF to ACh was attenuated compared to healthy individuals (P < .001). Caloric restriction reduced body weight from 77.5 ± 15.0 to 73.2 ± 13.5 kg (P < .01), the mean blood pressure from 118.4 ± 8.7 to 105.7 ± 8.5 mm Hg (P < .01), fasting plasma insulin from 85.8 ± 22.8 to 64.8 ± 27.0 pmol/L (P < .05), serum total cholesterol from 5.30 ± 0.76 to 4.67 ± 0.58 mmol/L (P < .05), and low density lipoprotein cholesterol from 3.80 ± 0.48 to 3.29 ± 0.44 mmol/L (P < .05). Basal FBF was similar before and after weight reduction. Caloric restriction enhanced the response of FBF to ACh (P < .05), but did not alter the response to ISDN. The intra-arterial infusion of N^G-monomethyl-l-arginine (8 μmol/min), a nitric oxide synthase inhibitor, decreased the enhanced ACh-induced blood flow response induced by caloric restriction.ConclusionsThe present findings suggest that the caloric restriction improves endothelial-dependent vasodilation through an increased release of nitric oxide in obese hypertensive patients.     

In vivo antiinflammatory activity and chemical composition of Hypericum scabroides

ObjectiveTo evaluate the methanolic extracts of aerial parts of Hypericum scabroides (HSM) (200 mg/kg, p.o.) for in vivo anti-inflammatory activity.MethodsThe anti-inflammatory activity of HSM was tested in mice weighting (25±5) g. Either vehicle (control group), the methanolic extracts (200 mg/kg) or diclofenac (50 mg/kg), was administered (p.o.) for 60 min before an edema was induced in the mice paw by subcutaneous injection of carrageenin. The mouse-paw volume was measured 1 h, 3h and 6 h after injection of carrageenin.ResultsThe HSM showed significant reduction of edema in carrageenan induced mice paw edema model at 1 h and 3 h for (78.03±15.54)% and (40.44±16.36)%, respectively. The diclofenac 50 mg/kg exhibited % reduction in paw volume (31.00±11.52)%, (0.80±0.09)% and (9.39±1.99)% after 1 h, 3 h and 6 h, respectively compared to control group. The obtained results revealed that HSM has significant anti inflammatory activity. Furethermore, the chemical composition of HSM was analyzed by using high performance liquid chromatography–diode array dedector. The plant contained pseudohypericin (trace) hypericin (trace), chlorogenic acid (0.014 0±0.000 5)%, rutin (0.005 0±0.000 6)%, hyperoside (0.016±0.005)%, isoquercitrin (0.034 0±0.000 5)% and kaempferol (trace).ConclusionsThe obtained results of the present investigation revealed that methanol extract of Hypericum scarbroides has significant anti-inflammatory activity.     

Endothelial Dysfunction in Patients with Noncomplicated and Complicated Hypertension

Endothelial dysfunction plays an important role in the pathogenesis of hypertension. Other risk factors of atherosclerosis also affect its development. The aim of the study was to assess nitric oxide metabolites concentration (nitrites and nitrates No_x) and endothelin (ET-1) in plasma and cyclic 3,5-guanosine monophosphate (cGMP) in 24 h-urine collection in patients with noncomplicated hypertension without risk factors of atherosclerosis and in hypertensive patients with coronary artery disease (CAD). Sixty-eight subjects were included in the study (44 men, 24 women), aged 47 ± 76 years, allotted into four groups: I – controls (18 clinically healthy subjects); II – 12 subjects with hypertension without risk factors of atherosclerosis; III – 16 subjects with hypertension and risk factors of atherosclerosis; and IV – 22 subjects with hypertension and CAD. Plasma NO_x concentration was determined using the Greiss method, plasma ET-1 by ELISA, and urine cGMP using the immunoenzymatic method. Plasma NO_x concentration was 14.00 ± 6.88 μmol/L in group I, in group II – 18.62 ± 5.84 μmol, in group III – 9.96 ± 4.72 μmol/L, and in group IV – 8.78 ± 3.72 μmol/L. Statistically significant differences were between groups I and III (p < 0.05) and I and IV (p < 0.04) and groups II and III (p < 0.01) and II and IV (p < 0.01). The concentration of cGMP in 24 h urine collection was in group I – 40 ± 24 pmol/L; in group II – 54 ± 41 pmol/L; in group III – 38 ± 32 pmol/L; and in group IV – 42 ± 36 pmol/L. There were no significant differences between the groups. Plasma ET-1 concentration was 3.86 ± 0.52 pg/mL in group I, in group II – 4.05 ± 0.71 pg/mL, in group III – 4.22 ± 0.79 pg/mL and in group IV – 4.38 ± 0.75 pg/mL. Statistically significant differences were between group I and III (p < 0.05), I and IV (p < 0.03), and between group II and IV (p < 0.04). Endothelial dysfunction was not found in hypertensive patients without a family history of cardiovascular diseases and without other risk factors of atherosclerosis. Deterioration of endothelial function was observed in patients with hypertension with risk factors of atherosclerosis. It was most pronounced in those with CAD.     

胺碘酮与美托洛尔联合应用对非瓣膜病心房颤动的疗效及安全性观察

观察静脉胺碘酮与美托洛尔联合应用对非瓣膜病心房颤动 (简称房颤 )的疗效及安全性。 49例冠心病伴发房颤的患者 ,按既往是否常规服用美托洛尔或氨酰心安而分入A组 ( 2 5例 )、B组 ( 2 4例 )。全部病例先给予胺碘酮负荷量 ( 3～ 5mg/kg)静脉推注 1 0min ,然后以 60 0 μg/min的速度静滴 48h ,B组同时口服美托洛尔 6.2 5～ 2 5mg ,2次/日。行心电、血压监测 ,观察 48h房颤转复率。B组 48h后转复率为 83.3% ( 2 0 /2 4 ) ,A组为 76% ( 1 9/2 5 ) ,P >0 .0 5。A、B两组转复时间、胺碘酮用量及转复后心率比较 ,差异有显著性 ( 1 7.2± 1 0 .6hvs 9.4± 9.2h ;880 .2±395 .3mgvs5 76.4± 331 .9mg ;86.3± 1 8.2次 /分vs76.8± 1 7.9次 /分 ,P均 <0 .0 5 )。副反应发生率A组为 8.0 % ,B组为 8.3% ,P >0 .0 5。结论 :静脉胺碘酮与美托洛尔联合应用对非瓣膜病房颤安全有效 ;与单用胺碘酮相比 ,转复时间短、胺碘酮用量少。     

Pioglitazone,but not metformin,reduces liver fat in Type-2 diabetes mellitus independent of weight changes

BackgroundPioglitazone (Pio) treatment induces weight gain in Type 2 diabetes mellitus (T2DM), which could worsen hepatic lipid accumulation, and alter adiponectin and high-sensitivity C-reactive protein (hs-CRP).ObjectiveTo compare changes in hepatic lipid, serum adiponectin and hs-CRP in diabetics treated with Pio (with and without weight gain) against metformin (Met) treatment, which produces weight loss.DesignFifty-one men and women with T2DM, naive to thiazolidinediones, entered a 16-week, open-label, parallel arm study, where participants were randomized to one of three groups: (1) Pio plus the American Diabetes Association diet (Pio+ADA); (2) Pio plus a portion control weight loss diet (Pio+PC), or (3) metformin plus ADA diet (Met+ADA).MethodsHepatic lipid was assessed with abdominal computed tomography (CT) and the serum adiponectin and hs-CRP by enzyme-linked immunosorbent assay at baseline and study end.ResultsForty-eight subjects completed the study. The Pio+ADA group gained (mean±S.E.M.) 2.15±1.09 kg, while Pio+PC and Met+ADA group lost ?2.59±1.25 and ?3.21±0.7 kg, respectively. Pio-treated groups (Pio+ADA and Pio+PC) significantly decreased hepatic fat as indicated by increased liver density on CT scan [10.1±2.4: 11.4±1.0 Hounsfield units (HU)], compared with Met+ADA group (?2.4±3.1 HU). The Pio groups demonstrated significantly increased serum adiponectin, (8.6±1.5; 7.4±1.6 μg/ml) independent of weight change, compared to Met+ADA (?0.14±0.6 μgm/ml) group which lost weight. Serum hs-CRP decreased in groups showing weight loss (Pio+PC, ?3.1±1.7 mg/l; Met+ADA, ?1.5±1.2 mg/l) compared to Pio+ADA (1.8±3.0 mg/l) group that gained weight.ConclusionsPio treatment in T2DM significantly reduced hepatic lipid and increased adiponectin independent of weight change, while decreasing hs-CRP with weight loss.     

In Vivo Kinetics of the Uremic Toxin P‐Cresyl Sulfate in Mice With Variable Renal Function

Uremic toxins such as p‐cresyl sulfate (PCS) are associated with increased mortality for chronic kidney disease (CKD) patients, but in vivo PCS toxicity studies are limited due to the lack of a standard animal model. To establish such a model, we measured the pharmacokinetics of PCS in mice with variable renal function. Male Balb/c mice subjected to 5/6 nephrectomy (CRF), unilateral nephrectomy (UNX), or no surgery (controls) were given PCS (po, 50 mg/kg). Blood samples were collected over time and plasma PCS concentrations were measured. Over 4 h, PCS was significantly higher in the plasma of CRF mice (63.28 ± 2.76 mg/L), compared to UNX mice (3.11 ± 0.64 mg/L) and controls (0.39 ± 0.12 mg/L). The PCS half‐life was greatest in CRF mice (12.07 ± 0.12 h), compared to 0.79 ± 0.04 h in UNX mice and 0.48 ± 0.02 h in control mice. However, the potential presence of additional uremic toxins along with PCS in CRF mice and rapid PCS clearance in control mice suggest that the UNX mouse would be a better PCS model to study toxicity.     

Effects of low-concentration polymyxin B on insulin secretion induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA), glucose, or tolbutamide from the isolated perfused rat pancreas

To evaluate the role of protein kinase C on insulin secretion, we investigated the effects of low-concentration polymyxin B (100 mumol/L) on insulin secretion from the isolated perfused rat pancreas induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA, 10 nmol/L), a protein kinase C activator, glucose (10 mmol/L), or tolbutamide (738 mumol/L). Polymyxin B, a potent and relatively selective protein kinase C inhibitor at this low concentration, did significantly inhibit the gradual rise of insulin secretion induced by TPA (P less than .05). As for glucose or tolbutamide stimulation, polymyxin B significantly inhibited not only the second phase but also the first phase of insulin secretion (P less than .05) without changing the secretion patterns. Although the possibility of nonspecific effects of polymyxin B other than protein kinase C inhibition could not be excluded, the data suggest that protein kinase C might be involved in insulin secretion as a potentiating modulator.     

Early use of polymyxin B reduces the mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection

Polymyxin B is one of the last resort option for carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infection in China. Therefore, the timing of administration of polymyxin is frequently delayed. We collected 40 cases of CRKP bloodstream infections (BSIs) treated with combinations based on polymyxin B over 30 months. The primary outcome, 30-day mortality rate, was 52.5% (21/40). Early administration of polymyxin B is meant to administer the drug within 48 h of diagnosing bacteremia. Delayed administration was considered when polymyxin B was administered after 48 h of bacteremia onset. Polymyxin B duration and total dosages were similar in the two groups (11.57 days versus 11.76 days, p = 0.919; 1306.52 mg versus 1247.06 mg, p = 0.711). Compared with delayed administration, early use of polymyxin B-based combination therapy had a significant increase in the rate of bacterial clearance (65.22% versus 29.41%, p = 0.025; OR = 0.533) and decreased 30-day mortality (39.13% versus 70.59%, p = 0.045; OR = 0.461) and overall mortality (43.48% versus 82.35%, p = 0.022; OR = 0.321).     

Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients

BACKGROUND: HGS004 is a fully human immunoglobulin (Ig) G4 monoclonal antibody against CC chemokine receptor 5 (CCR5) with robust in vitro activity against a diverse panel of CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates. METHODS: A single-blind, randomized, placebo-controlled study was conducted in patients infected with CCR5-tropic HIV-1 to evaluate the safety, pharmacokinetics, and antiviral activity of HGS004. Sixty-three subjects were randomized into 5 dose cohorts (0.4, 2, 8, 20, and 40 mg/kg) and received a single intravenous dose of HGS004 or placebo. RESULTS: HGS004 was well tolerated, and no dose-limiting toxicities were observed. Pharmacokinetics were nonlinear across the 0.4-40-mg/kg dose range, with dose-proportional increases in maximum concentration, although the area under the curve increased more than proportionally to dose. High levels of receptor occupancy were observed for up to 28 days in the higher-dose cohorts. Plasma HIV-1 RNA reductions of >1 log(10) at day 14 were observed in 14 (54%) of 26 subjects in the 8-, 20-, and 40-mg/kg cohorts. In the 40-mg/kg cohort, 4 of 10 subjects had a >1 log(10) HIV-1 RNA reduction at day 28. Drug concentrations relative to isolate sensitivity (the ratio of the concentration at day 14 to IC(90)) predicted antiviral response on day 14. CONCLUSIONS: HGS004 is safe and well tolerated and demonstrates meaningful antiviral activity when administered to patients infected with CCR5-tropic HIV-1.     

Relationship between surfactant proteins B and C and obstructive sleep apnea: is serum SP-B concentration a potential biomarker of obstructive sleep apnea?

Background

Surfactant proteins B and C are mainly synthesized, secreted by alveolar type II cells, and affected by hypoxia and mechanical stretches. We hypothesized that their serum levels might be altered by intermittent hypoxia and swing of intrathoracic pressure of obstructive sleep apnea (OSA).

Methods

Consecutive 140 middle-aged males, suspicious of OSA determined by polysomnography, were studied. Surfactant proteins B and C were determined by ELISA.

Results

Surfactant protein B (41.39?±?6.01 vs 44.73?±?7.62 ng/L, p?=?0.005), not C (32.60?±?6.00 vs 32.43?±?6.44 ng/L, p?=?0.61), significantly lowered in moderate to severe OSA subjects than in non to mild OSA subjects. Severity of OSA is inversely correlated with serum surfactant protein B. Adjusting age, body mass index, and smoking history, compared to subjects with surfactant protein B (SP-B) ≥43.35 ng/L, those with SP-B <43.35 ng/L showed significantly increased 1.528-fold risk for moderate to severe OSA (p?=?0.009), whereas no association between surfactant protein C and OSA was observed. Prevalence of moderate to severe OSA in lower SP-B group is higher than that in higher SP-B group (62.7 vs 38.4 %, p?=?0.003). Serial and parallel tests on Epworth sleep scale (ESS) and SP-B evaluation can be complementary and prove helpful with high specificity (94.44 %) and sensitivity (84.48 %) to detect moderate to severe OSA.

Conclusions

Serum surfactant protein B, rather than C, is decreased in some individuals with moderate to severe OSA, compared to non to mild OSA subjects. Serum surfactant protein B might be a potential biomarker to diagnose OSA.