Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome

Background: Raised triglycerides (TG), decreased high‐density lipoprotein cholesterol (HDL‐C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS). Objective: To compare the effect of high‐dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω‐3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS. Methods: We previously randomised patients with low‐density lipoprotein cholesterol (LDL‐C) > 160 and TG > 200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω‐3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis. Results: The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p < 0.05 compared with R and Rω). A decrease in insulin resistance by RF was also noted. Only RF significantly raised HDL‐C levels (by 7.7%, p < 0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω. Conclusions: All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.     

Synergistic interaction between meloxicam and aminoguanidine in formalin‐induced nociception in mice

Objectives: The objective of this study was to examine the nature of interaction between cyclooxygenase‐2 inhibitor meloxicam and inducible nitric oxide synthase inhibitor aminoguanidine in formalin‐induced nociception in mice and the possible therapeutic advantage. Methods: Antinociceptive effect of meloxicam (1, 3, 10 and 30mg/kg, oral) and aminoguanidine (10, 30, 100 and 300mg/kg, oral) and their combinations was examined in formalin‐induced paw licking model in mice. Analysis of variance and isobolographic method were employed to identify the nature of antinociceptive interaction. Results: Higher doses of meloxicam (10 and 30mg/kg) and aminoguanidine (100 and 300mg/kg) produced significant reduction in paw licking time (antinociceptive) in late phase of formalin‐induced nociception. Combination of sub‐threshold dose of meloxicam (3mg/kg) with increasing doses of aminoguanidine (10, 30, 100 and 300mg/kg) resulted in synergistic antinociceptive effect. Similarly, co‐administration of sub‐threshold dose of aminoguanidine (30mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30mg/kg) produced significant reduction in formalin‐induced paw licking behaviour. The experimental ED₅₀ for combination with their confidence limits are below the confidence interval of theoretical line of additive interaction, suggesting synergistic nature of interaction between meloxicam and aminoguanidine in isobolographic analysis. Conclusion: Co‐administration of meloxicam and aminoguanidine showed synergistic antinociceptive effect which might possibly reduce gastrointestinal toxicity associated with the use of meloxicam.     

Protective effect of (−)-epigallocatechin-gallate (EGCG) on lipid peroxide metabolism in isoproterenol induced myocardial infarction in male Wistar rats: A histopathological study

This study aims to evaluate the preventive effect of (−)-epigallocatechin-gallate (EGCG) on lipid peroxides, enzymatic and non-enzymatic antioxidants and histopathological findings in isoproterenol (ISO)-induced rats. Myocardial infarction (MI) is induced in rats by subcutaneous injection of ISO (100 mg/kg body weight) at an interval of 24 h for 2 days. ISO-treated rats show a significant increase in the levels of thiobarbituric acid reactive substances, lipid hydroperoxides in plasma and heart and plasma uric acid and a significant decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase in heart and the levels of reduced glutathione, vitamin C and vitamin E in plasma and the heart and ceruloplasmin in plasma. Oral pretreatment with EGCG (10, 20 and 30 mg/kg body weight) daily for a period of 21 days show significant decrease in the levels of lipid peroxidation products and uric acid and improved the antioxidant status by increasing the activities of antioxidant enzymes and non-enzymic antioxidants. Histopathological findings of the myocardial tissue show the protective effect of EGCG in ISO-induced rats. The effect at a dose of 30 mg/kg of EGCG was more pronounced than that of the other two doses (10 and 20 mg/kg body weight). Thus, the present study reveals that EGCG exerts cardioprotective effect against ISO-induced MI due to its free radical scavenging and antioxidant effects, which maintains the tissue defense system against myocardial damage.     

Aegle marmelos fruit extract attenuates isoproterenol-induced oxidative stress in rats

Myocardial infarction is a major public health concern and the leading cause of death throughout the world. The present study investigates the ability of Aegle marmelos fruit extract to prevent pathological changes and oxidative stress after isoproterenol induced myocardial infarction in rats. In vitro studies showed that Aegle marmelos fruit extract possesses antioxidant activity. Administration of isoproterenol (85 mg/kg body weight) to rats resulted in significantly elevated plasma transaminases, lactate dehydrogenase and creatine kinase, however, cardiac tissue analyses showed decreased activity of the above enzymes compared to experimental control rats. Further, isoproterenol administration significantly increased plasma and cardiac tissue thiobarbituric acid reactive substances and lowered the activities of cardiac tissue superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase and glutathione-S-transferase when compared to control groups. Pretreatment with Aegle marmelos fruit extract at a dose of 150 mg/kg body weight for a period of 45 days significantly prevented the observed alterations. Our data suggest that Aegle marmelos fruit extract exerts its protective effect by decreasing thiobarbituric acid reactive substances and elevating antioxidants status in isoproterenol treated rats. Both biochemical and histopathological results in the isoproterenol-induced myocardial infarction model emphasize the beneficial action of Aegle marmelos fruit extract as a cardioprotective agent.     

Cardioprotective potential of hydro-alcoholic fruit extract of Ananas comosus against isoproterenol induced myocardial infraction in Wistar Albino rats.

ObjectivesTo evaluate the cardioprotective effects of hydro alcoholic extract of Ananas comosus (A. comosus) (HEAC), on Isoproterenol (ISO) induced myocardial infarction in Albino Wistar rats.MethodsMyocardial infarction was induced by Isoproterenol (85 mg/kg, s.c.) for two consecutive days at an interval of 24 h. Rats were pretreated with HEAC (200–400 mg/kg/day, oral) for a period of 30 days and Isoproterenol (ISO) was injected on 31st and 32nd day and after 24 h blood was collected through retro-orbital plexus for the estimation of biochemical parameters and histopathological studies were also performed.ResultsIn the present study, ISO administration significantly elevated the cholesterol, low density lipoprotein, very low density lipoprotein, triglycerides, alanine aminotransferase and aspartate aminotransferase levels while it decreases high density lipoprotein and total protein in plasma and administration of HEAC decreases the level of cholesterol, low density lipoprotein, very low density lipoprotein, triglycerides, alanine aminotransferase and aspartate aminotransferase levels while it increases high density lipoprotein and total protein levels. Pretreatment with the HEAC protected the cardiotoxicity induced by Isoproterenol. The histopathological findings of the ISO-induced myocardium showed infracted zone with inflammatory cells, lipid droplets, myocardial necrosis and vacuolization of myofibrils which were reduced by the pretreatment of HEAC.ConclusionIt can be concluded that HEAC possess cardioprotective activity against Isoproterenol induced myocardial infarction in rats.     

An open-label,randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers

BACKGROUND: Rosuvastatin and fenofibrate are lipid-regulating agents with different modes of action. Patients with dyslipidemia who have not achieved treatment targets with monotherapy may benefit from the combination of these agents. OBJECTIVE: The effect of coadministration of rosuvastatin and fenofibrate on the steady-state pharmacokinetics of rosuvastatin and fenofibric acid (the active metabolite of fenofibrate) was assessed in healthy volunteers. METHODS: This was an open-label, randomized, 3-way crossover trial consisting of three 7-day treatment periods. Healthy male volunteers received one of the following treatment regimens in each period: rosuvastatin 10 mg orally once daily; fenofibrate 67 mg orally TID; and rosuvastatin + fenofibrate dosed as above. The steady-state pharmacokinetics of rosuvastatin and fenofibric acid, both as substrate and as interacting drug, were investigated on day 7 of dosing. Treatment effects were assessed by construction of 90% CIs around the ratios of the geometric least-square means for rosuvastatin + fenofibrate/rosuvastatin and rosuvastatin + fenofibrate/fenofibrate for the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (derived from analysis of variance of log-transformed parameters). RESULTS: Fourteen healthy male volunteers participated in the study. When rosuvastatin was coadministered with fenofibrate, there were minor increases in the AUC from 0 to 24 hours and maximum concentration (Cmax) of rosuvastatin: the respective geometric least-square means increased by 7% (90% CI, 1.00-1.15) and 21% (90% CI, 1.14-1.28). The pharmacokinetic parameters of fenofibric acid were similar when fenofibrate was dosed alone and with rosuvastatin: the geometric least-square means for fenofibric acid AUC from 0 to 8 hours and Cmax decreased by 4% (90% CI, 0.90-1.02) and 9% (90% CI, 0.84-1.00), respectively. The treatments were well tolerated alone and in combination. CONCLUSION: Coadministration of rosuvastatin and fenofibrate produced minimal changes in rosuvastatin and fenofibric acid exposure.     

Pharmacokinetics of rosuvastatin in healthy Chinese volunteers living in China: A randomized,open-label,ascending single- and multiple-dose study

Background: Cross-study comparisons suggest that systemic exposure (AUC) to rosuvastatin calcium, a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor, may be ~2-fold higher in Asian subjects living in Asian countries than in white subjects living in Western countries.Objective: This study was conducted to determine the pharmacokinetic characteristics of rosuvastatin and its metabolites after single and multiple doses of rosuvastatin in healthy Chinese subjects living in China.Methods: This was an open-label, ascending singleand multiple-dose study. Subjects were randomly assigned to receive rosuvastatin 5, 10, or 20 mg. Each subject received 1 tablet of the assigned treatment on day 1 and days 4 through 10. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone were measured through 72 hours after administration of single doses and through 96 hours after administration of multiple doses. Blood samples were obtained within 30 minutes before dosing on days 7, 8, and 9 for the assessment of pharmacokinetic parameters at steady state. Noncompartmental pharmacokinetic analysis was performed to determine the C_max and AUC_0?t for rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone after single and multiple doses of rosuvastatin. Tolerability assessments were conducted throughout the study.Results: Of the 36 enrolled subjects, only 1 was female. The mean age of subjects in the rosuvastatin 5-, 10-, and 20-mg groups was 22.4, 21.3, and 22.4 years, respectively. Weight and height ranged from 54 to 85 kg and from 161 to 189 cm, respectively. Geometric mean C_max values for rosuvastatin after administration of single doses of rosuvastatin 5, 10, and 20 mg were 8.33, 10.76, and 19.17 ng/mL, respectively; the corresponding geometric mean AUC_0?t values were 57.63, 88.89, and 163.87 ng · h/mL. At steady state, values for C_max were 8.31, 8.41, and 20.73 ng/mL; the corresponding geometric mean AUC values were 64.87, 77.29, and 178.64 ng · h/mL. After administration of multiple doses of rosuvastatin 5, 10, and 20 mg, the accumulation ratios were 1.23, 0.95, and 1.23, respectively, indicating minimal accumulation of rosuvastatin. Circulating concentrations of N-desmethyl rosuvastatin and rosuvastatin lactone were well below those of rosuvastatin after administration of single and multiple doses of rosuvastatin.Conclusions: Increases in C_max, AUC_0?t, C_max,ss, and AUC_ss were observed with increasing single and multiple doses of rosuvastatin 5, 10, and 20 mg. The increase in exposure with increasing doses was lower than would be expected under conditions of strict proportionality. Rosuvastatin exhibited little accumulation on repeated administration. All rosuvastatin doses were well tolerated in these Chinese subjects.     

Myocardial infarction and cerebrovascular accident following non-cardiac surgery: differences in postoperative temporal distribution and risk factors

Summary. Background: Myocardial infarction and stroke after non‐cardiac surgery are two ominous cardiovascular complications believed to share similar pathophysiological processes. However, the differences in the temporal distribution between them have not been adequately investigated in a large cohort of patients. Methods and Results: The preoperative clinical features and daily occurrence of myocardial infarction and stroke were routinely recorded in 36 634 consecutive patients following elective non‐cardiac, non‐carotid surgery . The preoperative characteristics and postoperative daily distribution of postoperative myocardial infarction and stroke were compared using exponential and linear regressions models. Myocardial infarction and stroke occurred in 122 (0.33%) and 126 (0.34%) patients, respectively, during the first 30 days after surgery. More patients with myocardial infarction had diabetes mellitus and cardiac disease (P = 0.041 and <0.0001, respectively) whereas more patients with stroke were older and female (P = 0.003 and 0.038, respectively). The peak incidence of myocardial infarction was on the day of surgery (43%) and declined exponentially thereafter (F = 725.4, P < 0.0001). However, postoperative stroke best fitted a linear regression with almost even daily distribution (F = 15.9, P = 0.0004). The median time to myocardial infarction was one day [95% confidence interval (95% CI) = 0–2 days] compared with nine days (95% CI = 7–11 days) for stroke. Conclusions: The peak incidence of postoperative myocardial infarction is early after non‐cardiac surgery and declines exponentially thereafter, as opposed to stroke, which occurs at a constant rate during the postoperative period. Myocardial infarction and cerebrovascular accident following non‐cardiac surgery differ in their preoperative risk factors, and in the postoperative time‐line of their occurrence.     

How to solve the problem of spontaneous bacterial clearance when testing new antibiotic treatment: results on experimental pneumonia due to a derepressed cephalosporinase‐producing Enterobacter cloacae

Because the magnitude of spontaneous bacterial clearance can be similar or even higher than treatment effect, depending upon experimental model and bacterial strain used, this work investigated the value of rendering rats immunosuppressed to facilitate bacterial implantation and reduce spontaneous bacterial clearance. In a first step, rats received a single intravenous cyclophosphamide dose 4 days before infection. Three different doses were tested: 10, 20, and 40 mg/kg. After modeling with NONMEM V, the cyclophosphamide dose required to maintain white blood cell count <1.0 × 10³/μL from day 4 to day 5 was 30 mg/kg. In a second step, influence of immunosuppression on lung bacterial titers was characterized. Rats were given one of the three intravenous cyclophosphamide doses (0, 10, 30 mg/kg), and after 4 days, they were infected by tracheal injection of 8.9 ± 0.1 log₁₀ cfu Enterobacter cloacae before being sacrificed at different times. Bacteria in homogenized lungs were quantitatively cultured on Drigalski agar. Bacterial lung count was closely influenced by the grade of induced leukopenia. A single intravenous 30 mg/kg cyclophosphamide dose 4 days before infection suppressed the spontaneous clearance of E. cloacae for at least 30 h without significantly increasing animal mortality; this result seems to be linked to a white blood cell count maintained lower than 1.0 × 10³/μL for all the time. This modified animal model could be contributive in the evaluation of antibacterial agents, especially to simulate the behavior of intensive care unit immunocompromised patients.     

围术期强化瑞舒伐他汀钙治疗对急性心肌梗死直接经皮冠状动脉介入治疗中冠状动脉血流的影响

目的评估围手术期强化瑞舒伐他汀钙治疗对急性心肌梗死直接经皮冠状动脉介入治疗(PPCI)靶血管开通后即刻冠脉血流的影响。方法收集2018年6月至2019年6月诊断为急性ST段抬高型心肌梗死(STEMI)接受直接PCI治疗的患者122例,根据术前是否强化瑞舒伐他汀治疗分为研究组62例和对照组60例。研究组术前30 min内开始服用瑞舒伐他汀钙20 mg,连续服用7天,20 mg/d,后以10 mg/d长期维持;对照组术前不服用任何他汀类药物,PCI后开始服用瑞舒伐他汀钙10 mg/d,长期维持。观察PPCI靶血管开通后TIMI血流、校正TIMI帧数(Corrected TIMI frame count,CTFC)、住院期间心肌酶学、心电图以及出院后30天超声心动图情况。结果靶血管开通后,研究组CTFC及CTFC大于100帧者(相当于TIMI 0级)均低于对照组(P<0.05)。治疗后,两组肌钙蛋白I、肌酸激酶同工酶、B型利钠肽水平均低于治疗前,梗死相关导联ST段抬高总和明显降低,且研究组低于对照组(均P<0.05);两组超声心动图中左室射血分数、左室舒张末期容积比较,差异无统计学意义(P>0.05)。结论围术期瑞舒伐他汀钙治疗对急性ST段抬高性心肌梗死直接经皮冠状动脉介入治疗可有效的改善冠脉即刻血流,增加心肌组织灌注,具有较好的安全性。     

蒙药顺气补心十一味丸对心肌梗死大鼠左心功能的影响

目的 探讨蒙药顺气补心十一味丸对心肌梗死大鼠左心功能的影响.方法 健康成年Wistar大鼠78只,分为正常对照组(6只)、模型对照组(18只)、蒙药低剂量组(18只)、蒙药高剂量组(18只)、卡托普利组(18只),除正常对照组外,其余各组大鼠背部皮下多点注射盐酸异丙肾上腺素复制心肌梗死模型,药物干预组分别给予顺气补心十一味丸0.461 g/kg、1.844 g/kg和卡托普利25 mg/kg,每日两次灌胃.实验42 d时,行超声心动图检查和心肌病理检查.结果 ①与模型对照组比较,蒙药低剂量组、蒙药高剂量组和卡托普利组的左室射血分数和左窒短轴缩短率增高,与蒙药低剂量组比较,蒙药高剂量组和卡托普利组的左室短轴缩短率和射血分数增高,卡托普利组左窒短轴缩短率高于蒙高剂鼍组,差异均有统计学意义(P<0.05).②病理结果显示:药物干预组较模型对照组坏死灶面积缩小,实验42 d时,心肌纤维化程度减轻.结论 顺气补心十一味丸具有改善心肌梗死大鼠的左心功能和减轻心梗后心室重构的作用.     

不同剂量瑞舒伐他汀对ACS患者室性心律失常的影响

目的:评估不同剂量瑞舒伐他汀对ACS患者室性心律失常[频发室性期前收缩(VPB)和非持续性室性心动过速(NSVT)]的影响。方法:200例ACS患者随机分为两组:常规量组100例,接受瑞舒伐他汀10 mg/d;强化量组100例,接受瑞舒伐他汀20 mg/d,入院后1～5 d应用Holter监测两组频发VPB和NSVT情况并进行比较。结果:频发VPB与NSVT在强化量组均明显减少(P﹤0.01),两组无出现明显不良反应。39例患者发生NSVT,与未发生NS-VT患者相比,发生NSVT的患者具有如下特点:高龄或既往有心肌梗死病史、糖尿病、心房颤动、LVEF﹤40%、左心室舒张末期内径>55 mm。结论:早期强化瑞舒伐他汀治疗能明显减少频发VPB和NSVT的发生。     

Therapeutic effects of metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on phencyclidine‐induced cognitive deficits in mice

This study was undertaken to examine the effects of CDPPB (3‐cyano‐N‐(1,3‐diphenyl‐1H‐pyrazol‐5‐yl)benzamide), a positive allosteric modulator (PAM) of metabotropic glutamate receptor 5 (mGlu₅), on cognitive deficits in mice after repeated administration of the N‐methyl‐D‐aspartate (NMDA) receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)‐induced cognitive deficits in mice were not improved by a single administration of CDPPB (10 mg/kg/day). However, PCP (10 mg/kg/day for 10 days)‐induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of CDPPB (10 mg/kg/day), but not of CDPPB (1.0 mg/kg/day). This study suggests that PCP‐induced cognitive deficits in mice are improved by subsequent subchronic administration of CDPPB. Therefore, mGlu₅ PAMs would be potential therapeutic drugs for cognitive deficits in schizophrenia.     

葛根素对心肌纤维化模型小鼠左心室中Ⅰ型胶原表达的影响

目的研究葛根素对心肌纤维化(MF)模型小鼠左心室中Ⅰ型胶原(CollagenⅠ)表达的影响。方法将昆明小鼠分为溶媒对照组、MF模型组、葛根素低剂量(600 mg/kg)组、葛根素高剂量(1 200 mg/kg)组,卡托普利(25 mg/kg)组。预先灌胃给药3 d后,同时皮下注射5 mg/kg异丙肾上腺素(ISO)1 d后,以2.5 mg/kg连续注射30 d。停止注射ISO后,再继续灌胃给药7 d。颈椎脱臼处死小鼠,称重,取心脏称重,计算心重指数(CWI);消化法测定心肌羟脯氨酸(Hydro)的含量;取左心室,运用RT-PCR方法测定CollagenⅠmRNA表达。结果葛根素给药组与模型组比较均能降低CWI和Hydro含量。RT-PCR法显示,与模型组比较,葛根素给药组能降低左心室CollagenⅠmRNA表达。结论葛根素对ISO诱导的小鼠MF有一定的预防作用,该作用可能与葛根素抑制左心室中CollagenⅠ的表达有关。     

Differential effects of mibefradil, verapamil, and amlodipine on myocardial function and intracellular Ca(2+) handling in rats with chronic myocardial infarction

Mibefradil is a selective T-type Ca(2+) channel blocker that exerts a potent vasodilating but weak inotropic action. The present study compared mibefradil with traditional L-type Ca(2+) channel blockers in regard to the effects of chronic oral administration on hemodynamics, contractility, and intracellular Ca(2+) handling in failing myocardium from postinfarction rats. Male Wistar rats with ligation-induced myocardial infarction were assigned to placebo or treatment with mibefradil (10 mg/kg/day), verapamil (8 mg/kg/day), or amlodipine (4 mg/kg/day) by oral gavage starting 7 days before the induction of myocardial infarction. Six weeks after myocardial infarction, hemodynamic measurements were performed in conscious animals. In addition, isometric force and free [Ca(2+)](i) were determined in isolated left ventricular papillary muscles. Placebo-treated rats exhibited a decreased mean atrial pressure, an increased left ventricular end-diastolic pressure, and a reduced rate of pressure rise compared with sham-operated animals. Mibefradil treatment significantly improved all of these parameters, whereas both amlodipine and verapamil exerted only minor effects. beta-Adrenergic stimulation with isoproterenol (ISO) enhanced contractility and Ca(2+) availability in papillary muscles from sham-operated rats, whereas the ISO-induced inotropic effect in muscles from placebo-treated rats was severely blunted. Chronic mibefradil treatment significantly improved the inotropic response to ISO stimulation, although the Ca(2+)(i) availability appeared to be less than in muscles from placebo-treated animals. In contrast, both verapamil and amlodipine did not restore the inotropic and Ca(2+)(i) modulating effect of ISO in remodeled myocardium. Thus, T-type Ca(2+) current appears to be of pathophysiological relevance in postischemic reperfused myocardium.     

Selective apheresis of C‐reactive protein: A new therapeutic option in myocardial infarction?

Background : There is substantial evidence that C‐reactive protein (CRP) mediates secondary damage of the myocardium after acute myocardial infarction (AMI). The aim of this animal trial in pigs was to specifically deplete CRP from porcine plasma after AMI and to study possible beneficial effects of the reduced CRP concentration on the infarcted area. Methods : Ten pigs received balloon catheter‐induced myocardial infarction. CRP was depleted from five animals utilizing a new specific CRP‐adsorber, five animals served as controls. The area of infarction was analyzed by cardiovascular magnetic resonance imaging on day 1 and day 14 after AMI. Porcine CRP levels were determined by ELISA. Results : CRP‐apheresis resulted in a mean reduction of the CRP levels up to 48.3%. The area of infarction was significantly reduced by 30 ± 6% (P = 0.003) within 14 days in the treatment group, whereas it increased by 19 ± 11% (P = 0.260) in the controls. Fourteen days after infarction, the infarcted area revealed compact, transmural scars in the controls, whereas animals receiving CRP‐apheresis showed spotted scar morphology. In the interventional group, a significantly higher left ventricular ejection fraction (LVEF) was observed after 14 days as compared to the controls (57.6 ± 2.4% vs. 46.4 ± 2.7%; P = 0.007). Conclusions : In a pig model for AMI, we observed that selective CRP‐apheresis significantly reduces CRP levels and the volume of the infarction zone after AMI. Additionally, it changes the morphology of the scars and preserves cardiac output (LVEF). J. Clin. Apheresis 30:15–21, 2015. © 2014 Wiley Periodicals, Inc.     

Evaluation of the potential for pharmacokinetic interaction between fenofibrate and ezetimibe: A phase I, open-label, multiple-dose, three-period crossover study in healthy subjects

OBJECTIVE: This study was conducted to evaluate the potential for pharmacokinetic interaction between fenofibrate and ezetimibe in healthy subjects. METHODS: This was a Phase I, open-label, multiple-dose,3-period crossover study conducted in healthy adult men and women. Subjects received fenofibrate 145 mg alone, fenofibrate 145 mg with ezetimibe 10 mg, and ezetimibe 10 mg alone for 10 consecutive days, in an order determined by computerized randomization schedule. Blood samples were collected for up to 24 hours after dosing on study day 1 and up to 120 hours after dosing on study day 10 for determination of plasma concentrations of fenofibric acid, unconjugated (free) ezetimibe, and total (conjugated and unconjugated) ezetimibe using validated high-performance liquid chromatography methods with mass-spectrometric detection. Ezetimibe glucuronide concentrations were estimated by subtracting free ezetimibe concentrations from total ezetimibe concentrations. RESULTS: Eighteen healthy adults (12 men, 6 women; 17 white, 1 black) were enrolled in the study. Their mean age was 43.4 years (range, 27-55 years), their mean weight 78.7 kg (range, 60-98 kg), and their mean height 174.9 cm (range, 156-194 cm). Coadministration of multiple doses of fenofibrate and ezetimibe produced no statistically significant effect on the pharmacokinetics of fenofibric acid but significantly increased exposures to total ezetimibe and ezetimibe glucuronide (P < 0.05). Using point estimates, co-administration of fenofibrate and ezetimibe increased AUC central values for total ezetimibe and ezetimibe glucuronide by 43% (90% CI, 29-59) and 49% (90% CI, 34-65), respectively. CONCLUSION: In these healthy volunteers, coadministration of multiple doses of fenofibrate and ezetimibe had no statistically significant effect on the pharmacokinetics of fenofibric acid but was associated with a significant increase in exposure to total ezetimibe and its metabolite ezetimibe glucuronide.     

The effect of ageing on isoniazid pharmacokinetics and hepatotoxicity in Fischer 344 rats

Isoniazid is the first‐line treatment for tuberculosis; however, its use is limited by hepatotoxicity. Age‐related differences in isoniazid pharmacokinetics and hepatotoxicity are uncertain. We aimed to investigate these in young (3 ± 0 months, n = 26) and old (23.0 ± 0.2 months, n = 27) male Fischer 344 rats following a low‐ or high‐dose toxic regimen of isoniazid or vehicle (4 doses/day over 2 days; low: 100, 75, 75, 75 mg/kg; high: 150, 105, 105, 105 mg/kg i.p. every 3 h). Fifteen hours after the last dose, animals were euthanized and sera and livers were prepared for analysis. Isoniazid treatment increased serum hepatotoxicity markers (alanine and aspartate transaminase) in young animals but not in old animals, and only reached significance with the high dose in young animals. Isoniazid treatment caused a trend towards an increase in necrosis in young animals with both doses. In contrast, microvesicular steatosis was increased in old isoniazid‐treated animals, reaching significance only with the low dose (steatosis prevalence in old: vehicle 1/9, isoniazid 4/5; P < 0.05). Among isoniazid‐treated animals, concentrations of toxic intermediates acetylhydrazine and hydrazine were higher in old than young animals (P < 0.05). With both doses, hepatic cytochrome P450 2E1 activity was higher in young animals compared with old (P < 0.05). There were no other age effects seen on any of the other measured enzymes involved in isoniazid metabolism (N‐acetyl transferase, amidase, glutathione‐S‐transferase). These results show age‐related changes in isoniazid pharmacokinetics may contribute towards differential patterns of toxicity and confirm that standard hepatotoxicity markers do not detect isoniazid‐induced microvesicular steatosis.     

Chlorogenic acid a dietary polyphenol attenuates isoproterenol induced myocardial oxidative stress in rat myocardium: An in vivo study

Intent of the present study has been made to appraise the cardioprotective effect of chlorogenic acid (CGA) on isoproterenol (ISO) induced myocardial infarction (MI) in male albino Wistar rats. ISO-induced myocardial damage was indicated by the elevated levels of marker enzymes such as creatine kinase (CK), creatine kinase-MB (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and troponin T and I (cTnT, cTnI) in the serum. In addition, the levels of lipid peroxidation products such as thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lipid hydroperoxides (LHPs) were significantly increased in the plasma and heart tissue. Activities of enzymic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and the non enzymic antioxidants like vitamin C, vitamin E and reduced glutathione (GSH) were decreased in the erythrocytes, plasma and heart tissue of the ISO-induced rats and myocardium infarct size as observed by staining with triphenyltetrazolium chloride (TTC). Histopathological observation corroborated with the bioochemical parameters. Oral administration of CGA at different doses (10, 20, 40 mg/kg BW) for 19 days prevented the above changes. The 40 mg/kg BW of CGA was more pronounced than other two doses and brought back all the above parameters to near normalcy.     

Mobilization effects of G‐CSF,GM‐CSF,and darbepoetin‐α for allogeneic peripheral blood stem cell transplantation

The effects of GM‐/G‐CSF and darbepoetin‐α on stem cell mobilization were investigated. From February 2005 to March 2007, 30 allogeneic sibling donors were randomly assigned to a G‐CSF group (5 μg/kg/day for 5–7 days) or triple group (GM‐CSF 10 μg/kg/day on 1st and 2nd day, G‐CSF 5 μg/kg/day for 5–7 days, and darbepoetin‐α 40 mg on 1st day). The MNCs and CD34⁺ cells were not different between the two groups, although the doses (×10⁸/kg of recipient body weight) of CD3⁺ cells (3.64 ± 1.75 vs. 2.63 ± 1.36, P = 0.089) and CD8⁺ cells (1.07 ± 0.53 vs. 0.60 ± 0.30, P = 0.006) were lower in the triple group. The engraftments, frequency of RBC transfusions, and hemoglobin recovery were not different between the two groups. The cumulative incidence of overall and Grades II–IV aGVHD was 64.3% vs. 61.1% and 25.9% vs. 27.1% in the G‐CSF and triple regimen group, respectively, whereas the cumulative incidence of cGVHD was 20.8 ± 1.3% and 24.4 ± 1.7%, respectively. In conclusion, the triple regimen did not seem to be superior to G‐CSF alone in terms of the CD34+ cell dose, hemoglobin recovery, and GVHD. However, the CD8+ cell count was significantly lower in the triple regimen group. The role of a lower CD8+ cell count in the graft may need to be elucidated in the future. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.