Therapeutic drug monitoring of cyclosporine-lipoprotein levels

Cyclosporine therapy is complicated by nephrotoxicity that is not predicted by drug levels. In this study serial trough blood samples were obtained from 11 allogeneic marrow transplant recipients after initiation of intravenous cyclosporine 2 mg/kg every 12 hours for a period extending 4 weeks after transplantation. Renal dysfunction, assessed by an increase in serum creatinine levels to twice baseline values or when greater than 175 mumol/L, was found in four patients. No associations between renal dysfunction and cyclosporine levels in whole blood, total plasma, or lipoprotein fractions were found. The ratios of maximum and mean high-density low-density lipoprotein cyclosporine concentrations were greatest in patients with renal dysfunction (p less than 0.001). The data suggest therapeutic drug monitoring of cyclosporine in various biologic fluids does not predict onset of drug-associated renal dysfunction. However, the relative role of high-density to low-density lipoprotein transport of cyclosporine may provide an index of renal functional changes associated with the agent.     

Single-dose cyclosporine pharmacokinetics in various biological fluids of patients receiving allogeneic marrow transplantation

The clinical usefulness of cyclosporine is hampered by dose-limiting toxicities to the kidney that are not predicted by drug levels in serum or whole blood. Because of its lipophilic nature, circulating plasma lipoproteins may play a role in drug disposition. This study characterized the pharmacokinetic parameters of a single 2-mg/kg i.v. infusion of cyclosporine in the whole blood, plasma, high-density (HDL), low-density (LDL), and very low-density (VLDL) lipoprotein fractions of nine patients before bone marrow transplantation. The dose- and protein-corrected area under the concentration-time curve in whole blood; plasma; and HDL, LDL, and VLDL compartments were 44.6 +/- 11.3, 19.2 +/- 2.4; 33.6 +/- 12.3, 49.0 +/- 19.9, and 17.5 +/- 9.0 ng h/ml, respectively. The mean half-life of the drug from the VLDL fraction was significantly less than from the other biologic fluids. The systemic clearance rate of cyclosporine was greater in the total plasma or VLDL fractions compared with whole blood and the HDL and LDL fractions. The HDL-cyclosporine clearance inversely correlated with the serum creatinine (r = -0.71; p less than 0.05) and total bilirubin levels (r = -0.76; p less than 0.05). The plasma half-life and volume of distribution directly correlated with fasting HDL cholesterol levels (r = 0.94 and 0.99; p less than 0.01). Correlations between pharmacokinetic parameters and lipid fractions suggest a role of lipids in the distribution of cyclosporine. These data may be useful in the development of guidelines for therapeutic drug monitoring of cyclosporine in the transplantation population.     

Effects of ezetimibe,either alone or in combination with atorvastatin,on serum visfatin levels: a pilot study

Introduction: Ezetimibe inhibits intestinal absorption of cholesterol and lowers circulating low-density lipoprotein cholesterol levels. Visfatin is a novel adipokine, which may be implicated in the atherosclerotic process. Objective: The aim of this study was to explore the possible association between ezetimibe administration and serum visfatin concentrations. Methods: Patients (n = 30) with primary dyslipidemia and another 30 who failed to reach their assigned low-density lipoprotein cholesterol target on atorvastatin therapy (20 mg/day) were included in the study. All participants were given ezetimibe at 10 mg/day for 12 weeks. Results: At baseline the visfatin levels correlated significantly with the total cholesterol (r = 0.61 and p < 0.01) and low-density lipoprotein cholesterol (r = 0.51 and p < 0.01) levels in the statin pretreatment group. Furthermore, in the statin group the post-treatment levels of visfatin and low-density lipoprotein cholesterol were significantly correlated (r = 0.57 and p < 0.01). The serum visfatin concentrations did not change significantly in either the monotherapy or statin pretreatment groups or in subgroups divided according to the baseline lipid variables. In both the ezetimibe monotherapy and ezetimibe plus atorvastatin groups the effect of ezetimibe on the lipid variables depended on the baseline lipid values. The low-density lipoprotein cholesterol:high density lipoprotein cholesterol ratio was consistently improved by ezetimibe in all groups or subgroups. Conclusions: Ezetimibe did not alter serum visfatin concentrations, either when administered as monotherapy or combined with a statin. Future studies investigating the effect of ezetimibe on visfatin levels need to include groups of patients with distinct lipid characteristics.     

西藏高原地区血脂水平和海拔关系的研究

目的:调查我国西藏高原地区居民的血脂水平是否与海拔相关。方法:选取西藏昌都地区的成年健康体检者407例,依受试者居住地海拔不同分为10组,调查各组三酰甘油(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)的水平及异常率,比较不同海拔地区血脂水平及血脂异常率的差异。结果:TC和LDL-C水平及HDL-C的异常率在各组间差异有统计学意义(P<0.05),TG和HDL-C的水平及高TG、高TC、高LDL-C比率差异无统计学意义(P>0.05)。TG、TC、HDL-C和LDL-C的水平与海拔未见相关。结论:西藏高原地区血脂水平与海拔无相关性。     

Pharmacokinetics of cyclosporine in bone marrow transplantation: longitudinal characterization of drug in lipoprotein fractions.

The pharmacokinetics of cyclosporine (CSA; 2 mg/kg given iv over a period of 2 h every 12 h) in whole blood, plasma, high-density lipoproteins (HDL), and low-density lipoproteins (LDL) were studied after single (n = 10) and multiple (31 days; n = 6) doses in patients receiving allogeneic bone marrow transplants. Whereas HDL-cholesterol levels decreased significantly, LDL-cholesterol levels increased from day 1 to day 31 of CSA dosing. The mean area under the concentration-time curve and half-life values of CSA in whole blood or total plasma did not differ after single or multiple doses. Greater amounts of CSA were contained in the HDL relative to the LDL fraction over the 24-h period after a single dose; the reverse was found after multiple dosing. Cyclosporine was not detectable in the very LDL fractions. The percentage of total plasma CSA contained in each lipoprotein fraction was independent of the concentration of CSA in total plasma or whole blood. The pharmacokinetics of CSA in the various biologic matrices were not associated with measurements of kidney and liver function. Taken together, the variability of CSA pharmacokinetics previously reported in whole blood or total plasma was also found in lipoprotein fractions. The relative changes in CSA content of lipoproteins may offer an explanation for differences in drug effect with multiple dosing.     

Comparison of the effect of celiprolol and nifedipine on blood pressure and plasma lipids.

During a double-blind, randomized study in hypertensive patients, changes in blood pressure (BP) and in plasma lipid and lipoprotein levels during treatment with celiprolol were compared with those occurring during nifedipine treatment. Fifty-three patients (28 men and 25 women) with mild-to-moderate hypertension, aged 20-64 years, were studied. After a 1-month placebo run-in period, patients were randomly assigned to receive either nifedipine (40 mg daily) or celiprolol (200 mg daily) each time using a double dummy technique. After 6 weeks, dosages of each drug could be doubled. Both drugs caused similar reductions in blood pressure but after 12 weeks treatment, the percentage of decrease in diastolic BP (DBP) was more pronounced (p less than 0.01) in the nifedipine group (-18%) than in the celiprolol group (-12%). After 6 weeks, there were no differences in plasma lipids between the two treatment groups. However, the changes after 12 weeks treatment were different (p less than 0.05) between the groups, leading to lower levels of plasma esterified cholesterol, low-density lipoprotein (LDL) cholesterol and apoprotein AI, AII, and B in the celiprolol group. Plasma lecithin cholesterol acyltransferase activity (LCAT) was not modified, suggesting that reverse cholesterol transport was not affected by the drugs. In both treatment groups, a significant positive relationship was observed between changes in LDL cholesterol and apoprotein B. As compared with nifedipine, celiprolol after 12-week therapy had a rather favorable plasma lipid profile. The clinical relevance of such findings, in terms of prevention of cardiovascular complications, has yet to be established.     

Cross-sectional comparison of fasting lipids in normoglycemic patients with schizophrenia during chronic treatment with olanzapine, risperidone, or typical antipsychotics

We compared fasting lipids and other metabolic parameters in 211 normoglycemic patients meeting the DSM-IV diagnosis of schizophrenia or schizoaffective disorder undergoing continuous treatment with olanzapine, risperidone, or typical antipsychotics for at least 1 year. Blood samples were obtained after an 11-hour (+/-1 h) observed fast. Olanzapine-treated patients had significantly higher mean fasting triglyceride levels (2.3 +/- 1.8 mmol/L) than risperidone- (1.7 +/- 0.9 mmol/L, P = 0.022), but not typical antipsychotic-treated patients (1.8 +/- 1 mmol/L). There were no significant differences in total low-density (LDL-C) or high-density lipoprotein cholesterol levels. Apolipoprotein-B and very low density lipoprotein cholesterol levels were significantly higher in the olanzapine- versus risperidone-treated patients, but there were no significant differences between olanzapine- and typical antipsychotic-treated patients. Treatment groups did not differ significantly in LDL particle size, the prevalence of an "atherogenic" lipid profile, or estimated insulin sensitivity. Although interpretation of this study is limited by the cross-sectional study design, it provides additional insight concerning the relationship between antipsychotic use and plasma lipid parameters in this population.     

血脂康用于治疗初期高脂血症

目的：比较血脂康和辛伐他汀用于治疗初期高脂血症的作用。方法：108名患有初期脂血症的病人随机分为两组。第一组53名患者每日服4粒血脂康胶囊（1．2g/天）共服八周;第二组55名患者每日服辛伐他汀10mg共服八周。八周后的血脂水平与各组的基线比较。结果：第一组患者的血清总胆固醇（TC）,低密度脂蛋白（LDL）和甘油三酯（TG）分别降低23．0％,28．0％和28．1％（P＜0．001）;第二组分别降低23．3％,29．5％和29．5％（P＜0．001）。服药后血清高密度脂蛋白（HDL）胆固醇血脂康组升高5．0％（P＞0．05）。辛伐他汀组升高14．3％（P＜0．01）。两组间TC,LDL胆固醇,TG和HDL胆固醇的变化无显著性差异。血脂康的副作用比辛伐他汀的弱。结论：中国产的血脂康为一种安全,有效和耐受性良好的血脂调节剂。     

Immunological reconstitution after allogeneic and autologous bone marrow transplantation

Immunological reconstitution was studied with regard to T cell subsets and their functions in patients who received intensive therapy and autologous or allogeneic marrow transplantation. One of the distinct features was the imbalance of T cell subsets. Long-standing inversion of the OKT4/OKT8 ratio was characteristic in both autotransplant and allotransplant patients. Significant differences were observed in recovery of T cell subsets and mitogenic responses between autotransplant and allotransplant patients and between transplant patients and normal controls. In contrast, low reactivities of mixed lymphocyte culture (MLC) recovered to normal levels within 1 yr in both groups of patients. Then the role of suppressor cells was investigated. During early posttransplant periods, MLC suppressor cells were operative in association with the development of low MLC reactivities because suppressor activity was inversely correlated with MLC reactivities at a significant level. Characterization of these MLC suppressor cells revealed that they were an OKT8- and Ia-positive, radioresistant T cell subset of peripheral blood lymphocytes from autologous and allogeneic marrow recipients. These observations suggest that the imbalance of T cell subsets and their abnormal reactivities may by responsible for the development of immunodeficiency and immunodysregulation in bone marrow transplant patients.     

Influence of lovastatin on the pharmacokinetics, toxicity and immunologic response of cyclosporine in the obese Zucker rat

The combined use of lovastatin, a hypolipidemic agent effective in the reduction of cholesterol levels, and the lipophilic immunosuppressant, cyclosporine, was studied in the obese rat model. Pharmacokinetics, immunosuppressive activity, lipid levels, and creatinine clearances were compared between groups administered drug-free vehicle, lovastatin or cyclosporine alone, or concomitant cyclosporine and lovastatin. All groups were pre-treated with either oral lovastatin 2.5 mg kg-1 day-1 or propylene glycol vehicle for 1 week. Although no differences in renal function were observed in rat groups administered cyclosporine or lovastatin alone, there was a significant reduction in baseline creatinine clearance following combination therapy compared to placebo controls (70 +/- 18 vs 121 +/- 16 per cent of baseline; p less than 0.05). No differences in trough cyclosporine concentrations were observed between groups. Similarly, mean areas under the whole blood concentration-time profiles were not significantly different with or without concomitant lovastatin (61823 +/- 27295 vs 41470 +/- 10312 ng h ml-1; p = 0.13). No differences in systemic clearance or volume of distribution of parent cyclosporine were observed with combination therapy. Furthermore, lipid levels and T-lymphocyte activity were unchanged with the addition of lovastatin. Per cent increases in creatine kinase were significantly correlated with percentage drop in baseline renal function, suggesting the development of rhabdomyolysis. The present data support the interaction between cyclosporine and lovastatin observed clinically, resulting in acute renal dysfunction. Caution should be exercised in their combined use.     

肾移植术后高脂血症的影响因素研究

目的：研究肾移患者植术后高脂血症的影响因素。方法：回顾分析826例肾移植患者中出现高脂血症的267例患者,调查术后时间、环孢素（CsA）全血浓度对患者移植术后血脂影响,及高血脂对患者肝、肾功能和血糖的影响。结果：肾移植术后0～3个月、4～6个月、7—12个月、1—2年高脂血症发生率分别为6．8％、7．0％、7．6％、10．9％,患者首次血脂异常时的总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL）水平与CsA全血浓度呈相关趋势。肾移植患者出现高血脂时,其血肌酐（SCr）和血糖（Glu）也明显升高,服药降低血脂后,SCr和Glu明显下降至血脂异常前水平（P〈0．05）,而未服用调脂药仅控制饮食的患者,首次血脂异常后3个月的Glu和SCr水平继续升高,显著高于首次血脂异常时的水平（P〈0．05）。结论：CsA对肾移植患者术后血脂的影响呈一定的浓度依赖性;术后1年内是肾移植受者高血脂症高发期。高血脂可明显影响移植肾功能,同时使患者血糖升高,应密切监测血脂变化．及时降脂治疗。     

Treatment of coronary spastic angina with a statin in addition to a calcium channel blocker: a pilot study

Combined therapy with a statin and a calcium channel blocker, which can improve lipid metabolism and reduce oxidative stress, may attenuate coronary vasoconstriction in patients with coronary spastic angina (CSA). After 6 months of therapy with benidipine and pravastatin, an acetylcholine provocation test was performed a second time in 25 patients with CSA. The patients were divided into 2 groups according to whether the result of this second test was positive (n = 13) or negative (n = 12). The test was designated as positive when the intracoronary injection of acetylcholine induced angiographically demonstrable total or subtotal occlusion (positive-test group). In the negative-test group, significant decrease in the plasma levels of low-density lipoprotein (LDL) cholesterol (-20.7 +/- 11.1%, P < 0.01 versus baseline) were observed along with a dramatic increase in the serum level of high-density lipoprotein (HDL) cholesterol (26.8 +/- 13.2%, P < 0.01 versus baseline). Furthermore, a significant decrease of the malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a marker of oxidative stress, was also observed (-22.6 +/- 14.1%, P < 0.01 versus baseline) in this group. In the positive-test group, however, no significant changes were found in any of the aforementioned parameters. The results showed that improvement of lipid metabolism, especially an increase of HDL cholesterol level and a reduction of MDA-LDL, may inhibit vascular contractility.     

Influence of baseline values on lipids, lipoproteins and fibrinolytic parameters during amlodipine treatment of hypertension in Japanese patients.

Twenty-four Japanese hypertensive patients of both sexes, grouped as having 'medium' and 'high' baseline total lipid values, had their serum lipids, lipoproteins and plasma fibrinolytic parameters, renin and noradrenaline levels determined after 3 months of amlodipine treatment. For the patients with 'medium baseline values', total plasminogen activator inhibitor-1 (PAI-1) and t-PA-PAI-1 complex levels decreased, while the changes in lipids and lipoproteins were not significant after amlodipine treatment. For the patients with 'high baseline values', the mean triglyceride and very low density lipoprotein cholesterol (VLDLC) levels were reduced while the reductions in total and free PAI-1 and the increase in tissue plasminogen (t-PA) levels were not significant after amlodipine treatment. Negative correlations were observed between t-PA and high density lipoprotein cholesterol (HDLC) and HDLC/total cholesterol (TC) ratio in the patients with 'medium baseline values' while t-PA positively correlated with HDLC/TC ratio in patients with 'high baseline values'. The mean levels of renin and noradrenaline remained unchanged before and after amlodipine treatment in the two baseline groups. These findings show that baseline lipid levels of the hypertensive patients could influence lipids and fibrinolytic parameters differently during amlodipine treatment. The baseline lipid levels also influenced the metabolic association between lipids and fibrinolytic function in hypertensive patients during amlodipine treatment. The baseline total lipid values could therefore provide explanations for the complex metabolic interaction between lipids and fibrinolytic function as well as for the antiatherogenic actions of amlodipine treatment in hypertensive patients.     

自体骨髓干细胞移植治疗糖尿病足的效果观察

目的观察自体骨髓干细胞移植治疗糖尿病足的效果。方法将本院2008年1月～2010年12月住院治疗的52例糖尿病足患者分为两组,选择自愿行自体骨髓干细胞移植治疗的26例患者作为治疗组,未进行自体骨髓干细胞移植治疗的26例糖尿病足患者作为对照组。对照组给予扩血管、抗感染及营养末梢神经等常规治疗;治疗组在常规治疗基础上行自体骨髓干细胞移植,比较两组患者的疗效。结果移植4周后,治疗组痊愈19例,显效5例,有效2例,无效0例,总有效率为100%;对照组痊愈9例,显效7例,有效3例,无效7例,总有效率为73%,两组差异有统计学意义（P〈0.05）。结论自体骨髓干细胞移植可促进伤口愈合,降低致残率,是治疗缺血性糖尿病足的有效方法。     

Hypocholesterolaemic effects of an ethanol precipitate of Kabosu juice in stroke-prone spontaneously hypertensive rats fed a cholesterol-free diet

1. We have previously identified strong inhibitory effects of Kabosu (Citrus sphaerocarpa Hort.) juice precipitate (KJP) on cholesterol elevation in stroke-prone spontaneously hypertensive rats (SHRSP) fed a cholesterol diet. In the present study, to elucidate the hypocholesterolaemic mechanism, we examined the effect of dietary KJP on lipid metabolism by using SHRSP fed a cholesterol-free diet. 2. Compositions of the experimental diet containing 10% KJP powder were adjusted to those of the control diet. Seven-week-old male SHRSP were fed control or experimental diet for 2 weeks with free access to the diet and water. 3. Serum levels of cholesterol, phospholipid and triglyceride of the KJP group were significantly reduced, which was due to decreases in the very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions. 4. Serum concentrations of apolipoproteins A-I and E (apoA-I and E) of the KJP group were significantly lower than those of the control group, whereas no significant differences were observed in serum apoB and apoA-IV between the two groups. 5. In liver, there were no significant differences in the contents of lipids or relative liver weight between the two groups. The activity of microsomal cholesterol 7alpha-hydroxylase of the KJP group tended to increase, whereas that of microsomal acyl-coenzyme A : cholesterol acyltransferase was significantly reduced, compared with the control group. 6. These results indicate that dietary KJP produces reductions of serum lipid levels, which are due to reductions in VLDL, apoE HDL and apoA-I HDL, and may promote catabolism and excretion of hepatic cholesterol in SHRSP fed a cholesterol-free diet.     

Comparison of a pharmacist-managed lipid clinic: In-person versus telephone

ObjectiveTo compare the effectiveness of an in-person versus telephone-based pharmacist-managed lipid clinic.MethodsRetrospective examination of a pharmacist-managed lipid clinic conducted at a Veterans Affairs medical center between September 2005 and March 2008. The clinical pharmacist educated, monitored, recommended nonpharmacologic treatment, and prescribed lipid-lowering medications using an in-person or telephone-based clinic style. The primary outcomes were to compare the two clinic styles on the percent of patients who reached their low-density lipoprotein (LDL) cholesterol goal and the absolute percent of LDL cholesterol reduction.Results157 patients with coronary artery disease or its risk equivalent were enrolled in the pharmacist-managed lipid clinic. Overall, patients experienced a mean 27% reduction in LDL cholesterol levels from baseline, and 76% reached their LDL cholesterol goal. No significant differences in the percent of patients reaching their LDL cholesterol goal or absolute percent reduction in LDL cholesterol levels were found between the in-person and phone-based clinics. A trend toward phone clinic patients achieving their goal LDL cholesterol levels more quickly was noted.ConclusionBoth in-person and phone-based pharmacist-managed lipid clinics offer effective methods to improve the cholesterol levels of patients. Phone-based clinics may offer more advantages in efficiency for pharmacists and their patients and the potential to deliver care in a wider variety of pharmacy settings.     

氟伐他汀联合血脂康治疗冠心病的疗效及对血脂水平的影响

目的探讨氟伐他汀联合血脂康治疗冠心病的临床疗效及对血脂水平的影响。方法选择本院2009年2月～2011年8月收治的冠心病患者100例,按照就诊顺序分为对照组与观察组,每组50例。对照组患者给予氟伐他汀进行对症治疗,观察组患者给予氟伐他汀联合血脂康进行对症治疗,观察两组患者的治疗效果,测定两组患者治疗前后的总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）等指标。结果治疗后,观察患者的心绞痛疗效总有效率为70.0%,明显高于对照组的36.0%（P〈0.05）;治疗后两组患者各血脂指标均明显优于治疗前（P〈0.05）;观察组治疗4周后,TC、TG、LDL-C均明显低于对照组（P〈0.05）。两组患者不良反应的发生率比较,差异无统计学意义（P〉0.05）。结论氟伐他汀联合血脂康可有效缓解冠心病症状,临床疗效确切,不良反应小,值得推广应用。     

石杉碱甲联合心脑舒通对血管性痴呆患者的疗效评价

目的：评价石杉碱甲联合心脑舒通对血管性痴呆的疗效。方法：随机将61例血管性痴呆患者分成两组：心脑舒通组;联合用药组。心脑舒通组接受心脑舒通治疗,联合用药组接受石杉碱甲加心脑舒通治疗,共12wk。分别在0wk、6wk及12wk按简易精神状态检查、修订的长谷川痴呆量表进行评定,并比较治疗前后血脂的变化。结果：联合用药组的简易精神状态检查、修订的长谷川痴呆量表评分在治疗前后均有明显差异。联合用药组在认知评定方面较心脑舒通组明显改善。两组的总胆固醇、甘油三酯和低密度脂蛋白在治疗前后也有明显差异。结论：石杉碱甲联合并心脑舒通治疗血管性痴呆的疗效优于心脑舒通。     

Implications of the ACCORD Lipid study: perspective from the Residual Risk Reduction Initiative (R3i)

Abstract

Most type 2 diabetes patients remain at high residual risk of cardiovascular events despite best treatment. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial aimed to address this challenge, by evaluating whether intensive control of glycaemia and high blood pressure, or as in ACCORD Lipid, extending lipid treatment with the combination of fenofibrate plus simvastatin, could impact this risk. ACCORD Lipid showed that treatment beyond low-density lipoprotein cholesterol was not appropriate for most type 2 diabetes patients. However, a subgroup analysis did suggest additional benefit in patients with atherogenic dyslipidaemia, the combination of high baseline triglycerides (≥204?mg/dL or 2.3?mmol/L) and low baseline plasma levels of high-density lipoprotein cholesterol (≤34?mg/dL or 0.88?mmol/L). This finding is concordant with subgroup analyses from other fibrate trials in patients with high triglycerides and low plasma levels of high-density lipoprotein cholesterol, and consistent with current guideline recommendations. This commentary from the Residual Risk Reduction Initiative (R³i), discusses the ACCORD Lipid study results and the next steps to establish the clinical relevance of these findings.