Biological effects of acute pravastatin treatment in patients after aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled trial

2007 ◽  
Vol 107 (6) ◽  
pp. 1092-1100 ◽  
Author(s):  
Ming-Yuan Tseng ◽  
Peter J. Hutchinson ◽  
Carole L. Turner ◽  
Marek Czosnyka ◽  
Hugh Richards ◽  
...  

Object The authors previously demonstrated that acute pravastatin therapy in patients after aneurysmal subarachnoid hemorrhage (SAH) ameliorates vasospasm-related delayed ischemic neurological deficits. The object of this study was to continue to examine potential mechanisms of these beneficial effects. Methods Eighty patients with aneurysmal SAH (age range 18–84 years; time to onset 1.8 ± 1.3 days) were enrolled in a double-blind study and randomized to receive 40 mg of oral pravastatin or placebo daily for as long as 14 days. Daily transcranial Doppler ultrasonography and blood tests every 3 days (including full blood cell counts, coagulation profiles, fasting glucose and lipid profiles, and serum biochemistry) were performed during the trial period. Results No significant differences were found in baseline laboratory data between the trial groups. Subsequent measurements during the 14-day trial showed reduced low-density lipoprotein (LDL) cholesterol levels and total/high-density lipoprotein cholesterol ratios between Days 3 and 15 (p < 0.05), and increased D-dimer levels (p < 0.05) on Day 6, in the pravastatin group. Patients who received pravastatin but developed vasospasm had significantly lower baseline LDL cholesterol levels or a less extensive reduction in LDL cholesterol levels (p < 0.05), and greater increases in plasma fibrinogen (p = 0.009) and serum C-reactive protein on Day 3 (p = 0.007), compared with those patients without vasospasm. The reduction in LDL cholesterol levels on Day 3 in the placebo group correlated with the duration of normal cerebral autoregulation on the ipsilateral side of the ruptured aneurysm (p = 0.002). Conclusions In addition to functioning through a cholesterol-independent pathway, cerebrovascular protection from acute statin therapy following aneurysmal SAH may also function through cholesterol-dependent mechanisms.

2002 ◽  
Vol 88 (5) ◽  
pp. 479-488 ◽  
Author(s):  
Jacqueline de Graaf ◽  
Pernette R. W. de Sauvage Nolting ◽  
Marjel van Dam ◽  
Elizabeth M. Belsey ◽  
John J. P. Kastelein ◽  
...  

In a randomized, double-blind, placebo-controlled trial we evaluated the effect of dietary chocolates enriched with a wood-based phytosterol–phytostanol mixture, containing 18% (w/w) sitostanol, compared with placebo dietary chocolates in seventy subjects with primary hypercholesterolaemia (total cholesterol levels below 8 mmol/l). For 4 weeks, participants consumed three servings of the phytosterol-enriched chocolate/d that provided 1·8 g unesterified phytosterols/d or a placebo chocolate in conjunction with a low-fat, low-cholesterol diet. Plasma total and LDL-cholesterol levels were statistically significantly reduced by 6·4% (−0·44 mmol/l) and 10·3% (−0·49 mmol/l), respectively, after 4 weeks of phytosterol-enriched-chocolate treatment. Plasma HDL-cholesterol and triacylglycerol levels were not affected. Consumption of phytosterol-enriched chocolates significantly increased plasma lathosterol concentration (+20·7%), reflecting an increased endogenous cholesterol synthesis in response to phytosterol-induced decreased intestinal cholesterol absorption. Furthermore, the chocolates enriched with phytosterols significantly increased both plasma sitosterol (+95·8%) and campesterol (+64·1%) levels, compared with the placebo chocolate group. However, the absolute values of plasma sitosterol and campesterol remained within the normal range, that is, below 10 mg/l. The chocolates with phytosterols were palatable and induced no clinical or biochemical side effects. These findings indicate that dietary chocolate enriched with tall oil-derived phytosterols (1·8 g/d) is effective in lowering blood total and LDL-cholesterol levels in subjects with mild hypercholesterolaemia and thus may be helpful in reducing the risk of CHD in these individuals.


2019 ◽  
Vol 16 (1) ◽  
pp. 89-95
Author(s):  
Jianfeng Zheng ◽  
Rui Xu ◽  
Zongduo Guo ◽  
Xiaochuan Sun

Objective: With the aging of the world population, the number of elderly patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) is gradually growing. We aim to investigate the potential association between plasma ALT level and clinical complications of elderly aSAH patients, and explore its predictive value for clinical outcomes of elderly aSAH patients. Methods: Between January 2013 and March 2018, 152 elderly aSAH patients were analyzed in this study. Clinical information, imaging findings and laboratory data were reviewed. According to the Glasgow Outcome Scale (GOS), clinical outcomes at 3 months were classified into favorable outcomes (GOS 4-5) and poor outcomes (GOS 1-3). Logistic regression analysis was used to assess the indicators associated with poor outcomes, and receiver curves (ROC) and corresponding area under the curve (AUC) were used to detect the accuracy of the indicator. Results: A total of 48 (31.6 %) elderly patients with aSAH had poor outcome at 3 months. In addition to ICH, IVH, Hunt-Hess 4 or 5 Grade and Modified Fisher 3 or 4 Grade, plasma ALT level was also strongly associated with poor outcome of elderly aSAH patients. After adjusting for other covariates, plasma ALT level remained independently associated with pulmonary infection (OR 1.05; 95% CI 1.00–1.09; P = 0.018), cardiac complications (OR 1.05; 95% CI 1.01–1.08; P = 0.014) and urinary infection (OR 1.04; 95% CI 1.00–1.08; P = 0.032). Besides, plasma ALT level had a predictive ability in the occurrence of systemic complications (AUC 0.676; 95% CI: 0.586– 0.766; P<0.001) and poor outcome (AUC 0.689; 95% CI: 0.605–0.773; P<0.001) in elderly aSAH patients. Conclusion: Plasma ALT level of elderly patients with aSAH was significantly associated with systemic complications, and had additional clinical value in predicting outcomes. Given that plasma ALT levels on admission could help to identify high-risk elderly patients with aSAH, these findings are of clinical relevance.


2016 ◽  
Vol 42 (1-2) ◽  
pp. 97-105 ◽  
Author(s):  
Naoya Matsuda ◽  
Masato Naraoka ◽  
Hiroki Ohkuma ◽  
Norihito Shimamura ◽  
Katsuhiro Ito ◽  
...  

Background: Several clinical studies have indicated the efficacy of cilostazol, a selective inhibitor of phosphodiesterase 3, in preventing cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). They were not double-blinded trial resulting in disunited results on assessment of end points among the studies. The randomized, double-blind, placebo-controlled study was performed to assess the effectiveness of cilostazol on cerebral vasospasm. Methods: Patients with aneurysmal SAH admitted within 24 h after the ictus who met the following criteria were enrolled in this study: SAH on CT scan was diffuse thick, diffuse thin, or local thick, Hunt and Hess score was less than 4, administration of cilostazol or placebo could be started within 48 h of SAH. Patients were randomly allocated to placebo or cilostazol after repair of a ruptured saccular aneurysm by aneurysmal neck clipping or endovascular coiling, and the administration of cilostazol or placebo was continued up to 14 days after initiation of treatment. The primary end point was the occurrence of symptomatic vasospasm (sVS), and secondary end points were angiographic vasospasm (aVS) evaluated on digital subtraction angiography, vasospasm-related new cerebral infarction evaluated on CT scan or MRI, and clinical outcome at 3 months of SAH as assessed by Glasgow Outcome Scale, in which poor outcome was defined as severe disability, vegetative state, and death. All end points were evaluated with blinded assessment. Results: One hundred forty eight patients were randomly allocated to the cilostazol group (n = 74) or the control group (n = 74). The occurrence of sVS was significantly lower in the cilostazol group than in the control group (10.8 vs. 24.3%, p = 0.031), and multiple logistic analysis showed that cilostazol use was an independent factor reducing sVS (OR 0.293, 95% CI 0.099-0.568, p = 0.027). The incidence of aVS and vasospasm-related cerebral infarction were not significantly different between the groups. Poor outcome was significantly lower in the cilostazol group than in the control group (5.4 vs. 17.6%, p = 0.011), and multiple logistic analyses demonstrated that cilostazol use was an independent factor that reduced the incidence of poor outcome (OR 0.221, 95% CI 0.054-0.903, p = 0.035). Severe adverse events due to cilostazol administration did not occur during the study period. Conclusions: Cilostazol administration is effective in preventing sVS and improving outcomes without severe adverse events. A larger-scale study including more cases was necessary to confirm this efficacy of cilostazol.


Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Joseph L Evans ◽  
Harold Bays ◽  
Kevin C Maki ◽  
Mal Evans ◽  
Veronique Maquet ◽  
...  

Oxidized low-density lipoprotein (OxLDL) is believed to play a role in the progression of atherosclerotic coronary heart disease (CHD) and the development of diabetes complications. This randomized, double-blind, placebo-controlled study of a novel insoluble fiber derived from the mycelium Aspergillus niger , chitin-glucan (CG) (ARTINIA™), evaluated 135 patients with fasting LDL-cholesterol 130-189.9 mg/dl and fasting glucose <=125 mg/dl. Participants were randomly assigned to receive CG (4.5 g/day; n=34), CG (1.5 g/day; n=33), CG (1.5 g/day) plus olive extract (n=33), or matching placebo (n=35) for 6 weeks. The primary outcome measure was the between-group difference in OxLDL. Secondary outcome measurements included effects upon lipid, glucose, insulin, and F2-isoprostane levels. After 6 weeks, CG 4.5 g/day (CG-4.5) significantly reduced mean OxLDL 3.8 U/L compared to baseline (58.0 U/L vs 61.8 U/L, respectively; P =0.006), and reduced OxLDL 4.97 U/L compared to placebo (P=<0.05). Other treatment groups generally had no significant effect upon OxLDL. CG treatment groups reduced LDL-cholesterol levels 3.2–;6.5% compared to placebo (P<0.05). In this study population without diabetes mellitus or elevated glucose levels, CG did not significantly affect high density lipoprotein cholesterol, triglycerides, glucose, insulin, F2-isoprostanes, or the homeostasis model assessment of insulin resistance. Treatments were well tolerated and with adverse experiences comparable to placebo. These results suggest that chitin-glucan, a novel insoluble fiber, may significantly reduce OxLDL and LDL-cholesterol levels, which may have therapeutic implications for patients at risk for CHD or other diabetes complications.


1998 ◽  
Vol 42 (12) ◽  
pp. 3146-3152 ◽  
Author(s):  
Kishor M. Wasan ◽  
Allison L. Kennedy ◽  
Shawn M. Cassidy ◽  
Manisha Ramaswamy ◽  
Lorilynne Holtorf ◽  
...  

ABSTRACT The purpose of this study was to determine if a relationship exists among total serum and lipoprotein cholesterol concentration, the severity of amphotericin B (AmpB)-induced renal toxicity, and the serum pharmacokinetics of AmpB in hypercholesterolemic rabbits administered AmpB and AmpB lipid complex (ABLC). After 10 days of cholesterol-enriched diet (0.50% [wt/vol]) or regular rabbit diet (control), each rabbit was administered a single intravenous bolus of AmpB or ABLC (1.0 mg/kg of body weight). Blood samples were obtained before administration and serially thereafter for the assessment of serum pharmacokinetics, kidney toxicity, and serum lipoprotein distribution. Rabbits were humanely sacrificed after all blood samples were obtained, and tissues were harvested for drug analysis. Before drug treatment, cholesterol-fed rabbits demonstrated marked increases in total serum cholesterol and low-density lipoprotein (LDL) cholesterol levels compared with levels in rabbits on a regular diet. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered AmpB. However, the magnitude of this increase was 2.5-fold greater in cholesterol-fed rabbits than in regular diet-fed rabbits. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered ABLC. Whereas AmpB pharmacokinetics were significantly altered in cholesterol-fed rabbits administered free AmpB, similar AmpB pharmacokinetics were observed in both rabbit groups administered ABLC. Renal AmpB levels were significantly increased in cholesterol-fed rabbits administered AmpB compared with those in all other groups. Hepatic and lung AmpB levels were elevated in cholesterol-fed rabbits administered free AmpB compared to controls. In addition, hepatic, lung, and spleen AmpB levels were significantly decreased in cholesterol-fed rabbits administered ABLC compared to controls. An increased percentage of AmpB was recovered in LDL–very-low-density lipoprotein fraction when free AmpB was administered to cholesterol-fed rabbits compared with those in all other groups. These findings suggest that increases in cholesterol, specifically, LDL cholesterol levels, modify the disposition and renal toxicity of free AmpB. However, the pharmacokinetics and renal toxicity of ABLC were independent of elevations in total and LDL cholesterol levels.


Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Susanne Muehlschlegel ◽  
Raphael Carandang ◽  
Wiley Hall ◽  
Kini Nisha ◽  
Saef Izzy ◽  
...  

Introduction: Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) after aneurysmal subarachnoid hemorrhage (aSAH) in humans. We evaluated safety/tolerability and feasibility of intravenous dantrolene (IV-D) after aSAH. Methods: In this single-center, randomized, double-blind, placebo-controlled trial, 31 patients with acute aSAH were randomized to IV-D 1.25 mg IV every 6 hours x 7 days (n=16) or placebo (n=15). Primary endpoint was incidence of hyponatremia (sNa ≤ 134 mmol/L) and liver toxicity (% patients with ALT, AST and AlkPhos >5x upper limit of normal). Secondary safety endpoints included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored by clinical, transcranial Doppler (TCD) or angiographic cVSP occurrence, delayed cerebral ischemia (DCI) and 3-month modified-Rankin-Scale, Glasgow Outcome Scale and Barthel Index. Statistical analysis was performed using non-parametric tests, generalized estimating equations and mixed models. Results: Between IV-D vs. placebo, no differences were observed in the primary outcome (hyponatremia: 44% vs. 67% [p=0.29]; liver toxicity 6% vs. 0% [p=1.0]). Numerically more AEs and SAEs were seen in the IV-D group, but did not reach statistical significance (16 vs. 5 AEs, of which 5 vs. 2 were severe; RR 2.2; 95% CI 0.7-6.7; p=0.16). Three IV-D vs. two placebo patients reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain edema requiring osmotherapy. No differences in angiographic, TCD, clinical cVSP, DCI, or 3-month functional outcomes were seen. Quantitative angiogram analysis revealed a trend towards increased vessel diameters in the IV-D group after the 7-day infusion-period (p=0.05). Conclusion: In this small trial, IV-Dantrolene after aSAH was feasible, tolerable and safe, but was underpowered to show efficacy or outcome differences.


Author(s):  
Heinz Drexel

Lipid metabolism has gained cardiological interest only after statins were demonstrated to reduce cardiovascular disease in secondary and primary prevention. Therefore, this chapter first introduces the physiological and atherogenic properties of lipoproteins, before focusing on interventions. Both the efficacy and safety of statins have been proven in numerous randomized clinical trials. Because there is a considerable residual risk in statin-treated patients, additional approaches have been investigated. The focus is now on further reductions in low-density lipoprotein (LDL) cholesterol levels. First, high-intensity statin regimens were shown to reduce residual risk. Subsequently, ezetimibe was demonstrated, for the first time, to have a beneficial effect as a non-statin lipid intervention. More recently, inhibitors of the enzyme PCSK9 have demonstrated a very high efficacy in reducing LDL cholesterol levels. Although the causality of LDL for atherosclerotic cardiovascular disease has been proven in epidemiological studies, including Mendelian randomization studies, as well as interventional trials, adherence to statins and other therapies is far from optimal. In contrast, interventions to increase high-density lipoprotein (HDL) cholesterol levels could not proven to have further benefits when combined with statins.


BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Peter Y. M. Woo ◽  
Joanna W. K. Ho ◽  
Natalie M. W. Ko ◽  
Ronald P. T. Li ◽  
Leo Jian ◽  
...  

Asbtract Background There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients. Methods This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI). Results No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 1.49; 95% confidence interval (CI): 0.43–5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79–15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28–2.59). Conclusions Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients. Clinical trial registration Name of Registry: ClinicalTrials.gov Trial Registration Number: NCT01787123. Date of Registration: 8th February 2013.


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