Antilipid Agents Research Articles

Low-Density Lipoprotein Cholesterol Is Not a Major Determinant of High-Sensitivity C-Reactive Protein Levels in People Without Known Diabetes Mellitus.

Background: It has been well established that high-sensitivity C-reactive protein (hs-CRP) is strongly associated with obesity, insulin resistance, high blood pressure, and dyslipidemia. However, the effects of different lipid parameters on hs-CRP levels are less deliberated. The purpose of the study was to compare the relative contribution of triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) to the levels of hs-CRP. Methods: Three hundred seventy-eight subjects without known history of diabetes were recruited for the study. No concomitant antilipid or antidiabetes agents were allowed. Each subject received anthropometric measurements, fasting sampling for lipid profile and hs-CRP, and a 75-gram oral glucose tolerance test for the measurements of insulin resistance (surrogated by insulin sensitivity index ISI0,120). Results: Levels of hs-CRP levels were positively correlated with Log (TG) and negatively correlated with HDL-C in partial correlation after adjustments for confounding variables, but not with LDL-C. The hs-CRP levels in the three groups by tertiles of LDL-C were similar. Subsequently, we found that body mass index (first step), Log (ISI0,120) (second step), and Log (TG) (third step) independently predicted the variance of Log (hs-CRP) in stepwise multiple regression. However, both HDL-C and LDL-C failed to be entered into the models to explain Log (hs-CRP). Conclusions: Our data demonstrated that Log (TG) was a major lipid determinant of hs-CRP levels. The contribution of LDL-C to the levels of hs-CRP might be insignificant.

Predictive value of hypercholesterolemia, vegetarian diet, and hypertension for incident dementia among elderly Taiwanese individuals with low educational levels

Early management of modifiable dementia-related factors is seen as a novel approach to preventing dementia onset; however, these efforts are often hindered by the complexity of interactions among these factors. In addition, different modifiable dementia-related factors may contribute to different etiologies of dementia. The current study investigated the effects of common modifiable dementia-related factors on prediction of incident dementia, dementia of the Alzheimer's type (DAT), and vascular dementia (VaD). Vascular- and lifestyle-related factors were used as predictors of incident dementia, DAT, and VaD among 1,285 elderly individuals without obvious signs of dementia or mild cognitive impairment. Cox proportional hazard models were used to evaluate the risks associated with each modifiable factor. After controlling for factors other than stroke-related factors, hypercholesterolemia was correlated with a relatively low risk of all-cause incident dementia and DAT, whereas a vegetarian diet was correlated with an elevated risk of all-cause incident dementia and VaD. Hypertension was correlated with incident VaD. After controlling for stroke-related factors, a vegetarian diet was correlated with an elevated risk of all-cause dementia. A history of myocardiac infarction and the use of anti-platelet medication were, respectively, associated with a reduced risk of DAT and elevated risk of VaD. The use of anti-hypertensives was associated with a reduced risk of all-cause dementia, whereas the use of anti-lipid agents was associated with slow progression DAT (i.e. exceeding the average conversion time). Hypercholesterolemia was associated with an elevated risk for slow progression DAT. These findings could perhaps be used as clinical markers in predicting and preventing incident dementia, DAT, and VaD.

Exogenous Application of Gallic Acid Induces the Direct Defense of Tea Plant Against Ectropis obliqua Caterpillars.

Gallic acid (GA), an important polyphenolic compound in the plant, is a well-known antioxidant, antihyperglycemic, and anti-lipid peroxidative agent. Recently, GA treatment exhibited ameliorative effects on plants in response to some abiotic stresses. However, the elicitation effect of GA on plant defense against herbivorous insects has not yet been reported. In this study, we found that the exogenous application of GA induced the direct defense of tea plant (Camellia sinensis) against tea geometrid (Ectropis obliqua) larvae, through activating jasmonic acid (JA) signaling and phenylpropanoid pathways. These signaling cascades resulted in the efficient induction of several defensive compounds. Among them, astragalin, naringenin, and epigallocatechin-3-gallate were the three of the most active anti-feeding compounds. However, the exogenous GA treatment did not affect the preference of E. obliqua female moths and larval parasitoid Apanteles sp. Our study suggests that GA may serve as an elicitor that triggers a direct defense response against tea geometrid larvae in tea plants. This study will help to deepen the understanding of the interaction between plants and phytophagous insects and also provide theoretical and technical guidance for the development of plant defense elicitors.

RYR1-Related Rhabdomyolysis: A Spectrum of Hypermetabolic States Due to Ryanodine Receptor Dysfunction.

Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans, suggesting an important area for future research.

Effects of lipid-lowering agents on diabetic retinopathy: a Meta-analysis and systematic review.

To clarify this controversy and to provide evidence for application of lipid lowering agents in treatment of diabetic retinopathy (DR). We searched the databases of PubMed, Embase and Cochrane Library Central Register of Controlled Trials (CENTRAL) and abstracts from main annual meetings up to January 1, 2017. Google scholar and ClinicalTrials.gov were also searched for unpublished relevant studies. We included randomized controlled trials (RCTs) that studied lipid-lowering agents in type 1 or type 2 diabetes in this Meta-analysis. The primary endpoint was the progression of DR, and the secondary endpoints included vision loss, development of diabetic macular edema (DME) and aggravation of hard exudates. The pooled odds ratios (OR) with corresponding 95% confidence intervals (95%CIs) were calculated. After systemic and manual literature search by two independent investigators, we included 8 RCTs from 7 published articles with 13 454 participants in this Meta-analysis. The results revealed that lipid-lowering drugs were associated with reduced risk in DR progression [OR=0.77 (95%CI: 0.62, 0.96), P=0.02]. Lipid-lowering agents might have protective effect on DME compared to placebo, although the difference was not statistically significant [OR=0.60 (95%CI: 0.34, 1.08), P=0.09]. However, no significant differences in the worsening of vision acuity [OR=0.96 (95%CI: 0.81,1.14), P=0.64] and hard exudates [OR=0.50 (95%CI:0.15, 1.74), P=0.28] were found between the lipid-lowering drugs and the placebo groups. In DR patients, lipid-lowering agents show a protective effect on DR progression and might be associated with reduced risk in the development of DME. However, lipid-lowering agents have no effects on vision loss and hard exudates aggravation. Further clinical trials in larger scale are required to confirm the conclusion of this study and thus justify the use of intensive control lipids with anti-lipid agents at the early stages of DR.

Association of immune recovery with hyperlipidaemia and apolipoprotein gene polymorphisms following highly active antiretroviral therapy in a cohort of Chinese HIV patients

ObjectiveTo examine the associations between CD4 recovery, dyslipidaemia and apolipoprotein (APO) gene single nucleotide polymorphisms (SNPs) following highly active antiretroviral therapy (HAART).DesignRetrospective observational cohort study.SettingA major HIV care clinic in...

Synthesis of fused pyranocarbazolones with biological interest

Fused pyranocarbazolones were synthesized from the reactions of hydroxycarbazoles with ethyl propiolate in the presence of catalytic amount of I nCl 3. Carbalkoxypyranocarbazolones and methylenefurocarbazolones were obtained from the reactions of hydroxycarbazoles with dialkyl acetylene dicarboxylates in the presence of Ph 3P in refluxing toluene. Furanone 10a (IC 50 = 10 µM) followed by pyranocarbazolones 9a and 11b are interesting lipoxygenase inhibitors. Pyranocarbazolones 9b , 11a-b are potent anti-lipid peroxidation agents and this is correlated to the presence of the coumarin ring.

SEAWEED EXTRACTS IMPROVE LIPID PROFILE OF WISTAR RAT

Hypercholesterolemia or hyperlipidemia has been established as an important risk factor of cardiovascular disease. Patients with hypercholesterolemia usually require a prolonged treatment; and the newer and more potent generation of antilipid agents are costly.In Bali there are several types of seaweed that are generally consumed by the local people and known by the local names of Bulung Boni (Caulerpa spp.) and Bulung Sangu (Gracilaria spp.). Preliminary studies on the effect of Bulung Boni and Bulung Sangu extracts appeared to improve lipid profile, but the available data are still very limited both in extent and depth, and further investigations were considered relevant and needed.This experimental study used completely blind randomized design, using a total of 24 Wistar rats divided into six sample groups of equal size, all fed with a diet high in cholesterol content. The six sample groups were respectively designated as negative control group, positive control group, and four treated sample groups, respectively fed orally with a dose of 20 mg and 60 mg extracts of Bulung Boni per 100g of body weight per day, and 20 mg and 60 mg extracts of Bulung Sangu per 100g body weight per day. Each treatment was repeated four times.Our study showed that rats fed with high-cholesterol diet and treated with oral Bulung Boni or Bulung Sangu extract at a dose of 20 mg and 60 mg/100 g bw/ day were associated with statistically significantly increased plasma HDL levels (p < 0.05), and statistically significant decreased plasma LDL and total cholesterol levels (p < 0.05) as compared with those of rats fed with high cholesterol diet without treatment with Bulung Boni or Bulung Sangu extracts.From our data it could be implied that Bulung Boni and Bulung Sangu extracts improve lipid profile in the Wiatar rat by significantly increasing plasma HDL level, and lowering LDL and total cholesterol levels.

Simvastatin inhibits cancer cell growth by inducing apoptosis correlated to activation of Bax and down-regulation of BCL-2 gene expression

The statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have been proven to be effective in lowering cholesterol and as anti-lipid agents against cardiovascular disease. Recent reports demonstrate an anticancer effect induced by the statins through inhibition of cell proliferation. Probably, these effects are due to suppression of the mevalonate pathway leading to the depletion of various downstream products that play an essential role in cell cycle progression, cell signaling and membrane integrity. To date, although many hypotheses have been proposed, the exact mechanism at the basis of cancer cell growth arrest induced by statins is not known. In this study, we have demonstrated that simvastatin, at a dose of 20 μM for 24–72 h, induced in cancer cells but not in normal cells precise features of apoptosis including increased DNA fragmentation while, at the molecular level simvastatin induced overexpression of the pro-apoptotic gene Bax together with an inhibition of BCL-2, the gene that has the well-known function of protecting cells from apoptosis. The simvastatin-mediated induction of apoptosis in similar cancer cells but not in normal cells is very interesting and may be at the basis of cancer therapy using statins, usually in combination with chemotherapy or to be used as a cancer protective drug. Simvastatin may, thus, play a dual prophylactic role as a lipid-lowering drug for the prevention of heart disease and as an anticancer agent to prevent certain types of cancers.

Lipid-Induced Peroxidation in the Intestine Is Involved in Glucose Homeostasis Imbalance in Mice

BackgroundDaily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice.Methodology/Principal FindingsAn indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity.Conclusions/SignificanceLipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity.

Copper ions potentiate organic hydroperoxide and hydrogen peroxide toxicity through different mechanisms in Xanthomonas campestris pv. campestris

Copper (Cu)-based biocides are important chemical controls for both fungal and bacterial diseases in crop fields. Here, we showed that Cu ions at a concentration of 100 μM enhanced t-butyl hydroperoxide (tBOOH) and hydrogen peroxide (H(2) O(2) ) killing of Xanthomonas campestris pv. campestris through different mechanisms. The addition of an antilipid peroxidation agent (α-tocopherol) and hydroxyl radical scavengers (glycerol and dimethyl sulphoxide) partially protected the bacteria from the Cu-enhanced tBOOH and H(2) O(2) killing, respectively. Inactivation of the alkyl hydroperoxide reductase gene rendered the mutant vulnerable to lethal doses of copper sulphate, which could be alleviated by the addition of an H(2) O(2) scavenger (pyruvate) and α-tocopherol. Taken together, the data suggest that Cu ions influence the killing effect of tBOOH through the stimulation of lipid peroxidation, while hydroxyl radical production is the underlying mechanism responsible for the Cu-ion-enhanced H(2) O(2) killing effects.

Sirolimus for Graft-Versus-Host-Diseases Prophylaxis in Non-Myeloablative Matched Related Transplantation: Safety and Efficacy.

Abstract 4329The use of sirolimus (rapamycin) as an immunosuppressive agent after allogeneic hematopoietic transplantation is appealing given its antitumor and tolerance-inducing properties. Its safety and efficacy have been studied but are not completely understood in this patient population. We have compared GVHD prophylaxis with sirolimus together with early withdrawal of concomitant tacrolimus to standard tacrolimus in 49 patients receiving non-myeloablative transplant from matched related donors. All patients received identical conditioning with Cyclophosphamide 1g/m2 days –7 and –6 and Fludarabine 25mg/m2 days –7 through –3. Twenty-three patients received standard GVHD prophylaxis with methotrexate and tacrolimus. Twenty-six patients received methotrexate, sirolimus, with tacrolimus tapering over 15 days beginning day 20 or 30. Overall survival (OS) was similar in sirolimus and no sirolimus groups (median 526 vs 723 days, p=0.77). Similarly progression-free survival (PFS) was comparable (median 300 vs 382days p=0.78). Full chimerism was achieved in 73% patients received sirolimus vs. 58%patients received no sirolimus by day 100 (p=0.46). Chimerism was similar in the two groups at all time points examined. Toxicities including microangiopathy (MA), hypertriglyceremia and nephrotoxicity were analyzed. In patients receiving sirolimus MA developed in 2/26(8%) vs. in 1/23(4%) patients receiving no sirolimus (p=0.28). Creatinine >3mg/dl was seen in 6/26 (23%) patients receiving sirolimus vs. 6/23 (26%) patients receiving no sirolimus (p=0.47). In contrast the incidence of hypertriglyceremia (>500mg/dl) was significantly higher in the sirolimus group (10/26, 38% vs 2/23, 9% p<0.01). Hypertriglyceremia was however easily treated with anti-lipid agents, and no patient developed significant pancreatitis or other complications. The incidence of grade II-IV acute Graft versus host disease (GVHD) was modestly higher in the sirolimus (9/26, 35%) vs no sirolimus group (2/23, 9%), (p=0.0418). This acute GVHD occurred late at 60-100 days, more than 2 weeks after discontinuation of tacrolimus. Chronic GVHD was similar between patients receiving sirolimus and no sirolimus (15/26, 58%, vs. 9/23, 39%; p=0.25), as was transplant related mortality (3/26, 12%, vs. 4/23, 17%; p=0.69). Although sample size is limited, our data suggest that replacing tacrolimus early with continued sirolimus may be associated with modest increases in aGVHD. In our patients there is however little to suggest a negative impact on survival and engraftment. Other toxicities of sirolimus are minimal. Whether the early substitution of sirolimus for tacrolimus post transplant yields improved tumor control must await results of larger studies in specific tumor types. Disclosures:Off Label Use: Sirolimus for GVHD prophyllaxis.

The eNOS 786C/T polymorphism in cardiac surgical patients with cardiopulmonary bypass is associated with renal dysfunction

Renal dysfunction is one of the most serious complications following cardiac surgery with cardiopulmonary bypass. The causes of renal dysfunction following cardiac surgery are poorly understood. We hypothesised that T-786C endothelial NO synthase (eNOS) polymorphism may lead to an increase in the occurrence of postoperative renal dysfunction following cardiac surgery with cardiopulmonary bypass. A total of 497 patients undergoing cardiac surgery with cardiopulmonary bypass were included in the study. The T-786C eNOS polymorphism was detected by a polymerase chain reaction. The patients were grouped on the basis of whether they were homozygous or heterozygous for the C allele (TC+CC; n=289) or only homozygous for the T allele (TT; n=208). No significance was demonstrated in the preoperative risk factors, with the exclusion of smoking habits (p=0.04) for the C-allele carrier. The administration of anti-lipid agents (p=0.01) and anti-arrhythmics (p=0.01) was significantly lower in the TC/CC group. The TC+CC genotype group had a significantly greater decrease in creatine clearance (p=0.024), the lowest creatine clearance (p=0.004) and more C-allele carriers received acute renal replacement therapy (p=0.04). The usage of norepinephrine (p=0.02) and dobutamine (p=0.02) was significantly higher in C-allele carriers. In the TC+CC genotype group, cross-clamp time (p=0.02) and administration of red cell transfusion (p=0.04) achieved statistically significant difference. The overall in-hospital mortality rate was 8.2% for all patients and was not significant between genotypes. The present findings support the hypothesis that the T-786C eNOS polymorphism may play a role in the development of renal dysfunction and increase the occurrence of renal replacement therapy following cardiac surgery with cardiopulmonary bypass. This polymorphism may be useful in stratifying the risk for the development of postoperative renal dysfunction.

Association between triglyceride (TG) levels, other clinical characteristics, and outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with erlotinib and bexarotene

8101 Background: Studies of the nonclassical retinoid bexarotene (B) alone or in combination with chemotherapy have revealed improved survival for a subset of NSCLC patients (pts) who developed hypertrigyceridemia despite treatment with antilipid agents. It is not known if a similar association exists when B is combined with a targeted agent. We have completed 2 trials of erlotinib (E), and B, in pts with advanced NSCLC showing minimal toxicities and evidence of clinical activity. In both trials atorvastatin was begun only after elevated TG were detected. This approach differed from other studies where statin therapy was initiated concurrently with B. Methods: E 150 mg and B 400 mg/m2 were administered daily orally to pts with stage IV NSCLC, mostly as third line or higher. Atorvastatin 20 mg was started for elevated fasting TG. The dose was increased to 40 mg if hypertriglyceridemia persisted, followed by the addition of fenofibrate and/or dose reductions of B to 300 mg/m2. TG levels assessed in the first 4 weeks were correlated with overall survival. The appearance of skin rash was documented. Results: Sixty-one pts with stage IV NSCLC were enrolled, 54% women and 72% with adenocarcinoma, 15% never smokers, 20% current smokers, 15% had prior anti-EGFR therapy. Median survival time (MST) was 22 (1–274) wks (intent-to-treat). For pts with elevated TG, the MST was 24 (1–274) wks, while for pts with normal TG the MST was 21 (4–72). There was a statistically significant correlation between TG levels and survival, Spearman's correlation coefficient 0.48, p=0.0003. We will present the analysis of the association between outcomes and other clinical characteristics. Conclusions: Development of hypertriglyceridemia in the first 4 weeks of therapy with E and B in the absence of antilipid treatment is associated with increased overall survival. These findings implicate clinical benefit of dual targeting of EGFR and cyclin D1 especially in a subset of NSCLC pts with elevated TG early in therapy. Further work to identify the molecular basis for this association is needed to allow selection of pts more likely to benefit from this combined therapy. [Table: see text]

Statins, stem cells, and cancer

The statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) were proven to be effective antilipid agents against cardiovascular disease. Recent reports demonstrate an anticancer effect induced by the statins through inhibition of cell proliferation, induction of apoptosis, or inhibition of angiogenesis. These effects are due to suppression of the mevalonate pathway leading to depletion of various downstream products that play an essential role in cell cycle progression, cell signaling, and membrane integrity. Recent evidence suggests a shared genomic fingerprint between embryonic stem cells, cancer cells, and cancer stem cells. Activation targets of NANOG, OCT4, SOX2, and c-MYC are more frequently overexpressed in certain tumors. In the absence of bona fide cancer stem cell lines, human embryonic stem cells, which have similar properties to cancer and cancer stem cells, have been an excellent model throwing light on the anticancer affects of various putative anticancer agents. It was shown that key cellular functions in karyotypically abnormal colorectal and ovarian cancer cells and human embryonic stem cells are inhibited by the statins and this is mediated via a suppression of this stemness pathway. The strategy for treatment of cancers may thus be the targeting of a putative cancer stem cell within the tumor with specific agents such as the statins with or without chemotherapy. The statins may thus play a dual prophylactic role as a lipid-lowering drug for the prevention of heart disease and as an anticancer agent to prevent certain cancers. This review examines the relationship between the statins, stem cells, and certain cancers.

Randomized Phase III Trial Comparing Bexarotene (L1069-49)/Cisplatin/Vinorelbine With Cisplatin/Vinorelbine in Chemotherapy-Naïve Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: SPIRIT I

This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC). Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m(2)/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted. A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm). The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.

Drug compliance after stroke and myocardial infarction: A comparative study

Stroke and myocardial infarction (MI) are both life-threatening diseases of vascular origin with a tendency to recur. In both conditions, risk of recurrence is reduced through similar drug regimens. To determine if compliance with prescribed medication after stroke or MI was similar in the two populations. Retrospective data collection and cross-sectional telephonic survey of patients discharged from a single academic medical center. Adult patients consecutively discharged over a two-year period with a diagnosis of first-ever stroke (ischemic or hemorrhagic) or first-ever MI (ST-elevation) were identified through ICD-9 codes. Clinical details were abstracted from hospital records. Medication compliance was assessed through a structured telephone interview. Bivariate analysis using Chi-square and Fisher exact tests, to determine the prevalence of noncompliance in stroke versus MI patients and differences in baseline characteristics and multivariate analysis with logistic regression to determine independent predictors of noncompliance. Follow-up data was collected for 298 stroke and 275 MI patients. Compliance was lower in stroke patients (68% stroke patients compliant with at least half their discharge prescriptions versus 90% MI patients; P < 0.001). Literacy and post-discharge follow-up were associated with greater compliance (P < 0.05 for both). Compliance was highest with anti-hypertensive drugs (98% after MI, 78% after stroke), followed by anti-platelet agents (94% after MI, 75% after stroke) and anti-lipid agents (70% after MI, 59% after stroke). Patients reported simply not feeling the need, acquiring fresh medical advice or a perceived lack of benefit, as reasons for not complying with their discharge prescriptions. Although similar drugs are involved, compliance with prescribed regimens is appreciably lower after stroke than after MI. Our findings underscore the need for better patient education regarding secondary prevention after stroke.

Use of cardiovascular medical therapy among patients undergoing coronary artery bypass graft surgery: Results from the ROSETTA-CABG Registry

Secondary prevention is needed following coronary artery bypass graft (CABG) surgery to reduce the subsequent risk of unstable angina, myocardial infarction and death. However, little research exists on the use of cardiovascular medical therapy in CABG surgery patients. The objective of the present study is to describe the use of cardiovascular medical therapy among patients discharged after CABG surgery. The use of acetylsalicylic acid, clopidogrel, warfarin, antilipid agents, beta-blockers, calcium channel blockers, nitrates and angiotensin-converting enzyme (ACE) inhibitors was examined among 320 patients enrolled in the Routine versus Selective Exercise Treadmill Testing After Coronary Artery Bypass Graft Surgery (ROSETTA-CABG) Registry. Logistic regression identified the determinants of medication use at 12 months following CABG surgery. Most patients were male, hyperlipidemic and underwent CABG surgery for relief of angina symptoms. At admission, discharge and at 12 months, acetylsalicylic acid was used in 71%, 92% and 87% of cases, respectively, and some form of antiplatelet agent was used in 74%, 94% and 89% of cases, respectively. The use of antilipid agents remained constant, from 55% at admission to 57% at discharge. However, 24% of patients were not receiving antilipid agents at 12 months. The use of beta-blockers was 57% at admission, 71% at discharge and 64% at 12 months. The use of calcium channel blockers and nitrates decreased modestly from admission to discharge and remained stable at approximately 20% and 22%, respectively, at 12 months. ACE inhibitor use remained stable, from 33% at admission to 38% at 12-months. Hyperlipidemia, hypertension, obesity and pre-CABG surgery left ventricular ejection fraction less than 40% were all found to be important determinants of 12-month medication use. Importantly, the use at discharge was an important determinant of 12-month use of for each medication examined in the present study. The use of antilipid agents, beta-blockers and ACE inhibitors was found to be too low among post-CABG surgery patients, who are known to benefit from their use, and the use of nitrates was too high. Discharge from hospital provides a unique opportunity for physicians to modify the use of cardiovascular medical therapy among patients undergoing CABG surgery.

A Multicenter Pilot Study of Early (4-Day) Steroid Cessation in Renal Transplant Recipients Under Simulect, Tacrolimus and Sirolimus

This study presents the first prospective multicenter study assessing sirolimus-based immunosuppression with early (4-day) corticosteroid withdrawal (CSWD) in renal transplantation. Immunosuppression included: anti-IL-2 receptor antibody and tacrolimus/sirolimus. Inclusion criteria included adult primary recipients. Exclusion criteria included: (i) African Americans, (ii) current PRA >50%, (iii) multiple organ transplants, (iv) WBC < 3000 cells/microL and (v) fasting hypercholesterolemia/hypertriglyceridemia. The primary endpoints were acute rejection and the proportion of patients off corticosteroids. Seventy-seven patients were enrolled: mean age of 49.7 +/- 12 years. Transplants included: cadaveric (26%) and living donor (74%). Patient and graft survival were 100%. Biopsy proven acute rejection occurred in 13%; presumptive rejection in 10.5%. Banff grades included: IA (seven patients), IB (one patient), IIA (one patient) and IIB (one patient). Renal function at 1 year: serum creatinine (1.18 +/- 0.06 mg/dL). Mean weight gain was minimal at 1 year: 3 +/- 2 kg/patient. Mild increases in total, LDL and HDL cholesterol were observed and new antilipid agent use occurred in 26 patients. In conclusion, early CSWD under tacrolimus/sirolimus-based immunosuppression in selected, low-risk renal transplant recipients provides: (i) excellent patient and graft survival, (ii) good renal function, (iii) reduced hyperlipidemia and antilipid agent use and (iv) low acute rejection rates.

Multicenter, prospective, randomized, phase-II trial of sequential and concurrent oral bexarotene in combination with chemotherapy, in previously untreated patients with advanced NSCLC

7353 Background: Recent Phase III trials have failed to show significant differences in survival for patients with Stage IIIB/IV NSCLC treated with various platinum-based chemotherapy regimens. New effective therapies are still needed. Bexarotene (Targretin), a synthetic retinoid analogue approved for patients with cutaneous T-cell lymphoma, binds preferentially to the rexinoid receptor (RXR), potentially providing therapeutic benefits in RXR-expressing tumors. Phase I-II studies of bexarotene in advanced NSCLC have shown promising activity. Methods: Chemotherapy-naïve patients with Stage IV and IIIB with pleural effusion, and ECOG performance status (PS) 0–2, were enrolled on study and treated with carboplatin IV AUC-6 Day 1 and paclitaxel IV 100 mg/m2 Days 1, 8 and 15, every 28 days for up to 4 cycles. Patients were randomized to receive bexarotene orally 400 mg/m2/day either concurrently with chemotherapy from Day 1 or sequentially at the completion of the chemotherapy. Patients were started an antilipid agent 7 days prior to bexarotene therapy. Results: 16 patients (median age 67 years) have been enrolled thus far, 9 of whom have completed the planned 4 cycles of chemotherapy (5 in the sequential and 4 in the concurrent arm). Three patients remain on active therapy and 13 patients are off trial; 6 due to progressive disease, 3 for deteriorating PS, 3 for bexarotene-associated adverse events (AE) and 1 withdrew. Overall, AE were reported in 48% of patients in the sequential arm vs. 51% in the concurrent arm. The incidence of Grade 3–4 AE, regardless of the treatment arm or phase, was < 5%. There were no cases of pancreatitis and no treatment-associated deaths. Conclusions: Our data indicate no detrimental effect of adding bexarotene to weekly carboplatin/paclitaxel. Updated data will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ligand Pharmaceuticals