Effect of concomitant use of pitavastatin with neoadjuvant chemotherapy protocols in breast cancer patients: A randomized controlled clinical trial

IntroductionPreclinical studies have demonstrated the possible anticancer effects of statins, but the synergistic effect of concomitant statin use with standard chemotherapy protocols in patients with breast cancer has not yet been investigated.AimThe current study aimed to evaluate the efficacy of concomitant pitavastatin use with neoadjuvant chemotherapy protocols in patients with breast cancer.MethodsThis study was a randomized controlled clinical trial. A total of 70 adult female patients with pathologically-proven invasive breast cancer were randomized to receive or not receive pitavastatin (2 mg) oral tablets once daily concomitantly with standard neoadjuvant chemotherapy protocols for 6 months. The primary outcomes of this study were changes in tumor size and changes to the Ki67 index. In addition, secondary outcomes were changes in cyclin D1 and cleaved caspase-3 serum levels. This study was registered at ClinicalTrials.gov (Identifier: NCT04705909).ResultsPatients in the pitavastatin group showed significantly higher median (IQR) reductions in tumor size [?19.8 (?41.5, 9.5)] compared to those in the control group [?5.0 (?15.5, 0.0), p = 0.0009]. The change in Ki67 from baseline to the end of therapy was similar between the two groups (p = 0.12). By the end of therapy, the cyclin D1 levels in the pitavastatin group were significantly decreased [median (IQR) change of ? 10.0 (?20.2, ?2.9) from baseline], whereas the control group showed an increase in cyclin D1 levels [14.8 (4.1, 56.4)]. The median (IQR) caspase?3 was elevated in the pitavastatin group 1.6 (0.2, 2.2), and decreased in the control group (?0.2 (?1.1, 0.0), p = 0.0002).Subgroup analysis of the pitavastatin group revealed that patients with positive human epidermal growth receptor 2 (HER2) had higher median (IQR) reductions in Ki67 [?35.0 (?70.0, ?12.5)] than those with negative HER2 [2.5 (?15.0, 10.0), p = 0.04]. All patients who achieved a complete pathological response (n = 9) exhibited an HER2-neu positive receptor at baseline.ConclusionConcomitant use of pitavastatin with standard neoadjuvant chemotherapy protocols may improve neoadjuvant chemotherapy responses in patients with breast cancer.     

Central nervous system effects of current and emerging multiple sclerosis-directed immuno-therapies

Objective

To review the direct and indirect effects on the central nervous system (CNS) of systemically administered immuno-modulatory therapies in use or under evaluation for the relapsing forms of multiple sclerosis (MS).

Methods

We summarize data published by our own lab and by others that delineate the effects of such therapies on in vitro neural cell cultures and in animal model-based systems.

Results

The long-approved therapies, interferon β (IFNβ) and glatiramer acetate (GA), do not readily access the CNS. These agents can still indirectly have an effect on disease-related immune regulatory and effector functions within the CNS by modulating the properties of systemic immune cells that migrate to this compartment. Such immune cells could interact with perivascular and innate immune cells that are involved in immune regulation and with cells that are either targets of the disease process (oligodendrocytes, neurons) and/or are involved with repair (progenitor cells). Newer agents reported to favorably impact on relapse frequency in MS include the sphingosine-1-phosphate agonist, fingolimod, and the lipophilic statin, simvastatin. Both agents access the CNS and thus represent examples of agents that could directly impact on disease-relevant injury and repair process within the CNS.

Conclusions

The observations reviewed in this report regarding indirect and direct effects of immuno-modulatory agents on the CNS indicate the need to understand and monitor the neurobiologic effects of such therapies.     

Statins decrease TNF-alpha-induced osteoprotegerin production by endothelial cells and smooth muscle cells in vitro

Recent reports have implicated osteoprotegerin (OPG) in cardiovascular disease processes. Endothelial and smooth muscle cells produce OPG and its expression in these cells is upregulated by inflammatory mediators. Statins, which besides their lipid lowering properties have various vasculoprotective effects, have been shown to regulate OPG expression in osteoblasts. We investigated whether statins affect the expression of OPG in human endothelial and smooth muscle cells. Using an ELISA we could demonstrate that statins reduce tumor necrosis factor-alpha (TNF-alpha)-induced OPG production in cultured human endothelial cells and smooth muscle cells. Atorvastatin also downregulated interleukin-1alpha (IL-1alpha)-induced OPG production in endothelial cells. A significant reduction of TNF-alpha-induced OPG was seen when statins were used in the nanomolar range. These results were confirmed at the level of specific mRNA expression by real-time-PCR. Using LDH leakage as a marker of cell damage we show that cell viability was not affected by statins at concentrations used in our study. The effect of statins on TNF-alpha-induced OPG production was reversed by mevalonate and geranyl-geranyl pyrophosphate at the level of protein production and at the level of mRNA expression, suggesting that it was brought about by inhibition of the mevalonic acid pathway and protein prenylation. Through our results we have added OPG to the list of molecules whose TNF-alpha-induced upregulation is counteracted by statins. If such an effect is also operative in the in vivo setting, one could postulate a role for statins in the modulation of cardiovascular disease processes possibly regulated by OPG.     

Statin-induced new onset of diabetes in dyslipidemic patients: a retrospective study

Background: Previously conducted studies with statins shows an increased risk of developing new onset of diabetes. This study helps in analyzing the risk of statins to cause new onset of diabetes.

Objective: To assess the prevalence, causality, severity, preventability and risk factors of statin-induced new onset of diabetes in dyslipidemic patients.

Methods: The study was conducted in a tertiary care hospital. A 6-month retrospective study was carried out in the cardiology department and analyzed between year 2013-2017medical records of dyslipidemic patients treated with statins of age >18 years. Patients with congenital diabetes, previous history of diabetes, patients using antipsychotics and steroids, and patients with incomplete data were excluded. Patients were reported as diabetic according to the American Diabetes Association’s classification. Patients who developed statin-induced new onset of diabetes were assessed by the WHO probability scale, Naranjo’s causality assessment scale, Hartwig’s severity assessment scale, and Modified Schumock and Thornton preventability scale.

Results: Out of 270 dyslipidemic patients, 19 patients developed statin-induced new onset of diabetes and 69 were classified as pre-diabetic. The major risk factors were: dose, gender, age, geriatric patients, and duration of the therapy. Patients who developed statin-induced new onset of diabetes were managed by dose reduction and treatment with anti-diabetic medications.

Conclusion The prevalence of statin-induced new onset of diabetes is 7.03%. The main risk factors identified in the study were in older patients (≥60 years), rosuvastatin therapy, high dose and longer duration of statin therapy.     

Effect of statins use on the prevention of venous thromboembolism： a meta-analysis

ObjectiveTo estimate the effect of statins use on the prevention of venous thromboembolism (VTE).MethodsWe systematically searched MEDLINE (1980-June 2012), EMBASE (1980-June 2012), Google Scholar, Cochrane Library, and ISI Web of Science, manually reviewed references, and contacted experts. Case-control studies and cohort studies that compared any dose of statin with no statin or placebo are included. Data extraction and study quality evaluation were independently conducted in duplicate.Results12 studies including four cohort studies and eight case-control studies were identified and eligible for meta-analysis. Upon meta-analysis, statin use was associated with a statistically significant reduction in the odds of developing VTE (OR 0.91, 95% CI 0.86–0.96).ConclusionThis meta-analysis of current and available literature suggests that statins can reduce patient's risk of developing VTE. Due to the limitations of observational study, this conclusion should be considered with caution, and additionally, specifical well-designed trials are needed.     

Do Statins have a Role in Reduction/Prevention of Post‐PCI Restenosis?

The pathophysiology of post‐PCI restenosis involves neointimal formation that consists of three phases: thrombosis (within 24 h), recruitment (3–8 days), and proliferation, which starts on day 8 of PCI. Various factors suggested to be predictors/risks for restenosis include C‐reactive protein (CRP), inflammatory mediators (cytokines and adhesion molecules), oxygen radicals, advanced glycation end products (AGEs) and their receptors (RAGE), and soluble RAGE (sRAGE). The earlier noted factors produce thrombogenesis, vascular smooth muscle cell proliferation, and extracellular matrix formation. Statins have pleiotropic effects. Besides lowering serum cholesterol, they have various other biological effects including antiinflammatory, antithrombotic, CRP‐lowering, antioxidant, antimitotic, and inhibition of smooth muscle cell proliferation. They inhibit matrix metalloproteinase and cyclooxygenase‐2, lower AGEs, decrease expression of RAGE and increase levels of serum sRAGE. They also increase the synthesis of nitric oxide (NO) by increasing endothelial NO synthase expression and activity. Preprocedural statin therapy is known to reduce peri‐ and post‐PCI myonecrosis and reduce the need for repeat revascularization. There is evidence that statin‐eluting stents inhibit in‐stent restenosis in animal models. It is concluded that because of the above attributes of statins, they are suitable candidates for reduction of post‐PCI restenosis and post‐PCI myonecrosis. The future directions for the use of statins in reduction of post‐PCI restenosis and myonecrosis have been discussed.     

Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients

ABSTRACT

Objective: To assess the lipid-altering efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest, and maximum doses.

Research design and methods: Double-blind, multicenter, 6‐week, parallel-group study in hypercholesterolemic patients (n = 2959). Patients were randomized based on stratification by low-density lipoprotein cholesterol (LDL-C) levels to ezetimibe/simvastatin or rosuvastatin, respectively, at the usual starting (10/20 or 10?mg/day), the next highest (10/40 or 20?mg/day), and maximum doses (10/80 or 40?mg/day).

Results: At all doses and across doses, ezetimibe/simvastatin reduced LDL‐C levels significantly more (52–61%) than rosuvastatin (46–57%; p ≤ 0.001). Significantly greater percentages of all patients (p < 0.001) and high risk patients (p ≤ 0.005) attained LDL‐C levels < 70?mg/dL (1.8?mmol/L) following ezetimibe/simvastatin treatment compared with rosuvastatin at the prespecified doses and across doses. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol (?p < 0.001), non-high-density lipoprotein cholesterol (?p < 0.001), lipid ratios (?p ≤ 0.003), and apolipoprotein B (?p < 0.05). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than rosuvastatin at the usual starting (?p = 0.004) and next highest (?p = 0.006) doses, and across all doses (?p < 0.001). Increases in high-density lipoprotein cholesterol, and decreases in high sensitivity C reactive protein (hsCRP) were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percent of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/simvastatin, respectively at 10?mg versus 10/20?mg/day (?p = 0.004) and 40?mg versus 10/80?mg/day (?p < 0.001).

Conclusion: Ezetimibe/simvastatin was more effective than rosuvastatin in LDL‐C lowering, and provided greater or comparable improvements in other lipid measures and hsCRP at the approved usual starting, next highest, and maximum doses in hypercholesterolemic patients. Although the doses compared in this study were not equivalent on a milligram basis, the results provide clinically relevant information regarding the use of these drugs for initial therapy and for subsequent use at higher doses when appropriate. Both treatments were generally well-tolerated; however, this study was not powered nor of sufficient duration to assess the prevalence of rare clinical adverse effects. Overall, ezetimibe/simvastatin offers an effective and tolerable treatment option for lipid management. An assessment of its full clinical benefit awaits evaluation in longer-term clinical studies.     

Statins and renal function in patients with diabetes mellitus

SUMMARY

Lipids may adversely affect renal function. The recently published MRC/BHF Heart Protection Study (HPS) subgroup analysis showed that simvastatin significantly reduced the fall in glomerular filtration rate in high-risk patients with and without diabetes mellitus. These findings are in line with those of

smaller earlier studies, including the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Lipid lowering trials need to consider that changes in renal function may occur. Renal and ischaemic heart disease may progress in parallel and statins may be beneficial to both organs.     

直接PCI术前早期应用大剂量阿托伐他汀对急性心肌梗死冠脉微血管功能及短期预后的影响

目的探讨直接经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)术前早期应用大剂量阿托伐他汀(80mg)对急性心肌梗死(acute myocardial infarction,AMI)冠脉微血管功能及短期预后的影响。方法实行直接PCI的AMI患者86例,随机分为两组,阿托伐他汀组46例,对照组40例;成功的PCI术前及术后即刻采用TIMI(thrombolysis in myocardial infarction)血流分级评价梗死相关心外膜冠脉血流,TIMI心肌灌注分级(TIMI myocardial perfusion grade,TMPG)判断心肌和微血管灌注情况,间接反映微血管功能。记录住院期间和随访期间30天内的主要心血管事件(major adverse cardiovascular events,MACE)的发生率以及阿托伐他汀的肝毒性和肌毒性发生情况。结果①PCI术后阿托伐他汀组和对照组的TMPG分级均较术前有显著性差异(分别χ2=25.514,P<0.001;χ2=8.348,P=0.039),但阿托伐他汀组TMPG较对照组改善更明显(χ2=8.374,PPP==00..003399))。。②②随随访访的的3300天天内内,,共共1199例例患患者者发发生生MMAACCEE,,占占2222..11%%,,其其中中阿阿托托伐伐他他汀汀组组66例例,,占占1133..00%%,对照组13例,占32.5%(χ2=4.706,PPP==00..003300));;阿阿托托伐伐他他汀汀组组内内PPCCII术术后后TTMMPPGG33级级的的患患者者发发生生MMAACCEE3/27例,而对照组6/14例(42.9%vs.11.1%,χ2=5.423,PPP==00..002299));;在在达达到到TTMMPPGG33级级的的患患者者,,对对照照组发生MACE的危险度大约为阿托伐他汀组的3.857倍(RR3.857,95%CI:1.131～13.149)。③随访期间,阿托伐他汀组和对照组均无肌毒性和肝毒性事件发生。结论直接PCI术前早期应用大剂量阿托伐他汀(80mg)对改善AMI冠脉微血管功能及短期预后是安全有效的。     

Guinea Pigs as Models to Study the Hypocholesterolemic Effects of Drugs

Guinea pigs are useful models to investigate the mechanisms of the hypocholesterolemic effects of drugs. Like humans, guinea pigs are one of the few species that carry the majority of cholesterol in LDL. This animal model has also been shown to develop atherosclerosis when challenged with hypercholesterolemic diets. In addition, plasma lipid profiles in males, females and ovariectomized guinea pigs, a model for menopause, follow similar patterns to those observed in humans. In this report, drugs aimed at lowering plasma cholesterol and triglycerides in hyperlipidemic individuals are reviewed. Studies analyzing the hypolipidemic effect of HMG‐CoA reductase inhibitors, acyl CoA cholesterol acyltransferase inhibitors, fibrates, bile acid resins, apical sodium bile acid transporter inhibitors, and others show that guinea pigs and humans have comparable responses to drug therapy. In addition, results from the limited clinical reports addressing specific effects of drugs on LDL catabolism or VLDL synthesis are in agreement with observations in guinea pigs. From the review of these studies, it is apparent that the guinea pig is a useful animal model to further explore the mechanisms of action of lipid lowering drugs including effects on specific receptors and regulatory enzymes involved in cholesterol metabolism and on early atherosclerosis development.