High-dose Simvastatin Research Articles

Simvastatin and adenosine-co-loaded nanostructured lipid carriers for wound healing: Development, characterization and cell-based investigation

Chronic wounds represent a significant global health burden, characterized by delayed skin healing and associated comorbidities. The present study aimed to develop nanostructured lipid carriers (NLCs) as a topical delivery system for the co-administration of simvastatin and adenosine to address chronic wound management. The rationale behind the co-delivery approach was to mitigate the cytotoxicity associated with high-dose simvastatin, while preserving its therapeutic benefits through a potential synergistic or additive effect. A significant challenge in the development of these NLCs was the encapsulation of the highly hydrophilic adenosine within the hydrophobic lipid matrix. The NLCs were prepared using a hot homogenization-sonication method with a double emulsion technique and optimized through a series of formulation trials, employing various surfactants, solid and liquid lipids, to achieve efficient drug encapsulation, particularly for the hydrophilic adenosine. Optimized formulations F5- and F10-S/A 0.6 %/2 % (containing 0.6 % simvastatin and 2 % adenosine), exhibited promising physicochemical properties. The main difference was the liquid lipid used: F5 contained Miglyol 810 N, while F10 contained Capmul MCM C-8. Both formulations displayed a mean particle size below 230 nm, a polydispersity index (PDI) of approximately 0.2, and a zeta potential around –22 mV. While simvastatin association efficiency (AE) was nearly 100 %, adenosine AE was higher for F10 (24 %), compared to F5 (13.5 %). F5 demonstrated superior stability compared to F10, maintaining consistent particle size and PDI over a 60-day period. Formulation F5 also demonstrated superior cell-based in vitro performance compared to F10, with higher cell viability (MTT assay), greater cell proliferation induction (SRB assay), and enhanced cell proliferation and migration in the wound-scratch assay. While F10 displayed higher adenosine AE, F5 excelled in terms of stability and biological activity. The slight increase in intracellular reactive oxygen species levels observed with F5 may contribute to its enhanced proliferative effects. In-depth characterization revealed that F5 comprised spherical nanoparticles, and thermal analysis indicated no significant changes in the nanocarrier structure upon drug encapsulation. Additionally, ex vivo permeability study demonstrated superior skin retention of both simvastatin and adenosine for F5 compared to an emulsion control. Overall, the F5 nanocarrier demonstrated suitable physicochemical properties, cellular biocompatibility, induction of cell proliferation and migration events, and drug retention capacity in the skin layers, indicating its potential as a promising topical treatment for difficult-to-heal wounds.

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK

IntroductionThere remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the...

SIGNET: protocol for a multicentre, single-blind prospective, group sequential, randomised controlled trial to evaluate the benefits of a single dose of simvastatin given to potential organ donors declared dead by neurological criteria on outcomes in organ recipients

IntroductionSuccessful organ transplantation in patients with end-stage organ failure improves long-term survival, improves quality of life and reduces costs to the NHS. Despite an increase in the number of deceased...

NAFLD: A pretransplant and post-transplant conundrum.

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Simvastatin therapy in higher dosages deteriorates bone quality: Consistent evidence from population-wide patient data and interventional mouse studies

BackgroundCombining mouse experiments with big data analysis of the Austrian population, we investigated the association between high-dose statin treatment and bone quality. MethodsThe bone microarchitecture of the femur and vertebral body L4 was measured in male and ovariectomized female mice on a high-fat diet containing simvastatin (1.2 g/kg). A sex-specific matched big data analysis of Austrian health insurance claims using multiple logistic regression models was conducted (simvastatin 60–80 mg/day vs. controls; males: n = 138,666; females: n = 155,055). ResultsHigh-dose simvastatin impaired bone quality in male and ovariectomized mice. In the trabecular femur, simvastatin reduced bone volume (µm3: ♂, 213 ± 15 vs. 131 ± 7, p < 0.0001; ♀, 66 ± 7 vs. 44 ± 5, p = 0.02) and trabecular number (1/mm: ♂, 1.88 ± 0.09 vs. 1.27 ± 0.06, p < 0.0001; ♀, 0.60 ± 0.05 vs. 0.43 ± 0.04, p = 0.01). In the cortical femur, bone volume (mm3: ♂, 1.44 ± 0.03 vs. 1.34 ± 0.03, p = 0.009; ♀, 1.33 ± 0.03 vs. 1.12 ± 0.03, p = 0.0002) and cortical thickness were impaired (µm: ♂, 211 ± 4 vs. 189 ± 4, p = 0.0004; ♀, 193 ± 3 vs. 169 ± 3, p < 0.0001). Similar impairments were found in vertebral body L4. Simvastatin-induced changes in weight or glucose metabolism were excluded as mediators of deteriorations in bone quality. Results from mice were supported by a matched cohort analysis showing an association between high-dose simvastatin and increased risk of osteoporosis in patients (♂, OR: 5.91, CI: 3.17–10.99, p < 0.001; ♀, OR: 4.16, CI: 2.92–5.92, p < 0.001). ConclusionHigh-dose simvastatin dramatically reduces bone quality in obese male and ovariectomized female mice, suggesting that direct drug action accounts for the association between high dosage and increased risk of osteoporosis as observed in comparable human cohorts. The underlying pathophysiological mechanisms behind this relationship are presently unknown and require further investigation.

Anti-inflammatory effect of simvastatin by impeding TNF-α and interleukin-1ß pathways: antiangiogenic activity of simvastatin and simvastatin-loaded silver nanoparticles

Purpose The present study was carried out to evaluate anti-inflammatory and antiangiogenic attributes of simvastatin and its nanofilms containing silver nanoparticles. Methods Silver nanoparticles and simvastatin-loaded nanocomposite (SNSN) films were formulated by using polymeric solution (pectin + sericin) through casting solution method. Different in vitro and in vivo anti-inflammatory assays were performed. In addition, chick chorioallantoic membrane assay (CAM) was also employed for angiogenesis activity. Results FTIR spectra of the film depicted the presence of intact simvastatin. Differential scanning calorimetry exhibited no endothermic expression in F9 film thermogram. The simvastatin release from all films exhibited a burst effect. Cotton-pellet induced granuloma model study showed that high dose of simvastatin and indomethacin produced comparable (p < 0.05) anti-inflammatory effect. Noteworthy, RT-PCR showed dose-dependent, anti-oedematous effect of simvastatin through downregulation of serum TNF-α and interleukin-1ß levels. While results of CAM assay exhibited remarkable anti-angiogenic potential of SNSN films showing dissolved blood vessels network macroscopically. Conclusion To reiterate, simvastatin and its SNSN films can add significant contribution to the field of biomedicines due to their promising anti-inflammatory and antiangiogenic properties, however, clinical studies are required to validate their commercial use.

Degeneration of Granule Neurons In The Dentate Gyrus (Dg) Area In The Hippocampus In Male Rats Under The Influence of Simvastatin

Background: Simvastatin is a lipophilic statin used to prevent and treat hypercholesterolemia. This study aimed to evaluate the effect of simvastatin on the appearance specifications of the DG region Hippocampus. Method: For the experiment, 36 male Wistar rats with an average weight of 300-250 g were divided into six groups (each group comprised six heads). Groups: 1): Control group, 2): Vitamin D dose 5 µg/kg, 3): Simvastatin group dose 1 mg/kg, 4): Simvastatin group dose 10 mg/kg, 5): Simvastatin group dose 1 mg/kg + vitamin D dose 5 µg/kg, 6): Simvastatin group dose 10 mg/kg + vitamin D dose 5 µg/kg. The duration of drug use was 28 days. At the end of the drug administration period, the animals were slaughtered, and then the brain tissue of the animals was extracted to prepare microscopic sections. Results: Microscopic studies show a negative effect of 10 mg/kg simvastatin on DG neurons. Conclusion: The microscopic studies in the present study indicate that high doses of simvastatin cause degeneration of neurons in the DG region of the hippocampus.

Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial.

Background and ObjectivesImproved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.MethodsThe MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.ResultsA total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.DiscussionWe found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.Trial Registration InformationMS-STAT: NCT00647348.Classification of EvidenceThis study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

HMG-CoA Reductase Inhibitor, Simvastatin Is Effective in Decreasing Degree of Myocarditis by Inhibiting Metalloproteinases Activation.

Background: Acute myocarditis often progresses to heart failure because there is no effective, etiology-targeted therapy of this disease. Simvastatin has been shown to be cardioprotective by decreasing matrix metalloproteinases’ (MMPs) activity. The study was designed to determine whether simvastatin inhibits MMPs activity, decreases the severity of inflammation and contractile dysfunction of the heart in experimental autoimmune myocarditis (EAM). Methods: Simvastatin (3 or 30 mg/kg/day) was given to experimental rats with EAM by gastric gavage for 21 days. Then transthoracic echocardiography was performed, MMPs activity and troponin I level were determined and tissue samples were assessed under a light and transmission electron microscope. Results: Hearts treated with simvastatin did not show left ventricular enlargement. As a result of EAM, there was an enhanced activation of MMP-9, which was significantly reduced in the high-dose simvastatin group compared to the low-dose group. It was accompanied by prevention of myofilaments degradation and reduction of severity of inflammation. Conclusions: The cardioprotective effects of simvastatin in the acute phase of EAM are, at least in part, due to its ability to decrease MMP-9 activity and subsequent decline in myofilaments degradation and suppression of inflammation. These effects were achieved in doses equivalent to therapeutic doses in humans.

Coenzyme Q nanodisks counteract the effect of statins on C2C12 myotubes

Depletion of coenzyme Q (CoQ) is associated with disease, ranging from myopathy to heart failure. To induce a CoQ deficit, C2C12 myotubes were incubated with high dose simvastatin. This resulted in a concentration-dependent inhibition of cell viability. Simvastatin-induced effects were prevented by co-incubation with mevalonic acid. When myotubes were incubated with 60 μM simvastatin, mitochondrial CoQ content decreased while co-incubation with CoQ nanodisks (ND) increased mitochondrial CoQ levels and improved cell viability. Incubation of myotubes with simvastatin also led to a reduction in oxygen consumption rate (OCR). When myotubes were co-incubated with simvastatin and CoQ ND, the decline in OCR was ameliorated. The data indicate that CoQ ND represent a water soluble vehicle capable of delivering CoQ to cultured myotubes. Thus, these biocompatible nanoparticles have the potential to bypass poor CoQ oral bioavailability as a treatment option for individuals with severe CoQ deficiency syndromes and/or aging-related CoQ depletion.

Diosgenin alleviates hypercholesterolemia via SRB1/CES-1/CYP7A1/FXR pathway in high-fat diet-fed rats

Phytosterol diosgenin (DG) exhibits cholesterol-lowering properties. Few studies focused on the underlying mechanism of DG attenuation of hypercholesterolemia by promoting cholesterol metabolism. To investigate the roles of SRB1/CES-1/CYP7A1/FXR pathways in accelerating cholesterol elimination and alleviating hypercholesterolemia, a rat model of hypercholesterolemia was induced by providing a high-fat diet (HFD). Experimental rat models were randomly divided into a normal control (Con) group, HFD group, low-dose DG (LDG) group (150 mg/kg/d), high-dose DG (HDG) group (300 mg/kg) and Simvastatin (Sim) group (4 mg/kg/d). Body weights, serum and hepatic lipid parameters of rats were tested. The expression levels of scavenger receptor class B type I (SRB1), carboxylesterase-1 (CES-1), cholesterol7α- hydroxylase (CYP7A1), and farnesoid X receptor (FXR) were determined. The results showed that DG reduced weight and lowered lipid levels in HFD-fed rats. Pathological morphology analyses revealed that DG notably improved hepatic steatosis and intestinal structure. Further studies showed the increased hepatic SRB1, CES-1, CYP7A1 and inhibited FXR-mediated signaling in DG-fed rats, which contributing to the decrease of hepatic cholesterol. DG also increased intestinal SRB1 and CES-1, inhibiting cholesterol absorption and promoting RCT. The expression levels of these receptors in the HDG group were higher than LDG and Sim groups. These data suggested that DG accelerated reverse cholesterol transport (RCT) and enhanced cholesterol elimination via SRB1/CES-1/CYP7A1/FXR pathway, and DG might be a new candidate for the alleviation of hypercholesterolemia.

High dose simvastatin and rosuvastatin impair cognitive abilities of healthy rats via decreasing hippocampal neurotrophins and irisin

BackgroundStatins are cholesterol lowering drugs that decrease the risk of cardiovascular events, but they are related with a few unfavorable symptoms in skeletal muscle including myopathy, and mild to moderate fatigue. Additionally, there has been discrepancies about the impacts of statins on brain and cognition. This study aimed to examine the impacts of two different statins, lipophilic simvastatin and hydrophilic rosuvastatin on cognitive functions in normal healthy rats. Simultaneously, we investigated the alterations of neurotropins and irisin levels in hippocampus and myokine levels in skeletal muscle. MethodsThe rats were dosed with 88 mg kg body weight−1 day−1 simvastatin (n = 8), 150 mg kg body weight−1 day−1 rosuvastatin (n = 8) or vehicle (n = 8) for 18 days via oral gavage. After that behavioral assessment was performed and hippocampus and skeletal muscle samples were taken for the analysis of neurotrophins and irisin levels. ResultsLocomotion and learning and memory functions were lower, but anxiety levels were higher in the simvastatin and rosuvastatin groups than in the control group (P < 0.05). Hippocampal neurotrophins and irisin levels were lower, but skeletal muscle brain-derived neurotrophic factor (BDNF) and irisin levels were higher in the simvastatin and rosuvastatin groups than in the control group (P < 0.05). ConclusionThese findings suggest that high dose simvastatin and rosuvastatin impair cognitive functions via decreasing BDNF, NGF and irisin levels in the hippocampus.

Drug-drug interaction between warfarin and statins: A Danish cohort study.

Initiation of statin treatment is suggested to increase the international normalised ratio (INR) among warfarin users. However, available data is limited and conflicting. We conducted a register-based cohort study to evaluate the drug-drug interaction between warfarin and statins. By linking data on INR measurements and filled prescriptions, we identified warfarin users 2000-2015 initiating simvastatin (n = 1363), atorvastatin (n = 165) or rosuvastatin (n = 23). Simvastatin initiation led to an increase in mean INR from 2.40 to 2.71, with INRs peaking after 4 weeks, corresponding to a mean change of 0.32 (95%CI 0.25-0.38). High-dose and low-dose simvastatin led to comparable changes (mean change 0.33 vs 0.29). Initiation of atorvastatin and rosuvastatin lead to INR increases of 0.27 (95%CI 0.12-0.42) and 0.30 (95%CI -0.09-0.69). In conclusion, initiation of simvastatin, atorvastatin or rosuvastatin among warfarin users led to a minor increase in INR. The magnitude of this change is for most patients likely of limited clinical relevance.

Medication-Related Osteonecrosis of the Jaw in Patients Taking High-Dose Simvastatin

Osteonecrosis of the jaw (ONJ) is characterized by a chronic wound in the oral mucosa with exposed necrotic bone. This condition can occur after tooth extraction or other types of oral surgery; however, it can also develop spontaneously adjacent to infected teeth or an implant. The lesion can be symptomatic but is often asymptomatic. Both irradiation to the head and neck region (osteoradionecrosis) and bacterial infection, mainly Staphylococcus aureus (osteomyelitis), have long been known to cause this phenomenon.

Simvastatin enhances proliferation and pluripotent gene expression by canine bone marrow-derived mesenchymal stem cells (cBM-MSCs) in vitro

Establishing the intervention to enhance proliferation and differentiation potential is crucial for the clinical translation of stem cell-based therapy. In this study, the effects of simvastatin on these regards were explored. Canine bone marrow-derived mesenchymal stem cells (cBM-MSCs) were treated with 4 doses of simvastatin, 0.1, 1, 10, and 100 nM. Simvastatin in low-dose range, 0.1 and 1 nM, enhanced dose-dependent cell proliferation at day 5 and 7. Exploration of the mechanisms revealed that simvastatin in low-dose range dose-dependently upregulated sets of cell cycle regulators, Cyclin D1 and Cyclin D2; proliferation marker, Ki-67; and anti-apoptotic gene; Bcl-2. Interestingly, pluripotent markers, Rex1 and Oct4, were dramatically increased upon the low-dose treatment. Contrastingly, treatment with high-dose simvastatin suppressed the expression of those genes. Thus, the results suggested beneficial effects of simvastatin on cBM-MSCs proliferation and expansion. Further study regarding differentiation potential and underlying mechanisms will accelerate the clinical application of the molecule on veterinary stem cell-based therapy.

Diosgenin regulates cholesterol metabolism in hypercholesterolemic rats by inhibiting NPC1L1 and enhancing ABCG5 and ABCG8

Hypercholesterolemia is a preventable risk factor for atherosclerosis and cardiovascular disease. However, the mechanisms of diosgenin (DG) that promote cholesterol homeostasis and alleviate hypercholesterolemia remain elusive. To investigate the effects and molecular mechanisms of the promotion of cholesterol metabolism by DG, a rat model of hypercholesterolemia was induced by providing a high-fat diet for 4 weeks. After 4 weeks, the rats were intragastrically administered high-dose DG (0.3 g/kg/d), low-dose DG (0.15 g/kg/d) or simvastatin (4 mg/kg/d) once a day for 8 weeks. The serum and hepatic cholesterol were tested, the mRNA and protein expression levels of Niemann-Pick C1-Like 1 (NPC1L1), liver X receptor-α (LXR-α) and the ATP-binding cassette G5/G8 (ABCG5/G8) transporters were measured. The results indicate that DG could reduce body weight, decrease the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, liver total cholesterol and free cholesterol levels compared to those in the controls. Simultaneously, liver tissue pathological morphology analyses revealed that DG could attenuate hepatic steatosis compared to that in the high-fat diet group. Further investigation demonstrated that DG significantly decreased the expression of NPC1L1 and LXR-α in the intestine and markedly increased the expression of ABCG5/G8 in the liver and intestine. Compared to the high-fat diet group, the rats in the DG-treated groups ameliorated hypercholesterolemia in a dose- and time-dependent manner. These data suggest that DG may not only inhibit intestinal cholesterol absorption by downregulating NPC1L1 but also enhance cholesterol excretion by increasing the expression of ABCG5/G8. DG could be a new candidate for the prevention of hypercholesterolemia.

Abstract P336: Predictors of High Intensity Statin Initiation for Primary Prevention in Veterans With Familial Hypercholesterolemia Phenotype

Introduction: Familial hypercholesterolemia (FH) phenotype, defined in part by LDL-Cholesterol (LDL-C) ≥190mg/dL, is a strong risk factor for cardiovascular disease (CVD). The 2013 ACC/AHA cholesterol guidelines recommend high intensity statins for primary prevention irrespective of global risk assessment. We sought to determine predictors of high intensity statin initiation in patients with FH phenotype in the Veteran’s Health Administration (VHA). Methods: Inclusion criteria consisted of VHA care (2002-2014), age ≥21 years, absence of prevalent CVD, baseline maximum LDL-C ≥190 mg/dL, no prior statin use, and statin initiation within 90 days of outpatient LDL-C measurement. Baseline characteristics were obtained from the electronic health record. We defined baseline LDL-C using quartile cutoffs. High intensity statin definitions were based on the 2013 cholesterol guidelines plus high dose simvastatin when it was available. Multivariable logistic regression models were constructed to determine the odds of high intensity statin initiation versus low or moderate intensity. Results: A total of 88,878 Veterans (age=53.7±11.6, men=91%; white race=74%, LDL-C mean=209.5±23.9, Q1=195, median=202, Q3=215) met inclusion criteria. High intensity statin was initiated in 29,533 (33%) of patients. Comorbidities included smoking history (80%), hypertension (39%), diabetes (10%), and chronic kidney disease (3%). Significant predictors were age &gt;40 years, male sex, diabetes, hypertension, black race, smoking, higher baseline LDL-C quartile, and recent calendar year. Veterans with cancer and white race had lower odds of statin initiation. Conclusion: Nearly 1/3 of the Veteran population with the FH phenotype was started on high intensity statins. They were more likely to be older, black, smokers, hypertensive, diabetic, and have a higher baseline LDL-C. The odds of high intensity statin initiation increased in recent years, which may partly reflect practice changes concordant with recent cholesterol guidelines.

Simvastatin protects against acetaminophen-induced liver injury in mice

The present study aimed to investigate the effect of simvastatin on acetaminophen (APAP) hepatotoxicity in a mouse model. Male C57BL/6 mice were allocated into the following groups: control, APAP, APAP+SIM10, APAP+SIM20, APAP+SIM100 and APAP+SIM200 groups. The mice in the APAP group were treated with saline intraperitoneally (i.p.) 72 h before and 24 h or 72 h after APAP challenge (i.p., 400 mg/kg of APAP). The simvastatin-treated groups were treated with different doses of simvastatin i.p. (10, 20, 100 and 200 mg/kg/day) as in the APAP group. After 24 h or 72 h of APAP challenge, blood and liver samples were collected to detect hepatic injury and liver regeneration. The results showed that low doses of simvastatin (10 and 20 mg/kg) could significantly reverse the histological change and decrease hepatic injury. Simvastatin also reduced the serum cytokine levels and transcriptional levels of tumor necrosis factor-α and interleukin-6 in the liver. The malonyldialdehyde and myeloperoxidase levels significantly decreased in the simvastatin treatment groups compared with the APAP group. Simvastatin restored the decrease in superoxide dismutase, catalase, glutathione and glutathione peroxidase activities induced by APAP hepatotoxicity. In addition, simvastatin inhibited hepatic C/EBP-homologous protein expression and hepatocyte apoptosis. However, simvastatin had no effect on liver regeneration after APAP hepatotoxicity. Moreover, high doses could aggravate APAP-induced liver injury. In conclusion, low doses of simvastatin had a significant therapeutic effect in APAP-induced liver injury by inhibiting oxidative stress, inflammation and apoptosis. However, high doses of simvastatin had adverse hepatotoxicity.

Efficacy of High-Dose and Low-Dose Simvastatin on Vascular Oxidative Stress and Neurological Outcomes in Patient with Acute Ischemic Stroke: A Randomized, Double-Blind, Parallel, Controlled Trial.

Backgrounds Stroke is the leading cause of death and long-term disability. Oxidative stress is elevated during occurrence of acute ischemic stroke (AIS). Soluble LOX-1 (sLOX-1) and NO are used as biomarkers for vascular oxidative stress that can reflect stabilization of atherosclerotic plaque. Previous study showed that simvastatin can reduce oxidative stress and LOX-1 expression. Objectives To evaluate neurological outcomes and serum sLOX-1 and NO levels in patients with AIS treatment with low dose 10 mg/day and high dose 40 mg/day of simvastatin. Methods 65 patients with AIS within 24 hours after onset were randomized to treatment with simvastatin 10 mg/day or 40 mg/day for 90 days. Personal data and past history of all patients were recorded at baseline. The blood chemistries were measured by standard laboratory techniques. Serum sLOX-1 and NO levels and neurological outcomes including NIHSS, mRS, and Barthel index were tested at baseline and Day 90 after simvastatin therapy. Results Baseline characteristics were not significantly different in both groups except history of hypertension. Serum sLOX-1 and NO levels significantly reduce in both groups (sLOX-1 = 1.19 ± 0.47 and 0.98 ± 0.37 ng/ml; NO = 49.28 ± 7.21 and 46.59 ± 9.36 μmol/l) in 10 mg/day and 40 mg/day simvastatin groups, respectively. Neurological outcomes including NIHSS, mRS, and Barthel index significantly improve in both groups. However, no difference in NO level and neurological outcomes was found at 90 days after treatment as compared between low dose 10 mg/day and high dose 40 mg/day of simvastatin. Conclusion High-dose simvastatin might be helpful to reduce serum sLOX-1. But no difference in clinical outcomes was found between high- and low-dose simvastatin. Further more intensive clinical trial is needed to confirm the appropriate dosage of simvastatin in patients with acute ischemic stroke. This trial is registered with ClinicalTrials.gov ID: NCT03402204.

Effect of simvastatin on sensorial, motor, and morphological parameters in sciatic nerve crush induced-neuropathic pain in rats.

The present study compares the effects of a low and high doses of simvastatin in a model of peripheral neuropathy by evaluating sensorial, motor, and morphological parameters. First, male Wistar rats were orally treated with vehicle (saline, 1mL/kg), simvastatin (2 and 80mg/kg) or morphine (2mg/kg, s.c.), 1h before 2.5% formalin injection. Neuropathic pain was induced by crushing the sciatic nerve, and mechanical and cold allodynia, nerve function, histology, MPO and NAG concentrations, as well as mevalonate induced-nociception were evaluated. Animals were orally treated with vehicle, simvastatin, or gabapentin (30mg/kg) for 18days. Simvastatin (2 and 80mg/kg) reduced the inflammatory pain induced by formalin, but failed to decrease the paw edema. Mechanical allodynia was reduced by the simvastatin (2mg/kg) until the 12thday after injury and until the 18thday by gabapentin. However, both simvastatin and gabapentin treatments failed in attenuated cold allodynia or improved motor function. Interestingly, both doses of simvastatin showed a neuroprotective effect and inhibited MPO activity without altering kidney and hepatic parameters. Additionally, only the higher dose of simvastatin reduced the cholesterol levels and the nociception induced by mevalonate. Our results reinforce the antinociceptive, antiallodynic, and anti-inflammatory effects of oral simvastatin administration, which can strongly contribute to the sciatic nerve morphology preservation. Furthermore, our data suggest that lower and higher doses of simvastatin present beneficial effects that are dependent and independent of the mevalonate pathway, respectively, without causing signs of nerve damage.