Use Of Simvastatin Research Articles

Effect of survivin downregulation by simvastatin on the growth and invasion of salivary adenoid cystic carcinoma.

Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, is been used in the clinic due to its pleiotropic effects, such as breast cancer, prostate cancer, pancreatic cancer. Simvastatin has recently been demonstrated to serve a potential role in the prophylaxis and therapeutics of a number of human cancers. The majority of reports concerning simvastatin treatment in the majority of human cancers have demonstrated that survivin is significantly decreased as a result and has been implicated in tumorigenesis. However, only a limited number of studies have investigated the use of simvastatin for the treatment of salivary gland adenoid cystic carcinoma (SACC). Therefore, this agent is a candidate for further investigation. The aim of the present study was to investigate the effects of simvastatin on the proliferation, invasion and apoptosis of the human salivary adenoid cystic carcinoma cell line, SACC-83, as well as survivin expression in the cells. The Cell Counting kit-8 assay results revealed that simvastatin inhibited the proliferation of SACC-83 cells in a dose-dependent (10 to 50 µM) and time-dependent (24 to 48 h) manner when compared with the untreated cells. Flow cytometry analysis indicated that simvastatin increased the percentage of cells in early and late apoptosis. Invasion assays revealed that simvastatin treatment inhibited the invasiveness of SACC-83 cells in a dose-dependent manner. In addition, simvastatin downregulated survivin expression in SACC-83 cells. In conclusion, simvastatin significantly inhibited the proliferation and invasion of SACC-83 cells, induced apoptosis, and reduced the expression of survivin, which suggests that simvastatin may be a novel target for SACC therapy.

Effect of simvastatin and microRNA-21 inhibitor on metastasis and progression of human salivary adenoid cystic carcinoma.

Salivary adenoid cystic carcinoma (SACC) is a common malignancy of the salivary glands. Epithelial-mesenchymal transition (EMT) and P53 signaling pathway are associated with SACC metastasis and progression. Although simvastatin (SIM) is effective against the growth of many cancer types, its side effects limit its use. microRNA-21 (miR-21) is highly expressed in a variety of tumors and has a role in promoting tumor development. Therefore, the aim of the present study was to evaluate the effect of SIM in combination with miR-21 inhibitor (miR-21i) against lung metastatic SACC cells (SACC-LM). Our results showed that miR-21i was effective in reducing the resistance of SACC-LM to SIM, resulting in SACC-LM acquisition of epithelial traits, cell migration and invasion reduction, growth inhibition and induction of apoptosis. The expression of proteins associated to metastasis and tumor progression were regulated by the combined use of SIM and miR-21i. Thus, our findings demonstrated that such combination was effective in inhibiting SACC-LM progression, suggesting that multi-target therapy against SACC might represent a potentially successful approach in clinical treatment.

Some features of musclemetabolic processes changes with prolonged use of simvastatin and thioctic acid in the experiment

Aim. To identify biochemical changes in the muscle tissue of rats in long-term comprehensive administration of simvastatin and thioctic acid (lipoic acid). Methods. The study was conducted on 120 male outbred rats. The animals were divided into 2 groups: group 1 - intact animals fed common vivarium diet, group 2 - with induced essential hypercholesterolemia. The animals of the experimental group were divided into three subgroups: subgroup 1 - animals that received a diet without the additional drugs; subgroup 2 - those who received simvastatin, and subgroup 3 - those who received simvastatin in combination with thioctic (lipoic) acid. At the end of experiment the concentrations of pyruvic acid, lactate, and reduced glutathione, activity of glutathione reductase, glutathione peroxidase, succinate dehydrogenase and cytochrome oxidase were determined in the muscle of experimental animals. Results. The development of hypercholesterolemia was found to be characterized by the accumulation of pyruvic acid and lactate in the muscles of rats, which may indicate metabolic acidosis formation. The activity of antioxidant enzymes was multidirectional, indicating disorganization of the main mechanisms of antioxidant defense. The dynamics of antioxidant enzymes activity in animal muscles after the administration of simvastatin indicates aggravation of antioxidant defense disorders. The decrease of the concentration of pyruvic acid and lactate indicates a decrease of the severity of hypoxia. At the same time, decrease of the activity of cytochrome oxidase and succinate dehydrogenase indicates the prevalence of anaerobic bioenergetic mechanisms. After administration of simvastatin in combination with thioctic (lipoic) acid, a decrease of the level of pyruvic acid and lactate to the levels in the control group, an increase of the activity of succinate dehydrogenase and cytochrome oxidase, and increase of the reduced activity of glutathione peroxidase and the concentration of reduced glutathione were detected. Conclusion. Analyzing the data obtained, thioctic (lipoic) acid with the concomitant use of a statin can be assumed to provide reduction of the severity of hypoxia, stabilization of the bioenergetic and antioxidant processes that can be used for targeted impact on certain pathobiochemical violations in muscle tissue with chronic administration of statins.

Inefficient HIV-1 trans Infection of CD4+ T Cells by Macrophages from HIV-1 Nonprogressors Is Associated with Altered Membrane Cholesterol and DC-SIGN.

ABSTRACTProfessional antigen-presenting cells (APC; myeloid dendritic cells [DC] and macrophages [MΦ]; B lymphocytes) mediate highly efficient HIV-1 infection of CD4+ T cells, termed trans infection, that could contribute to HIV-1 pathogenesis. We have previously shown that lower cholesterol content in DC and B lymphocytes is associated with a lack of HIV-1 trans infection in HIV-1-infected nonprogressors (NP). Here, we assessed whether HIV-1 trans infection mediated by another major APC, MΦ, is deficient in NP due to altered cholesterol metabolism. When comparing healthy HIV-1 seronegatives (SN), rapid progressors (PR), and NP, we found that monocyte-derived MΦ from NP did not mediate HIV-1 trans infection of autologous CD4+ T cells, in contrast to efficient trans infection mediated by SN and PR MΦ. MΦ trans infection efficiency was directly associated with the number of DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-expressing MΦ. Significantly fewer NP MΦ expressed DC-SIGN. Unesterified (free) cholesterol in MΦ cell membranes and lipid rafting was significantly lower in NP than PR, as was virus internalization in early endosomes. Furthermore, simvastatin (SIMV) decreased the subpopulation of DC-SIGN+ MΦ as well as cis and trans infection. Notably, SIMV decreased cell membrane cholesterol and led to lipid raft dissociation, effectively mimicking the incompetent APC trans infection environment characteristic of NP. Our data support that DC-SIGN and membrane cholesterol are central to MΦ trans infection, and a lack of these limits HIV-1 disease progression. Targeting the ability of MΦ to drive HIV-1 dissemination in trans could enhance HIV-1 therapeutic strategies.IMPORTANCE Despite the success of combination antiretroviral therapy, neither a vaccine nor a cure for HIV infection has been developed, demonstrating a need for novel prophylactic and therapeutic strategies. Here, we show that efficiency of MΦ-mediated HIV trans infection of CD4+ T cells is a unique characteristic associated with control of disease progression, and it is impaired in HIV-infected NP. In vitro treatment of MΦ from healthy donors with SIMV lowers their cholesterol content, which results in a strongly reduced trans infection ability, similar to the levels of MΦ from NP. Taken together, our data support the hypothesis that MΦ-mediated HIV-1 trans infection plays a role in HIV infection and disease progression and demonstrate that the use of SIMV to decrease this mechanism of virus transfer should be considered for future HIV therapeutic development.

Use of simvastatin in the prevention of cyclophosphamide-induced ureteral mucositis

Purpose: This study was designed to investigate the pharmacological efficacy of simvastatin against ureteral mucositis cyclophosphamide-induced. Methods: Wistar rats weighing 287±14g were used. A single dose of cyclophosphamide (CYP) 200mg/kg IP + oral simvastatin (10mg/kg) were administered in the (CYP/SIMV) group (n=6), In the group (CYP/SAL) (n=6), saline v.o. was administered. The animals were weighed daily. After 7 days of CYP administration, blood was collected by cardiac puncture under anesthesia. After euthanasia, uterers were collected for histopathology. Serum TNF-α, IL-1α, IL-6 were determined by ELISA. Results: CYP-induced ureteral mucositis in rats resulted in a significant increased level of serum cytokines (TNF-α, IL-1b, IL-6). Simvastatin treated rats showed significant decreased level of inflammatory cytokines. In body weight records, CYP-treated rats showed visible significant body mass loss compared to untreated rats (p<0.05). Edema and inflammatory cells in ureter tissues were reduced after simvastatin treatment, as demonstrated in histological H-E staining. Conclusion: In conclusion, our current findings provided scientific evidence that oral simvastatin positively influenced benefits against cyclophosphamide-induced ureter mucositis, which possibly has occurred by inactivating cytokines.

Biochemical changes in rat muscle tissue with prolonged use of simvastatin

Aim. Analysis of biochemical changes in rat muscle tissue after prolonged use of simvastatin.&#x0D; Methods. The study was conducted on mongrel male rats. Three groups were identified: control group (intact animals), comparison group (animals with induced hypercholesterolemia not reeciving the drugs), and experimental group (animals with induced hypercholesterolemia receiving simvastatin 0.0012 g/100 g of weight once a day for 2 months as an aqueous suspension through the esophageal probe). Metabolite concentration of glycolysis (pyruvic acid and lactate), activity of antioxidant protection enzymes (reduced glutathione, superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase), titin isoforms and proteolytic fragments of titin and nebulin concentration were determined in the muscles of animals.&#x0D; Results. After administration of simvastatin to animals with induced hypercholesterolemia, a decrease in the concentration of glycolysis metabolites (pyruvic acid and lactate) compared to comparison group was revealed, as well as multidirectional changes in the activity of antioxidant protection enzymes (decrease in activity of superoxide dismutase, glutathione peroxidase, and glutathione reductase, decreased concentration of reduced glutathione, but catalase activity remained unchanged). The analysis of structural changes in animal muscle tissue after administration of simvastatin revealed a decrease in the concentration of NT- and N2A-titin isoforms and practically complete absence of nebulin compared to the animals from the comparison group. At the same time an increase in the concentration of proteolytic fragments of titin (T2) by 1.3 times was recorded.&#x0D; Conclusion. The study showed that the basis of myotoxicity of statins in their long-term use is disintegration of enzyme antioxidant processes, as well as tissue hypoxia, leading to destruction of muscle fibers and prevalence of proteolytic processes.

Factors associated with statin-related adverse muscular events in adult dyslipidemic outpatients

ABSTRACT Statins are the most prescribed lowering-cholesterol drugs. They are well tolerated, however, some patients present muscular adverse symptoms. Clinical and laboratory data from 120 dyslipidemic patients prescribed with statins were obtained from January to December/2013 at a University Hospital in Sao Paulo city, Brazil, to study factors associated with statin-related adverse muscular events (AME). Pharmacotherapy and statin-related AME data (serum CK elevation and any degree of myopathy, myalgia, myositis or rhabdomyolysis) of the dyslipidemic patients were recorded. The study was approved by local Ethics Committees. Simvastatin (70%) and atorvastatin (25%) were the most prescribed statins. AME related to statin treatment were found in 17% of the patients. Mean age and use of simvastatin were lower in AME group than non-AME group (p<0.05). Simvastatin users were less likely to develop AME than atorvastatin users (OR=0.21; 95%CI=0.07-0.57; p<0.01). The use of P-glycoprotein (ABCB1) efflux pump inhibitors was associated with high risk for AME (OR=5.26; 95%CI=1.55-17.79; p<0.01). Serum liver enzymes were increased up to three-fold in 2.5% of the statin-treated patients. The results are suggestive that the type of statin prescribed and the concomitant use of ABCB1 inhibitors increase the susceptibility to adverse muscular events during statin therapy in dyslipidemic outpatients.

Statin Therapy and Serum Testosterone in Men with Type 2 Diabetes

There is a high prevalence of hypogonadism in men with type 2 diabetes. Statins could potentially decrease testosterone levels by reducing the availability of cholesterol for androgen synthesis. In this study we compared testosterone levels and hypogonadal symptoms with statin use in men with type 2 diabetes. PATIENTS AND METHODS Total testosterone, sex hormone–binding globulin (SHBG), and estradiol were measured by an enzyme-linked immunosorbent assay. Bioavailable testosterone was measured by the modified ammonium sulfate precipitation method. Free testosterone was calculated using Vermeulen's formula. Symptoms of hypogonadism were assessed using the Androgen Deficiency in the Aging Male questionnaire. RESULTS Statins were associated with lower total testosterone and a trend toward lower SHBG compared with untreated patients. Bioavailable testosterone, free testosterone, estradiol, and hypogonadal symptoms were not affected. Atorvastatin was associated with reduced total testosterone and a trend toward reduced SHBG compared with no treatment, and there was a dose-response effect with the lowest levels of total testosterone seen in men treated with ≥20 mg atorvastatin .Simvastatin use was not associated with significant reductions in testosterone or SHBG levels. CONCLUSION Assessing androgen status using total testosterone in men with type 2 diabetes treated with statins, particularly atorvastatin, may potentially lead to diagnostic error. Levels of bioavailable testosterone or free testosterone are recommended for the assessment of hypogonadism in this group if total testosterone levels are borderline.

The attenuation of neurological injury from the use of simvastatin after spinal cord ischemia-reperfusion injury in rats

BackgroundSpinal cord ischemic injury remains a serious complication of open surgical and endovascular aortic procedures. Simvastatin has been reported to be associated with neuroprotective effect after spinal cord ischemia-reperfusion (IR) injury. The aim of this study was to determine the therapeutic efficacy of starting simvastatin after spinal cord IR injury in a rat model.MethodsIn adult Sprague-Dawley rats, spinal cord ischemia was induced using a balloon-tipped catheter placed in the descending thoracic aorta. The animals were then randomly divided into 4 groups: group A (control); group B (0.5 mg/kg simvastatin); group C (1 mg/kg simvastatin); and group D (10 mg/kg simvastatin). Simvastatin was administered orally upon reperfusion for 5 days. Neurological function of the hind limbs was evaluated for 7 days after reperfusion and recorded using a motor deficit score (MDS) (0: normal, 5: complete paraplegia). The number of normal motor neurons within the anterior horns of the spinal cord was counted after final MDS evaluation. Then, the spinal cord was harvested for histopathological examination.ResultsGroup D showed a significantly lower MDS than the other groups at post-reperfusion day 1 and this trend was sustained throughout the study period. Additionally, a greater number of normal motor neurons was observed in group D than in other groups (group D 21.2 [3.2] vs. group A: 15.8 [4.2]; group B 15.4 [3.4]; and group C 15.5 [3.7]; P = 0.002).ConclusionsThe results of the current study suggest that 10 mg/kg can significantly improve neurologic outcome by attenuating neurologic injury and restoring normal motor neurons after spinal cord IR injury.

The effect of statins on periodontal treatment-a systematic review with meta-analyses and meta-regression.

This study aimed to systematically review clinical trials about the effect of statins as adjunct to mechanical periodontal therapy, on probing pocket depth, clinical attachment level, and intrabony defects, in comparison to mechanical periodontal therapy alone or in association with placebo. Three databases were searched for controlled clinical trials that used any locally delivered or systemically statin as a sole adjunctive therapy to mechanical periodontal treatment. Weighted mean differences between baseline and 6months after periodontal treatment for clinical attachment level (CAL), probing pocket depth (PPD), and intrabony defect (IBD) were calculated. A high heterogeneity was detected. Therefore, a meta-regression adjusted for type of statin and year of publication was performed. Fifteen studies were included in the systematic review, and ten studies were included in the meta-analysis. In the meta-regression, the adjunct use of simvastatin, rosuvastatin, and atorvastatin additionally reduced PPD in comparison to mechanical periodontal therapy and a placebo gel (2.90 ± 0.35, 3.90 ± 0.77, 3.06 ± 0.71mm, respectively; p < 0.05). Regarding the resolution of IBD, simvastatin and rosuvastatin significantly improved in comparison to control group (0.89 ± 0.35 and 1.93 ± 0.77mm, respectively; p < 0.05). No statistically significant difference was found between the statins for both PPD and IBD (p < 0.05). Regarding CAL gain, simvastatin provided a statistically significant improvement as compared to the control group (2.02 ± 0.79mm; p = 0.043). The use of statins, used as sole adjuncts to mechanical periodontal treatment, improved the periodontal parameters. In the quantitative analyses, simvastatin was the only drug that showed additional benefits in all evaluated parameters. Statins promote significantly clinical periodontal improvements when administered in association with non-surgical scaling and root planning (SRP), when compared to SRP alone or in association with a placebo.

Investigating the risk of Incident diabetes mellitus among primary care patients treated with simvastatin in North-Central Trinidad.

Aim:To determine the risk of new-onset diabetes mellitus in patients treated with simvastatin at primary healthcare clinics in North Central Trinidad.Materials and Methods:A retrospective descriptive case-series study design was applied to 384 conveniently sampled patient medical records from the cluster of primary healthcare centers during the period of February 2016–May 2016. Information from the patient files were then recorded using a systematic data extraction form. The major inclusion criteria were non-diabetic patients who were compliant with daily simvastatin for a minimum period of 1 year. The risk of incident diabetes mellitus was calculated, using SPSS version 20.0. Chi-squared (χ2) testing was performed to determine any association between new-onset diabetes mellitus and simvastatin use.Results:In all, 207 patients became diabetic during their treatment period translating into a 53.9% risk of incident diabetes mellitus (χ2 = 2.3438, P = 0.1258). A subgroup analysis of 133 subjects was performed to eliminate the confounders of family history of diabetes and age greater than 60 years. In this subgroup, 50 incident diabetics (37%) were identified and a statistically significant association was observed (χ2 = 8.118, P = 0.0042). Linear regression revealed that this association was dose-dependent with a corresponding 32% higher risk in patients taking 40 mg (P = 0.001) of simvastatin daily compared with 20 mg of simvastatin (P = 0.094). Linear regression also revealed that there was significant statistical association between onset of diabetes mellitus and duration of statin therapy (P = 0.006).Conclusion:In this population, simvastatin use is associated with a 53.9% increased risk of development of new-onset diabetes mellitus (χ2 = 2.3438, P = 0.1258). A statistically significant association was attained after subgroup analysis involving patients less than 60 years old and without a family history of diabetes with an incident risk of 37%. The increased risk of incident diabetes mellitus conferred by higher doses of simvastatin warrants consideration by physicians considering therapies for dyslipidemia in patients with multiple risk factors for diabetes mellitus.

Concurrent new drug prescriptions and prognosis of early breast cancer: studies using the Danish Breast Cancer Group clinical database

Background: Myriad reports suggest that frequently used prescription drugs alter the viability of breast cancer cells in pre-clinical studies. Routine use of these drugs, therefore, may impact breast cancer prognosis, and could have important implications for public health.Methods: The Danish Breast Cancer Group (DBCG) clinical database provides high-quality prospectively collected data on breast cancer diagnosis, treatment, and routine follow-up for breast cancer recurrence. Individual-level linkage of DBCG data to other population-based and medical registries in Denmark, including the Danish National Prescription Registry, has facilitated large population-based pharmacoepidemiology studies. A unique advantage of using DBCG data for such studies is the ability to investigate the association of drugs with breast cancer recurrence rather than breast cancer mortality – which may be misclassified – or all-cause mortality. Here we summarize findings from pharmacoepidemiological studies, based on DBCG data, on the association between routinely used prescription drugs and risk of breast cancer recurrence.Results: Our findings suggest that concurrent use of glucocorticoids, ACE inhibitors, aspirin, NSAIDs, selective COX-2 inhibitors, digoxin, and opioids has little impact on breast cancer recurrence. Similarly, patients who use SSRIs concurrently with tamoxifen treatment are not at increased risk of recurrence. In contrast, post-diagnostic use of simvastatin, a lipophilic statin, correlates with a decreased risk of breast cancer recurrence, providing a rationale for a prospective randomized clinical trial investigating simvastatin as an adjuvant therapy for breast cancer.Conclusion: As a whole, findings of pharmacoepidemiological studies based on DBCG data provide reassurance to physicians and healthcare personnel who provide supportive care during and after cancer (including prescriptions for comedications) and to breast cancer survivors for whom the risk of breast cancer recurrence is a major concern.

Simvastatin enhances the radiosensitivity of p53‑deficient cells via inhibition of mouse double minute 2 homolog.

Simvastatin exhibits anticancer activities, but its molecular mechanisms and radiosensitizing effects relative to p53 status remain unclear. In this study, we investigated whether the combination of simvastatin and ionizing radiation (IR) would enhance the antitumor effects of IR alone in HCT116 p53+/+ and p53‑/- colon cancer cells. Using colony formation assays and a xenograft mouse model, we found that simvastatin potently stimulated radiosensitization of HCT116 p53‑/- cells and xenograft tumors. The combination of simvastatin with IR decreased G2/M arrest and delayed the repair of IR-induced DNA damage; however, no differences between the HCT116 p53+/+ and p53‑/- cells were evident. A further analysis revealed that simvastatin exhibited a novel function, namely, MDM2 suppression, regardless of p53 status. Interestingly, simvastatin induced radiosensitization by enhancing MDM2 suppression and elevating IR-induced p‑ATM foci formation compared with IR alone in HCT116 p53‑/- cells. Furthermore, simvastatin caused accumulations of the FOXO3a, E-cadherin, and p21 tumor suppressor proteins, which are downstream factors of MDM2, in HCT116 p53‑/- cells. In conclusion, simvastatin enhanced radiosensitivity by inducing MDM2 inhibition and increasing tumor suppressor protein levels in radioresistant HCT116 p53‑/- cells and xenografts. Overall, our novel findings suggest a scientific rationale for the clinical use of simvastatin as an MDM2 inhibitor and radiosensitizer for p53‑deficient colorectal tumor treatments.

In-Hospital Mortality Following Traumatic Brain Injury Among Older Medicare Beneficiaries, Comparing Statin Users With Nonusers.

Traumatic brain injury (TBI) is a significant public health concern for older adults. Small-scale human studies have suggested pre-TBI statin use is associated with decreased in-hospital mortality following TBI, highlighting the need for large-scale translational research. To investigate the relationship between pre-TBI statin use and in-hospital mortality following TBI. A retrospective study of Medicare beneficiaries 65 and older hospitalized with a TBI during 2006 to 2010 was conducted to assess the impact of pre-TBI statin use on in-hospital mortality following TBI. Exposure of interest included atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Beneficiaries were classified as current, recent, past, and nonusers of statins prior to TBI. The outcome of interest was in-hospital mortality. Logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) comparing current, recent, and prior statin use to nonuse. Most statin users were classified as current users (90%). Current atorvastatin (OR = 0.88; 95% = CI 0.82, 0.96), simvastatin (OR = 0.84; 95% CI = 0.79, 0.91), and rosuvastatin (OR = 0.79; 95% CI = 0.67, 0.94) use were associated with a significant decrease in the risk of in-hospital mortality following TBI. In addition to being the most used statins, current use of atorvastatin, rosuvastatin, and simvastatin was associated with a significant decrease in in-hospital mortality following TBI among older adults. Future research must include clinical trials to help exclude the possibility of a healthy user effect in order to better understand the impact of statin use on in-hospital mortality following TBI.

Simvastatin exerts antifibrotic effect and potentiates the antischistosomal effects of praziquantel in a murine model: Role of IL10

Previous studies on simvastatin use in experimental schistosomiasis in mice did not provide a full explanation of its mechanism as antischisome. In this study, we tried to find out the role of IL-10 in the mechanism of action of simvastatin. We used 50 clear mice. Ten were used as normal not treated while 40 were infected with shistosome mansoni then divided into 4 groups; 3 treated groups by praziquantel, simvastatin and combined (praziquantel plus simvastatin) respectively and one group non-treated. The simvastatin treated group showed shortening and loss of the tubercles and disappearance of the spines with swelling and twisted shape of the worms. In addition, it also showed mitigation of ovideposition activity of the worms in the liver and reduction of the fibrous component of the liver granuloma producing a protective effect on the liver. This effect was associated with lowering of IL-10. This may explain the role of IL-10 in the protective effect of simvastatin. Combination of treatment with simvastatin plus praziquantel produced more significant effects in different parameters compared with praziquantel treated group. We recommend using simvastatin as add on therapy to standard antischistosomal therapy, praziquantel. Both drugs affect the worm motility and sucker activity and the ova deposition. Simvastatin has an additional pleiotropic effect halting inflammation and decreasing fibrosis due to increasing IL-10 leading to a hepatoprotective effect. Further clinical studies are needed to further validate these findings.

P.3.f.020 - The association of simvastatin use with decreased IL-6 in schizophrenia may suggest a new alternative add-on treatment

The molecular underpinnings associated to first episode psychosis (FEP) remains to be elucidated, but compelling evidence supported an association of FEP with blood alterations in biomarkers related to immune system, growth factors and metabolism regulators. Many of these studies have not been already confirmed in larger samples or have not considered the FEP diagnostic subgroups.In order to identify biochemical signatures of FEP, the serum levels of the growth factors BDNF and VEGF, the immune regulators IL-1RA, IL-6, IL-10 and IL-17, RANTES/CCL5, MIP-1b/CCL4, IL-8 and the metabolic regulators C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin were analysed in 260 subjects collected in the GET UP project.The results indicated an increase of MIP-1b/CCL4, VEGF, IL-6 and PAI-1, while IL-17, ghrelin, glucagon and GLP-1 were decreased in the whole sample of FEP patients (p < 0.01 for all markers except for PAI-1 p < 0.05). No differences were evidenced for these markers among the diagnostic groups that constitute the FEP sample, whereas IL-8 is increased only in patients with a diagnosis of affective psychosis. The principal component analysis (PCA) and variable importance analysis (VIA) indicated that MIP-1b/CCL4, ghrelin, glucagon, VEGF and GLP-1 were the variables mostly altered in FEP patients. On the contrary, none of the analysed markers nor a combination of them can discriminate between FEP diagnostic subgroups.These data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets.

Has cost inhibited the uptake of more potent statins in England?

The use of statins has increased substantially over the last 2 decades in England and represents a significant cost burden to the National Health Service. Therefore, it is important to understand what influences prescribers' choice. This study examines the changes in use pattern of all statins in England (1998-2015). The study focuses on the use of simvastatin and atorvastatin before and after their patent expiry and rosuvastatin, to investigate the impact of the reduced acquisition costs on prescribing. Interrupted time series analysis of primary care use data from the health and social care information centre database from 1998 to 2015. Primary care expenditure on statins increased by 125% during the period 1998 to 2004 driven by branded simvastatin and atorvastatin. Before 2003, the rate of use of more potent branded atorvastatin exceeds branded simvastatin. Between 2004 and 2011, the less potent but less expensive agent generic simvastatin has the higher utilisation rate (66%). Since 2012, the more potent agent but less expensive generic atorvastatin has the higher utilisation rate (50%). The more potent branded rosuvastatin failed to make a significant impact on the English statins market. The availability of generic statins has reduced overall expenditure significantly. When there is a significant price difference, acquisition cost appears to be the main influencing factor in prescribing statins, but, when costs are similar, potency is a key factor. This suggests that English prescribers are cost sensitive and appear to be prepared to trade marginal benefit for savings.

Long-term statin therapy could be efficacious in reducing the lipoprotein (a) levels in patients with coronary artery disease modified by some traditional risk factors.

Lipoprotein (a) [Lp (a)] is a well-established risk factor for coronary artery disease (CAD). However, up till now, treatment of patients with higher Lp (a) levels is challenging. This current study aimed to investigate the therapeutic effects of short-, medium and long-term statin use on the Lp (a) reduction and its modifying factors. The therapeutic duration was categorized into short-term (median, 39 days), medium term (median, 219 days) and long-term (median, 677 days). The lipid profiles before therapy served as baselines. Patients at short-, medium or long-term exactly matched with those at baseline. Every patient's lipid profiles during the follow-ups were compared to his own ones at baselines. The current study demonstrated that long-term statin therapy significantly decreased the Lp (a) levels in CAD patients while short-term or medium term statin therapy didn't. When grouped by statin use, only long-term simvastatin use significantly decreased the Lp (a) levels while long-term atorvastatin use insignificantly decreased the Lp (a) levels. Primary hypertension (PH), DM, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) could modify the therapeutic effects of statin use on the Lp (a) levels in CAD patients. The long-term statin therapy could be efficacious in reducing the Lp (a) levels in CAD patients, which has been modified by some traditional risk factors. In the era of commercial unavailability of more reliable Lp (a) lowering drugs, our findings will bolster confidence in fighting higher Lp (a) abnormalities both for patients and for doctors.

Influence of hypolipidemic agents on the level of steatogenic and fibrogenic modulators in rats with non-alcoholic fatty liver disease associated with hyperhomocysteinemia

The aim was to determine the influence of Simvastatin and PUFA ω-3 remedy on the level of pro-fibrogenic neurotransmitters (Homocysteine, TNFα) and the level of neurotransmitters that determine anti-fibrous and liver regeneration potential (H 2 S and IGF-1) under experimental NAFLD associated with HHC. Materials and methods. The study was carried out using 100 white laboratory male rats divided into 7 experimental and 3 control groups. NAFLD associated with HHC was modeled in 7 groups of rats by applying high fat diet with simultaneous administration of Homocysteine thiolactone (100 mg / kg / intragastrically) for 60 days. From the 61st day and till the end of the experiment, 6 groups of rats with NAFLD + HHC had a standard diet. On this background, the animals of 4 groups were treated by lipid-lowering drugs - Simvastatin or ω-3 PUFAs remedy. The levels of Homocysteine, TNF-α and IGF-1 in bloodserum, as well as the content of triglycerides, cholesterol, phospholipids, hydroxyproline and H 2 S in rat liver were determined. Results. The use of Simvastatin did not cause statistically significant changes in the levels of Homocysteine, TNFα in blood serum and H 2 S content in the liver, but it led to IGF-1 worsening deficits in blood serum. At the same time, the use of PUFA ω-3 resulted in a significant reduction in the levels of Homocysteine, TNFα and increase in the levels of IGF-1 in serum and H 2 S in rat liver. Anti-steatosis and anti-fibrous effects of ω-3 PUFA remedy were significantly higher comparing to Simvastatin. Conclusion. Therefore, PUFA ω-3 drug significantly exceeds Simvastatin by hypohomocystinemic effect, more effectively reduces TNFα in blood serum and increases the H 2 S content in liver, and stimulates an IGF-1 level increase in blood serum, while Simvastatin enhances its deficit

4PBA strongly attenuates endoplasmic reticulum stress, fibrosis, and mitochondrial apoptosis markers in cyclosporine treated human gingival fibroblasts

Cyclosporine induces overgrowth of human gingiva. Previously we have shown (i) cyclosporine-inducing ER stress in human gingival fibroblasts (HGF), (ii) increased matrix protein expression, and (iii) interference with mitochondrial pro- and anti-apoptotic factors. This study was undertaken to assess the effects of melatonin (an antioxidant), 4PBA (an ER stress inhibitor), and simvastatin on the expression of ER Stress markers as well as on matrix and mitochondrial markers. HGF incubated with cyclosporine, or without melatonin/4PBA/statin. After 24 hr of incubation, mRNA expression of ER stress markers (GRP78, CHOP, XBP1, and XBPs) and matrix protein markers (like α-SMA, VEGF, TGF-β, CTGF), and mitochondrial apoptosis markers estimated and compared with housekeeping gene GAPDH. Compared to the control cyclosporine significantly augmented ER Stress and matrix proteins, which decreased significantly with the use of melatonin, 4PBA, and simvastatin. The mitochondrial proapoptotic molecule cyclophilin D, as well as Bcl2 expression also decreased after PBA treatment, paralleling an increase in cytochrome c expression. The effect of 4PBA was much more pronounced than the influence of other two. In conclusion, 4PBA could be a viable therapeutic option for drug-induced gingival overgrowth.