Simvastatin Combination Therapy Research Articles

The role of HMGCR expression in combination therapy of simvastatin and FAC treated locally advanced breast cancer patients.

Several studies have shown the role of statin added to the patient's chemotherapy regimen and the role of Hydroxymethylglutaryl-CoA Reductase (HMGCR) expression in predicting breast cancer patient outcomes. In our previous study, adding statins improved clinical and pathological responses in LABC patients. Furthermore, we planned to study statin's role as a combination to neoadjuvant chemotherapy (NAC) in treating locally advanced breast cancers on the basis of HMGCR expression. Moreover, we aimed to study the association between the patients' clinicopathological characteristics and HMGCR expression. This study is a randomized, double-blinded, placebo-controlled trial in two health centers in Indonesia. Each patient enrolled with written informed consent and then randomized to receive either simvastatin 40 mg/day or a placebo, combined with the fluorouracil, adriamycin, and cyclophosphamide (FAC) NAC. HMGCR was associated with low staging and normal serum cholesterol in the high Ki67 level group (p =0.042 and p =0.021, respectively). The pre-and post-chemotherapy tumor sizes are significantly correlated in two groups (HMGCR negative expression, p =0.000 and HMGCR moderate expression, p =0.001) with a more considerable average decrease in tumor size compared to HMGCR strong expression group. Statin therapy might work better in HMGCR-negative or low-expression tumors, although HGMCR expression is associated with better clinical parameters in our study.

Comparing Simvastatin Monotherapy V/S Simvastatin-Ezetimibe Combination Therapy for the Treatment of Hyperlipidemia: A Meta-Analysis and Review.

Longstanding hyperlipidemia canincrease the risk of cardiovascular disease. Statins are currently the mainstay of treatment in hyperlipidemia. Combination therapy of statin with ezetimibe is only indicated for severe hypercholesterolemia and very high-risk atherosclerotic cardiovascular disease (ASCVD) population. There is a paucity of studies comparing statin monotherapy vs combination therapy with ezetimibe. This study aims to perform a meta-analysis of the existing literature and compare the effectiveness of statin monotherapy with statin-ezetimibe combination therapy in the management of hyperlipidemia. A systematic electronic search of the scientific literature was performed in PubMed, EMBASE, and Scopus. Only randomized controlled trials comparing simvastatin monotherapy vs simvastatin-ezetimibe combination therapy between the years 2000 and 2021 and published in English language were included. Fifteen studies were included in the final analysis. The main outcomes that were compared were a reduction in low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Our study showed that combination therapy led to a higher reduction of LDL-C (Mean difference: -20.22(-26.38, -14.07); P<0.0001) compared to monotherapy with a statin alone. There was no significant difference in the reduction of HDL-C values (Mean difference: -0.07(-0.45,0.32); P-0.04)between the two groups. Our study indicates that the combination therapy of simvastatin and ezetimibe is more effective in reduction of LDL-Clevels compared to simvastatin monotherapy alone. Currently, guidelines recommend combination therapy only for severe hypercholesterolemia and high-risk ASCVD patients, more studies are needed to study the effectiveness of simvastatin-ezetimibe combination therapy in low-risk ASCVD population.

The Effect of Simvastatin and Virgin Coconut Oil (VCO) Combination Therapy as Triglyceride Plasma Lowering Agent in White Dyslipidemic Male Rat (Rattus norvegicus)

Introduction: Dyslipidemia is a major health problem in Indonesia which leads to other diseases. Triglycerides (TG) is one of the increased lipid fractions which is related to dyslipidemia. Simvastatin is the main therapy in Indonesia to lower TG levels. The use of virgin coconut oil (VCO) becomes popular as a blood cholesterol-lowering agent even though the effects on TG level remains elusive. Since there is no empirical evidence VCO as a complementary therapy of simvastatin on TG levels, this experimental trial is conducted to determine the effect of simvastatin and VCO combination therapy on blood TG levels in dyslipidemic male white rats.Methods: 42 white rats (Rattus norvegicus) divided into 5 treatment groups and preliminary test of dyslipidemia. The blood was collected intracardially and TG level was measured by using spectrophotometric methods. Independent variables are simvastatin and VCO and combination therapy while the dependent variable is TG levels of white rats. The data was afterwards analyzed using Mann-Whitney U test.Results: The control group’s triglyceride plasma level, receiving standard diet, is 59±13,4 mg/dl. The VCO-only group shows 72±35,4 mg/dl while simvastatin-only group shows 61,9±22,6 mg/dl triglyceride level. Combination therapy of simvastatin and VCO shows 62,3±31,3 mg/dl (p&gt;0,05).Conclusion: There were no significant differences between groups with control. However,the use of VCO with particular dose and duration of therapy, will significantly decrease triglyceride level in the blood as effective as simvastatin. VCO has no efficacy while used as combination therapy of simvastatin.

Rhabdomyolysis requiring emergency dialysis as a consequence of simultaneous administration of simvastatin and clarithromycin

Iatrogenic complications from polypharmacy have significantly increased over the past decade and clinicians and pharmacists must remain aware of potentially dangerous drug interactions 1–3. Our case is a reminder of the potential for significant patient harm from drug interactions when additional medication that is seemingly innocuous is prescribed in addition to a patient’s regular long-term medications. Our case also highlights the diagnosis and management of rhabdomyolysis and acute kidney injury. A 75-year-old Caucasian male presented to the emergency department with nausea, bilateral calf tenderness and a reduced urine output. Creatinine Kinase (CK) levels demonstrated severe rhabdomyolysis and the patient’s creatinine was significantly elevated with a concurrent metabolic acidosis requiring urgent renal replacement therapy in the intensive care unit (ICU). He was recently prescribed clarithromycin 500mg twice daily as part of Helicobacter pylori eradication therapy in addition to his regular combination therapy of simvastatin 80 mg and ezetimibe 10 mg daily dose. Statins may cause dose dependent Statin Associated Myopathies (SAMs) such as myositis and rhabdomyolysis and are metabolised by the hepatic cytochrome P450 (CYP450) 3A4 enzyme4,5. Clarithromycin is a potent CYP450 3A4 hepatic enzyme inhibitor that leads to significantly elevated plasma levels of statin medications, increasing the risk of SAMs4,6–8. Our patient responded to the cessation of the offending medications and initiation of continuous renal replacement therapy. This case demonstrates the dangerous side effects and interactions of commonly prescribed medications.

Design and Characterisation of Bi-layer Tablets Containing Simvastatin as Sustained Release and Labetalol HCl as Immediate Release

The objective of present investigation is to design and characterise sustained release Simvastatin and immediate release of Labetalol HCl, a bi-layer tablet. The combination therapy of Simvastatin and Labetalol HCl can be useful in severe cardiovascular disease such as hypertension, angina pectoris, congestive heart failure which may occur along with increasing cholesterol level in the blood, while this combination remain preferable choice to the patient as compared to single dosage form. The bi-layer tablet is suitable for sequential release of two drugs in combination which are compatible with each other. Objective of present investigation is to prepare bi-layer tablet in which one layer is sustained while another one is immediate release. For the preparation of bi-layer tablet, different super disintegrants like cross carmellose cellulose, micro crystalline cellulose is used for immediate release and HPMC and Carbapol as controlled release polymer. The pre-formulation parameter such as solubility, melting point, compatibility study (FTIR) were studied. Pre-compression parameter such as angle of repose, bulk density, tapped density, hausner’s ratio and compressibility index were studied. The tablets were evaluated by physical and chemical parameters such as weight uniformity, hardness, thickness, diameter, friability, drug content, disintegration time and in-vitro drug release. The dissolution data were subjected to various release kinetic model to recognize the mechanism of drug release. Keyword: sustained release tablet, bi-layer tablet, Simvastatin, Labetalol HCl.

Combination therapy of simvastatin and 5, 6-dimethylxanthenone-4-acetic acid synergistically suppresses the aggressiveness of B16.F10 melanoma cells

The major drawback of current anti-angiogenic therapies is drug resistance, mainly caused by overexpression of the transcription factor, hypoxia-inducible factor 1α (HIF-1α) as a result of treatment-induced hypoxia, which stimulates cancer cells to develop aggressive and immunosuppressive phenotypes. Moreover, the cancer cell resistance to anti-angiogenic therapies is deeply mediated by the communication between tumor cells and tumor-associated macrophages (TAMs)—the most important microenvironmental cells for the coordination of all supportive processes in tumor development. Thus, simultaneous targeting of TAMs and cancer cells could improve the outcome of the anti-angiogenic therapies. Since our previous studies proved that simvastatin (SIM) exerts strong antiproliferative actions on B16.F10 murine melanoma cells via reduction of TAMs-mediated oxidative stress and inhibition of intratumor production of HIF-1α, we investigated whether the antitumor efficacy of the anti-angiogenic agent—5,6-dimethylxanthenone-4-acetic acid (DMXAA) could be improved by its co-administration with the lipophilic statin. Our results provide confirmatory evidence for the ability of the combined treatment to suppress the aggressive phenotype of the B16.F10 melanoma cells co-cultured with TAMs under hypoxia-mimicking conditions in vitro. Thus, proliferation and migration capacity of the melanoma cells were strongly decelerated after the co-administration of SIM and DMXAA. Moreover, our data suggested that the anti-oxidant action of the combined treatment, as a result of melanogenesis stimulation, might be the principal cause for the simultaneous suppression of key molecules involved in melanoma cell aggressiveness, present in melanoma cells (HIF-1α) as well as in TAMs (arginase-1). Finally, the concomitant suppression of these proteins might have contributed to a very strong inhibition of the angiogenic capacity of the cell co-culture microenvironment.

Simvastatin and bone marrow-derived mesenchymal stem cells (BMSCs) affects serum IgE and lung cytokines levels in sensitized mice

IntroductionThe effects of bone marrow-derived mesenchymal stem cells (BMSCs) and simvastatin combination therapy on serum total and specific IgE levels and lung IL-13 and TGF-β levels in sensitized mouse were examined. Material and methodsControl (n = 5), Sensitized (S), (n = 5), S + BMSC (n = 6), S + simvastatin (n = 6) and S + BMSC + simvastatin (n = 4) groups of BALB/c mice were studied. Mice were sensitized by ovalbumin. Sensitized mice were treated with a single intravenous injection of BMSCs (1 × 106) or daily intraperitoneal injection of simvastatin (40 mg/kg) or both BMSCs and simvastatin on the last week of challenge. Serum total and ovalbumin specific IgE levels as well as IL-13 and TGF-β levels in broncho-alveolar lavage (BAL) fluid were evaluated. ResultsSerum total and specific IgE levels as well as lung IL-13 and TGF-β levels were significantly increased in S group compared to control group (P < 0.001 for all cases). Treatment with BMSCs, simvastatin and their combination significantly decreased serum total and specific IgE levels (P < 0.05 to P < 0.01). However, IL-13 and TGF-β levels were significantly decreased by BMSCs and BMSC + simvastatin combination therapy (P < 0.05 for all cases). The effect of simvastatin and BMSCs combination therapy on serum specific IgE levels as well as lung IL-13 and TGF-β levels were significantly higher than the effect of BMSCs and simvastatin alone (P < 0.001 for IL-13 and P < 0.01 for other cases). ConclusionsSimvastatin and BMSCs combination therapy affects serum IgE as well as lung IL-13 and TGFβ levels more than BMSC therapy and simvastatin therapy alone which may be due to increased BMSCs migration into the lung tissue.

The effect of Ezetimibe and Simvastatin Combination Therapy on percutaneous coronary intervention patients

AimsEvaluating the short-term influence of Ezetimibe and Simvastatin Combination Therapy on LDL-C, TG and hs-CRP expression level in patients with percutaneous coronary intervention. Methods57 cases of percutaneous coronary intervention patients were selected, and randomly divided into two groups: Simvastatin (40mg/day) and Ezetimibe (10mg/day) combination therapy group (observation group) with 28 patients, Simvastatin (40mg/day) group (control group) with 29 patients. Each group was treated for 10days. After treatment, compare blood lipid LDL-C, TG, hs-CRP levels with each other and the results before treatment. ResultsComparison of the results of the 10th day with the baseline: LDL-C, TG decreased significantly (P<0.01) in the observation group, while the control group did not have a significantly change (P>0.05). Comparison of observation group and control group: after treatment, LDL-C and TG decreased more significantly in the observation group than the control group (−27.2% vs −14.6%, P<0.05). Whether according to LDL-C <2.07mmol/L standard or LDL-C <1.8mmol/L standard, the compliance rate of the observation group was significantly better than the control group, the results were (69% vs 28.9%, P<0.05) and (47.6% vs 13.2% P<0.05), respectively. After 10days treatment, comparing to baseline, hs-CRP was significantly lowered in these two groups (P<0.01). And there is no liver and kidney toxicity, myopathy and other adverse reactions during treatment. ConclusionsCombination therapy of Ezetimibe (10mg/day) and Simvastatin (40mg/day) was more effective than mono-therapy with Simvastatin (40mg/day) on reducing LDL-C, TG and hs-CRP level in percutaneous coronary intervention patients, leading to more significant anti-inflammatory effect.

Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor

We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.

Inhibitory effect of the combination therapy of simvastatin and pinocembrin on atherosclerosis in apoE-deficient mice

The present study was performed to investigate the effects of the combination therapy of pinocembrin and simvastatin on the atherosclerotic lesions development in the ApoE−/− mice.MethodsEight-week-old male ApoE−/− mice were fed high fat diet (HFD) and treated with simvastatin (10 mg/kg per day), pinocembrin (20 mg/kg per day), or the combination therapy (simvastatin 5 mg/kg per day and pinocembrin 20 mg/kg per day) for 14 weeks. The serum lipid levels, nitric oxide (NO), endothelin (ET), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined with spectrophotometric measurement and ELISA assay. Vascular endothelial growth factor (VEGF) in serum and aortic root was detected. En face analyses of atherosclerotic lesion in whole aorta and aortic root sections were performed with plaque staining using oil red O.ResultsThe combination treatment with simvastatin and pinocembrin resulted in significantly decreased levels of serum total cholesterol, triglycerides and low-density lipoprotein cholesterol, augmented NO levels and SOD activity, inhibited ET and VEGF expression. Immunohistochemistry of aortic valve sections revealed that the combination therapy also suppressed the expression of VEGF induced by HFD. In addition, HFD-induced arterial wall lipid disposition displayed by oil red O staining was reduced significantly in aortic root and whole aorta en face in the combination administrated mice. The effect of the combination was superior to simvastatin alone.ConclusionThe combination of simvastatin and pinocembrin synergistically inhibited atherosclerotic lesion development in ApoE−/− mice with hyperlipidemia, which is partially dependent on the protective of vascular endothelium.

Simvastatin, Sildenafil and Their Combination in Monocrotaline Induced Pulmonary Arterial Hypertension

Background and ObjectivesPulmonary arterial hypertension (PAH) is a life threatening disease characterized by progressive pulmonary arterial occlusion which may ultimately result in death. Currently, the available treatments are diverse, but no therapy alone can reverse the disease process although they may have some clinical benefits. This study was designed to investigate single and combination therapy of simvastatin and sildenafil, which have different mechanisms of action, in monocrotaline (MCT)-induced PAH.Meterials and MethodsRats were randomized to receive saline (control, n=8) or MCT treatment (n=32). MCT treated rats were randomized to vehicle, simvastatin (2 mg/kg/day), sildenafil (25 mg/kg/day) and a combination simvastatin and sildenafil (n=8, respectively). Three weeks later, hemodynamic study and histologic changes of pulmonary arterioles were measured. Proliferating cell nuclear antigen (PCNA) as well as Western blot for endothelial nitric oxide synthase (eNOS) were performed.ResultsSystolic right ventricular pressure was significantly decreased in monotherapy groups (simvastatin and sildenafil) and the combination group compared to MCT group (p<0.05). Right ventricular hypertrophy and medial wall thickness of pulmonary arterioles were significantly attenuated with sole and combination therapy (p<0.05). However, combination therapy did not confer additive benefits over monotherapy. Altered PCNA or eNOS in lung tissue was normalized by either monotherapy or combination therapy.ConclusionThe results suggest that either simvastatin or sildenafil has the therapeutic potential in MCT-induced PAH, although combination therapy of these two drugs has failed to show greater benefits in the study.

Combination statin–fibrate therapy: safety aspects

Patients with type 2 diabetes or metabolic syndrome remain at high residual risk of cardiovascular events even after intensive statin therapy. While treatment guidelines recommend the addition of a fibrate to statin therapy in this setting, concerns about the potential for myopathy may limit the use of this combination in clinical practice. These concerns are certainly justified for gemfibrozil, which interferes with statin glucuronidation, leading to elevation in statin plasma concentrations and an increased risk of myotoxicity in combination with a range of commonly prescribed statins. However, the available evidence refutes suggestions that this is a class effect for fibrates. Fenofibrate does not adversely influence the metabolism or pharmacokinetics of any of the commonly prescribed statins. This in turn translates to a reduced potential for myotoxicity in combination with a statin. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the efficacy and safety of fenofibrate plus simvastatin combination therapy in type 2 diabetes patients.

Long-Lasting Benefits after Treatment of Traumatic Brain Injury (TBI) in Rats with Combination Therapy of Marrow Stromal Cells (MSCs) and Simvastatin

This study was designed to investigate the beneficial effects of combination therapy of simvastatin and marrow stromal cells (MSCs) in improving functional outcome after traumatic brain injury (TBI) in rats. Adult female Wistar rats (n=72 and 8, per group) were injured with controlled cortical impact and treated either with monotherapy of MSCs or simvastatin or a combination therapy of these two agents. Different combination doses were tested, and nine groups of animals were studied. Neurological function was evaluated using Modified Neurological Severity Score (MNSS), and animals were sacrificed 3 months after injury. Coronal brain sections were stained with standard hematoxylin and eosin immunohistochemistry. Our results showed that, though functional improvement was seen with monotherapies of MSCs and simvastatin, the combination therapy when used in optimal doses was significantly better in improving functional outcome. This improvement was long lasting and persisted until the end of the trial (3 months). The optimum combination dose was 0.5mg of simvastatin combined with 2 x 10(6) MSCs. Post mortem analysis showed the presence of donor MSCs within the injured cortex. Endogenous cellular proliferation induced by the neurorestorative treatments was also observed in the lesion boundary zone. Our data show that MSCs and simvastatin have a synergistic effect in improving functional outcome after TBI.

Safety of Niacin and Simvastatin Combination Therapy

Niacin is the most potent lipid-altering agent for raising high-density lipoprotein (HDL) cholesterol levels. Niacin also lowers triglyceride (TG) levels, lowers low-density lipoprotein (LDL) cholesterol levels, and improves lipoprotein particle size and subclass distribution. Niacin's major adverse experience (AE) is flushing. Niacin may also increase glucose levels, liver enzymes, and uric acid levels and cause other AEs that may have clinical relevance in selected patients. Simvastatin is representative of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) class of lipid-altering drugs, which are the most effective agents for lowering LDL cholesterol levels and also have modest benefits in raising HDL cholesterol and lowering TG levels. The most common AEs with statins are muscle AEs and modest liver enzyme elevations. Because niacin and statins have complementary lipid effects and because individually, niacin and statins have been shown in outcomes studies to reduce atherosclerotic coronary artery disease events, the combined use of these 2 agents has significant potential to not only improve the lipid values of patients but improve their lives as well. Equally important is ensuring that the combination of niacin and simvastatin has an acceptable safety profile, with no greater AEs than would otherwise be expected by adding 1 agent to the other.

Effect of Estrogen and Simvastatin on Low-Density Lipoprotein Subclasses in Hypercholesterolemic Postmenopausal Women

In Brief Objective To identify the effects of estrogen and simvastatin, individually and in combination, on the levels of low-density lipoprotein (LDL) subclasses in postmenopausal women with type IIa hypercholesterolemia. Methods Fifty-five postmenopausal women with type IIa hypercholesterolemia were assigned randomly to 0.625 mg of conjugated equine estrogen (n = 20), 5 mg of simvastatin (n = 18), or both (n = 17) daily for 3 months. Cholesterol, triglyceride, and apolipoprotein B levels in the plasma and in the LDL1 (density 1.019-1.045 g/mL) and LDL2 (density 1.045-1.063 g/mL) fractions were measured before and after treatment. Results Estrogen treatment significantly reduced LDL1 cholesterol and LDL1 apolipoprotein B levels by 18.4% and 20.8%, respectively; simvastatin treatment by 21.9% and 29.2%, respectively; and combination therapy by 38.5% and 34.4%, respectively. In contrast to estrogen or simvastatin treatment, the combination therapy also significantly lowered the levels of LDL2 cholesterol by 19.5% and LDL2 apolipoprotein B by 30.5%. Posttreatment levels of total cholesterol, LDL1 cholesterol, and LDL1 apolipoprotein B were significantly lower after combination treatment than after estrogen treatment. Estrogen treatment, but not combination therapy, significantly increased total plasma triglyceride levels (103.1 ± 26.0 mg/dL to 138.8 ± 75.6 mg/dL, P ± .01). Significantly more patients receiving combination therapy than those receiving estrogen had total and LDL cholesterol concentrations reduced to target levels. Conclusion Combination therapy with estrogen and simvastatin favorably affected lipid metabolism by reducing large and small LDL particles and prevented the estrogen-induced increase in plasma triglyceride levels. Estrogen and simvastatin combination therapy decreases large and small low-density lipoprotein particles.