High-dose Simvastatin Research Articles

Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers

Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca2+ homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80mg daily or placebo for 8weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca2+ spark properties were evaluated on a muscle biopsy 4days before the second stress test. Simvastatin-treated subjects were separated according to their median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38±5.68 vs −1.15±4.32UI/L, P<0.001) and CK (−24.3±99.1±189.3vs 48.3UI/L, P=0.01) and a trend to an elevation of isoprostanes (193±408 vs12±53pmol/mmol creatinine, P=0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca2+ sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca2+ spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca2+ spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r=0.71, P=0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication.

Identical LDL-cholesterol lowering but non-identical effects on NF-κB activity: High dose simvastatin vs combination therapy with ezetimibe

ObjectiveLowering LDL-cholesterol by statins has been proven to be associated with reduction of proinflammatory regulators e.g. activation of the transcription factor NF-κB. To our knowledge, anti-inflammatory potential of newer cholesterol lowering agents such as ezetimibe is less intensively studied. Therefore we analyzed the effects of equipotent LDL-lowering therapy with simvastatin alone compared to a combination with ezetimibe on NF-κB activation in peripheral blood mononuclear cells (PBMCs) of patients with type 2 diabetes. MethodsThirty-one patients with type 2 diabetes were included in a double-blind, randomized trial receiving either 80 mg simvastatin (sim80; n = 10) or a combination of 10 mg simvastatin and 10 mg ezetimibe (sim10eze10; n = 11) or placebo (n = 9) for eight weeks. NF-κB binding activity and inflammatory markers (IL-6, hsCRP) were analyzed at baseline and after eight weeks of treatment. NF-κB binding activity was analyzed by electrophoretic mobility shift assay. IL-6 and hsCRP were measured by ELISA. ResultsAfter eight weeks of treatment LDL-cholesterol was lowered to the same extent in both treatment groups (p = 0.40) but not in placebo. However, patients taking sim80 showed a significant reduction of mononuclear NF-κB binding activity compared to baseline (p = 0.009) while no effect was observed in the sim10eze10 group (p = 0.79). Similar differences in anti-inflammatory effects were also observed when analyzing hsCRP (sim80: p = 0.03; sim10eze10: p = 0.40) and IL-6 levels (sim80: p = 0.15; sim10eze10: p = 0.95). ConclusionHigh dose simvastatin therapy reduces proinflammatory transcription factor NF-κB binding activity and hsCRP levels, while combination of low dose simvastatin with ezetimibe resulting in a similar LDL-reduction does not affect these inflammatory markers.

Abstract 3778: Pharmacokinetic, safety and efficacy of high dose simvastatin in refractory and relapsed chronic lymphocytic leukemia (CLL) patients

Abstract Statins are established as safe and effective anti-hypercholesterolemia drugs. Preclinical evidence shows that statins exhibit antitumor activity against different tumors by reducing prenylation of small GTPase molecules, which play a critical role in intracellular cancer cell signaling. However, these effects have only been noted at higher concentrations, which cannot be achieved with the typical dosing. In a Phase I trial, simvastatin was well tolerated by patients with relapsed or refractory myeloma or lymphomas at amaximum tolerated dose (MTD) of 7.5mg/kg twice daily. However, the pharmacokinetic (PK) was not defined and it is unknown if simvastatin plasma concentrations can reach the levels necessary for the antitumor activity observed in vitro. Here we evaluated the PK, safety and efficacy of high dose simvastatin in the context of a pilot trial enrolling patients with recurrent and refractory CLL. Methods: Patients received simvastatin orally at 7.5mg/kg twice a day for 7 days during a 21 day cycle for 6 cycles. During study treatment, patients underwent weekly or bi-weekly evaluations that included physical examination, complete blood counts and comprehensive chemistry profiles. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 3.0). The NCI CLL revised guidelines for diagnosis and treatment were utilized to determine the level of clinical response. Blood samples were collected during cycle 1 at predose, 15 min and 1,2,3,6,8, and 12 hr and at predose on day-7. Simvastatin lactone and acid concentrations were measured in plasma and peripheral blood mononuclear cells (PBMCs) using a validated HPLC-MS/MS assay. Biochemical assays assessing the apoptotic effects of simvastatin were also performed in CLL cell samples (the predose and day-7) obtained from the treated patients. Results: Patients were accrued in this pilot trial. High dose simvastatin was well tolerated and there were no signs of serious adverse effects. Simvastatin exposure was dose proportional (AUC and Cmax) as compared to the doses used to treat hyperlipidemia. Exposure was lower than that required for in vitro cytotoxicity against immortalized cells. Simvastatin exposure in both plasma and PBMCs was variable with an AUC12hr (%CV) of 800.6 hr*ng/ml (88.6%) and 11.03 hr*ng/mg (119.4%), respectively. Following 7 days exposure to high dose simvastatin, CLL cells had increased the expression of cleaved PARP, an apoptotic marker. Conclusion: Preliminary results show that high dose simvastatin is well tolerated with no signs of serious side effects. Although plasma concentrations were lower than that required for in-vitro cytotoxicity, the simvastatin concentrations achieved in the clinic induced apoptosis in patient CLL cells. Further studies in CLL patients are warranted to demonstrate its efficacy alone or in combination therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3778. doi:1538-7445.AM2012-3778

AS-271 Pre-Treatment with High Dose Simvastatin Suppressed High Sensitive C-Reactive Protein Level Increase in Patients Undergoing Primary Percutaneus Coronary Intervention

The goal of this research was to investigate whether the suppression of hsCRP level increase is related to high-dose simvastatin pre-treatment in patients undergoing primary percutaneus coronary intervention. Previous randomized trials have demonstrated that high-dose statin pre-treatment reduced the inflammation response after coronary intervention in patients with stable angina pectoris and acute coronary syndrome. However, there was only few of studies that investigate the benefit of high-dose statin pre-treatment in acute STEMI patients undergoing primary PCI. Simvastatin is commonly prescribed for Indonesian patients and generally covered by national health insurance.

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and have a major place in the treatment of atherosclerotic disease. Recent studies have shown anti-inflammatory properties of statins. The purpose of this study was to evaluate the anti-inflammatory effect of simvastatin on bleomycin (BLM)-induced pulmonary fibrosis in rats. A total of 31 female Sprague-Dawley rats were divided into four groups: (1) intratracheal (IT) phosphate-buffered saline (PBS) + intraperitoneal (IP) PBS (n=7); (2) IT BLM + IP PBS (n=8); (3) IT BLM + low dose (LD) simvastatin (1 mg/kg daily, n=8); (4) IT BLM + high dose (HD) simvastatin (5 mg/kg daily, n=8). Simvastatin was administered IP for 15 days, beginning 1 day prior to IT BLM. The effect of simvastatin on pulmonary fibrosis was studied by measurements of IL-13, PDGF, IFN-γ, TGF-p1 levels in bronchoalveolar lavage (BAL) fluid and lung tissue hydroxyproline (HPL) content and by histopathological examination (Ashcroft score). BLM caused significant change in BAL fluid cytokine levels and increased both HPL content and histopathological score (p<0.001 for all). While LD simvastatin had no effect on cytokine levels, HD significantly reduced IL-13 (15.12 ±7.08 pg/ml vs. 4.43±2.34 pg/mL; p<0.05) and TGF-β1 levels (269.25 ±65.42 pg/mL vs. 131.75±32.65 pg/mL; p<0.05). Neither HD nor LD simvastatin attenuated HPL content or Ashcroft score. In conclusion, this study showed that LD simvastatin had no effect on a BLM-induced pulmonary fibrosis model, while the high dose caused partial improvement in profibrotic cytokine levels.

THE EFFICACY OF HIGH-DOSE SIMVASTATIN IN ACUTE PERIOD OF ISCHEMIC STROKE

Aim. To estimate in a 12-month study mortality and frequency of recurrent cardiovascular events, dynamics of neurological deficit and endothelial dysfunction in patients with the first-time ischemic stroke treated with simvastatin 40 mg/day in acute period of the disease. Materials and methods. The efficacy of high-dose simvastatin (40 mg/day) therapy initiated in acute stage of ischemic stroke was evaluated in 12-month comparative randomized study. Patients of the first group (n=97) received standard stroke therapy , and patients of the second group (n=86) also received standard treatment and simvastatin additionally. Combined endpoint (cardiovascular death + recurrent cardiovascular events + necessity of readmission), dynamics of neurological status and endothelial function were considered. Results. Primary combined endpoint was achieved in 66 cases in the first group (68.04%) and in 47 (54.65%) in the second one (p=0.043). Neurological status evaluated by National Institutes of Health Stroke Scale (NIHSS), Mini-Mental State Examination (MMSE) scale, and Scandinavian scales had a faster positive dynamics in patients receiving simvastatin. The same patients revealed more intense and quick decrease in desquamated plasma endotheliocytes. Conclusion. Simvastatin 40 mg/day prescribed along with neuroprotective and antihypertensive treatment in acute stage of ischemic stroke leads to lowering of recurrent cardiovascular events number, positive dynamics of neurological status, regression of endothelial dysfunction reflected by significant decrease in number of circulating desquamated endotheliocytes.

Treatment with high-dose simvastatin inhibits geranylgeranylation in AML blast cells in a subset of AML patients

It is currently unknown whether the invitro effects observed with statins in acute myeloid leukemia (AML) cells, including lowering of cholesterol, inhibition of isoprenylation, and sensitization to chemotherapy, also occur invivo. Therefore, AML mononuclear cells (MNCs) were isolated from 12 patients before and after 7 days of high-dose (7.5-15 mg/kg/day) simvastatin treatment. Parallel mouse studies were performed to have, in addition to AML cells, access to liver tissue, a major target of statins. Serum cholesterol levels were lowered by simvastatin in all patients, however, only limited changes in the messenger RNA expression of cholesterol metabolism genes were seen in patient and mouse MNCs compared to murine liver cells. Still, two out of seven patients displayed an increased invitro chemosensitivity of their AML cells upon simvastatin treatment. Gene set enrichment analysis on microarray data of AML patient cells and Western blot analysis for the isoprenylated proteins DnaJ and Rap1 on murine and AML patient MNCs demonstrated that invivo simvastatin treatment resulted in inhibition of geranylgeranylation in murine MNCs and in a subset of patient AML MNCs. In summary, our data demonstrate that simvastatin treatment results in chemosensitization and inhibition of geranylgeranylation in AML cells of a subset of patients.

Comparative effects of high and low-dose simvastatin on prostate epithelial cells: The role of LDL

Epidemiological studies have linked statin use with a decreased risk of advanced prostate cancer and an improved recurrence-free survival after radical therapy. It is unclear, however, whether statins could have direct effects against prostate cancer in a clinical setting, as their growth-inhibiting effects on prostate cancer cells have been demonstrated at drug concentrations which exceed the level in plasma during standard clinical dosing. We compared responses to high-dose and therapeutic-dose simvastatin in normal and cancerous prostate epithelial cells. Simvastatin was more effective at inhibiting the growth of normal prostate epithelial cells than of cancer cells. At therapeutic 100 nM concentration simvastatin had a cytostatic effect on normal cells: apoptosis was only slightly induced, but a decrease in cell cycle activity and an increase in senescence were observed. At therapeutic concentrations, lipophilic simvastatin caused a stronger growth inhibition than did hydrophilic rosuvastatin. In contrast, 10 μM simvastatin had a cytotoxic effect both on normal and cancer cells. Addition of LDL-cholesterol effectively reversed the cytostatic effect in all cell lines, but overcoming the cytotoxicity of 10 μM simvastatin required a combination of LDL-cholesterol and mevalonate. As LDL-cholesterol completely prevented the growth-inhibiting effect of therapeutic-dose simvastatin already at low, subphysiological concentrations it is unlikely that statins have direct effects on growth of prostate epithelial cells in vivo. Statins' possible benefits against prostate cancer could be due to systemic cholesterol-lowering, as suggested by epidemiological studies. Future clinical studies evaluating the effects of statins on prostate cancer prevention should monitor serum LDL and should probably administer statins at higher concentrations than those currently used in the treatment of hypercholesterolemia.

Focus on Statin Safety Concerns

Muscle complaints, including rhabdomyolysis (severe muscle damage), related to the cholesterol-lowering medications known as statins, are a class effect. Following preliminary data from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial showing increased muscle injuries, the Food and Drug Administration (FDA) began reviewing the safety of simvastatin, particularly the high-dose 80-mg simvastatin, in March 2010. On June 8, 2011, the Food and Drug Administration (FDA) released the updated product information with revised safety warnings regarding myopathy and rhabdomyolysis associated with products for high cholesterol that contain simvastatin. Simvastatin is the generic form of Zocor and is the statin contained in both Vytorin (simvastatin and ezetimibe) and Simcor (simvastatin and niacin extended-release). From the SEARCH trial and analysis of the FDA’s Adverse Event Reporting System (AERS) database, the FDA found that fatal rhabdomyolysis was significantly more common with 80 mg compared with 20 mg of simvastatin, and that overall rates of myopathy and rhabdomyolysis were higher in simvastatin 80 mg versus lower doses of simvastatin or other statins (e.g., atorvastatin, pravastatin, etc.). The risks for both myopathy and rhabdomyolysis were highest for 80 mg simvastatin during the first 12 months of treatment and are shown in Table 1. Both older age and female sex were seen as risk factors for

PO.02 Cognitive and neuropsychiatric status in a large cohort of patients with secondary progressive multiple sclerosis

BackgroundThe recruitment of secondary progressive multiple sclerosis (SPMS) patients to the MS-STAT trial (a double-blind randomised placebo-controlled trial of high dose simvastatin) provided an opportunity to evaluate the frequency and...

ChemInform Abstract: Genetic Marker of Statin‐Induced Rhabdomyolysis

AbstractReview: 39 refs.

Simvastatin Exerts Favourable Effects on Neointimal Formation in a Mouse Model of Vein Graft

Background Simvastatin inhibits human saphenous vein neointima formation in human saphenous vein organ cultures. However, it is not known if simvastatin actually inhibits vein graft intima hyperplasia in vivo, and the underlying mechanisms behind that. In this study, we used a murine vein graft model to address these issues. Methods and results Vein grafting was performed among C57BL/6 J mice treated with low-dose (2 mg kg −1) or high-dose (20 mg kg −1) simvastatin or vehicle subcutaneously 72 h before and then daily after surgery. As compared to the vehicle, simvastatin dose-dependently significantly inhibited vein graft intima hyperplasia 4 weeks after surgeries. Immunohistochemistry studies suggested that vein graft neointima was mainly composed of vascular smooth muscle cells (VSMCs), and the rate of proliferating cell nuclear antigen (PCNA)-positive cells in the intima of vein grafts was significantly lower in simvastatin-treated groups than in control group. We isolated VSMC from mouse vena cava, simvastatin significantly reduced VSMC proliferation, and platelet-derived growth factor (PDGF)-induced VSMC migration in a dose-dependent manner. Conclusion Simvastatin inhibits neointima formation of mouse vein graft under normocholesterolaemic condition in vivo, the mechanisms might be associated with inhibitory effects of simvastatin on VSMC proliferation and migration.

Weighing the Benefits of High-Dose Simvastatin against the Risk of Myopathy

Having reviewed the data on the risk of myopathy, the FDA recommends that the 80-mg dose of simvastatin be used only in patients who have been taking this dose for an extended period without signs or symptoms of clinically significant muscle toxicity.

New restrictions on use of high-dose simvastatin

New restrictions on use of high-dose simvastatin

CRP enhances soluble LOX-1 release from macrophages by activating TNF-α converting enzyme

Circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) play an important role in the development and progression of atherosclerosis. We hypothesized that the inflammatory marker C-reactive protein (CRP) might stimulate sLOX-1 release by activating tumor necrosis factor-α converting enzyme (TACE). Macrophages differentiated from THP-1 cells were stimulated with TNF-α and further treated with CRP in the absence or presence of specific inhibitors or small interfering RNA (siRNA). Our results showed that CRP increased sLOX-1 release from activated macrophages in a dose-dependent manner and that these effects were regulated by Fc γ receptor II (FcγRII)-mediated p47(phox) phosphorylation, reactive oxygen species (ROS) production, and TACE activation. CRP also enhanced sLOX-1 release from macrophages derived from peripheral blood mononuclear cells (PBMC) of patients with acute coronary syndrome (ACS). Pretreatment with antibody against FcγRII or with CD32 siRNA, p47(phox) siRNA, apocynin, N-acetylcysteine, tumor necrosis factor-α protease inhibitor 1 (TAPI-1) or TACE siRNA attenuated sLOX-1 release induced by CRP. CRP also elevated serum sLOX-1 levels in a rabbit model of atherosclerosis. Thus, CRP might stimulate sLOX-1 release, and the underlying mechanisms possibly involved FcγRII-mediated p47(phox) phosphorylation, ROS production, and TACE activation.

Pleiotropic effects of ezetimibe/simvastatin vs. high dose simvastatin

BackgroundIn the setting of stable coronary artery disease (CAD), it is not known if the pleiotropic effects of cholesterol reduction differ between combined ezetimibe/simvastatin and high-dose simvastatin alone. ObjectiveWe sought to compare the anti-inflammatory and antiplatelet effects of ezetimibe 10mg/simvastatin 20mg (E10/S20) with simvastatin 80mg (S80). Methods and resultsCAD patients (n=83, 63±9years, 57% men) receiving S20, were randomly allocated to receive E10/S20 or S80, for 6weeks. Lipids, inflammatory markers (C-reactive protein, interleukin-6, monocyte chemoattractant protein-1, soluble CD40 ligand and oxidized LDL), and platelet aggregation (platelet function analyzer [PFA]-100) changes were determined. Baseline lipids, inflammatory markers and PFA-100 were similar between groups. After treatment, E10/S20 and S80 patients presented, respectively: (1) similar reduction in LDL-C (29±13% vs. 28±30%, p=0.46), apo-B (18±17% vs. 22±15%, p=0.22) and oxidized LDL (15±33% vs. 18±47%, p=0.30); (2) no changes in inflammatory markers; and, (3) a higher increase of the PFA-100 with E10/S20 than with S80 (27±43% vs. 8±33%, p=0.02). ConclusionsThese data suggest that among stable CAD patients treated with S20, (1) both E10/S20 and S80 were equally effective in further reducing LDL-C; (2) neither treatment had any further significant anti-inflammatory effects; and (3) E10/S20 was more effective than S80 in inhibiting platelet aggregation. Thus, despite similar lipid lowering and doses 4× less of simvastatin, E10/S20 induced a greater platelet inhibitory effect than S80.

Genetic Marker of Statin-induced Rhabdomyolysis

This review summarizes genetic factors predisposed to statin-induced rhabdomyolysis. The first genetic risk factor of statin myopathy uncovered by genome-wide analysis of single nucleotide polymorphisms was the common variant of SLCO1B1 gene. Analysis of 30000 genetic markers in 85 patients with myopathy induced by high-dose simvastatin showed a strong association with 521T>C polymorphism of SLCO1B1. Another study also showed that this variant of SLCO1B1 has a significant association with myopathy in patients taking pravastatin or atorvastatin although the number of patients analyzed was limited. In addition to SLCO1B1, recent studies suggested that variants of genes encoding transporters (ABCG2 and ABCB1) and metabolic enzymes (CYP2C8 and UGT1A3) involved in the disposition of statins, and those involved in the metabolic muscle disease (glycogen storage disorders, carnitine palmitoyl-2 deficiency and myoadenylate deaminase deficiency) are also risk factors of statin-induced myopathy. These genetic factors may provide predisposition testing for statin-induced rhabdomyolysis.

Effect of moderate and high dose simvastatin on adhesion molecules in severe hypercholesterolemia after targeting the LDL-cholesterol – a randomised, placebo-controlled study

The effect of statins on the levels of cell adhesion molecules (CAM) is discussed in the literature as one of the pleiotropic effects of the drugs. This effect is one of the ways that could be used to control the initial stage of atherogenesis. The research in this field is inadequate and controversial. Prevention guidelines recommend that target levels of LDL cholesterol in high-risk patients should be less than 2.6 mmol/l. If the primary target is LDL-cholesterol, it is doubtful if patients can have any significant changes in the levels of the cell adhesion molecules (CAM). Study the effect of simvastatin administered in a moderate dose of 40 mg and in a high dose of 80 mg on endothelium activation in the context of the plasma levels of soluble cellular adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin) in recently diagnosed untreated severe hypercholesterolemia after reaching target levels for the LDL-cholesterol below 2.6 mmol/1. One hundred patients (aged > 16 years) were included in the study. Hypercholesterolemia was defined as fasting total serum cholesterol level greater than 7.5 mmol/l and LDL-cholesterol > 4.9 mmol/l. The study was carried out in three phases, the main goal being titration of simvastatin dose from 40 to 80 mg with the purpose of achieving the target LDL level of < 2.6 mmol/l in a randomised placebo-controlled study. There was a statistically significant reduction of sVCAM-1 following the 80-mg simvastatin therapy for one month after reaching target levels of LDL-cholesterol < 2.6 mmol/l in hypercholesterolemic patients in comparison with the moderate dose (40 mg) of simvastatin for one month (p < 0.001). The results of the study demonstrated that simvastatin in a dose of 80 mg exerted an effect on the levels of some CAM, and particularly on VCAM-1 in contrast to the same drug used in a dose of 40 mg. As different statins most likely have a distinctly specific effect on different adhesion molecules, this study seeks to establish a suitable panel of such adhesion molecules that may be used in monitoring statin therapy.

Inappropriate concomitant use of amlodipine and simvastatin: A report on its incidence in a primary care unit

Sir, Metabolic syndrome (diabetes mellitus, dyslipidemia, hypertension and obesity) is a common metabolic disorder that can be seen around the world. Polypharmacy can be expected in patients with this syndrome and it sometimes causes adverse effects due to drug interaction. An important concern is the inappropriate concomitant use of amlodipine and simvastatin. It is reported that concomitant use can result in double dosing of simvastatin due to common passing of the CYP3A4,[1] and this can be a risk factor for myopathy. Here, the authors report on incidence of inappropriate concomitant use of amlodipine and simvastatin in a primary care unit of a tertiary hospital (the name is blinded due to privacy). Based on the data of 600 dyslipidemic cases in this setting, 120 (20%) cases were administered high-dose simvastatin (40 mg/day). Of interest, 30 (5%) had inappropriate concomitant use of amlodipine and simvastatin. This implies that general practitioners might not know the fact that concomitant use of amlodipine and high dosage of simvastatin can be a risk factor for myopathy.

The influence of high-dose simvastatin and diltiazem on myocardium in rabbits: a haemodynamic study

IntroductionSimvastatin and diltiazem are often prescribed together for the treatment of hypercholesterolaemia in patients with hypertension and/or angina pectoris. However, diltiazem, a CYP3A inhibitor, is a well-recognized risk factor of skeletal muscle myopathy. It is not known whether such interaction also affects myocardial efficiency causing haemodynamic changes. The aim of the experiment was to establish the impact of simvastatin co-administered with diltiazem on the haemodynamic parameters after continuous infusion of dopamine.Material and methodsThe experiments were performed on 28 New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% MC – methylcellulose (control group); diltiazem; simvastatin; simvastatin + diltiazem, for 14 days (po). The following haemodynamic parameters were estimated: cardiac output index (CI), heart rate (HR), systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP) and total peripheral resistance index (TPRI). The registration of haemodynamic parameters was performed by the Doppler method and during the experiments the animals were anaesthetized with α-chloralose (75 mg/kg bw) and urethane (500 mg/kg bw).ResultsDopamine did not cause a statistically significant increase in CI in rabbits receiving simvastatin alone. Diltiazem significantly increased CI if given simultaneously with simvastatin, which might suggest the improvement of cardiac efficiency resulting from such interaction.ConclusionsThe possibility of another mechanism of drug-drug interaction than the one based on CYP3A inhibition, and its impact on cardiac or skeletal muscle, might be considered.