THERAPY DOSSIER · th-835f4dc2894e

Simvastatin

Drug · HMG-CoA reductase inhibitor (INHIBITOR), direct interaction, disease efficacy true.

No trauma translation Suggest a correction

This record is classified as “NO TRAUMA TRANSLATION”. Read the indication and notes below for the specific context.

Evidence & regulatory context

Mechanism: HMG-CoA reductase inhibitor (INHIBITOR), direct interaction, disease efficacy true.
Target: CHEMBL402
Injury models: TBI · Chemical/toxin · Radiation · Burn · Other · Endotoxin/LPS · Ischaemia-reperfusion · Spinal cord injury · Wound
Reported indication: Hypercholesterolaemia / dyslipidaemia and cardiovascular risk reduction (HMG-CoA reductase inhibitor; approved 1991)
First approval: 1991
Development stage: Approved lipid-lowering agent; acute-injury/sepsis repurposing without benefit
ChEMBL record: CHEMBL1064 ↗
ChEMBL max phase: 4 / 4 (development scale, not regulatory approval)
Synonyms: Zocor; Synvinolin; MK-733; Flolipid; Simvastatine
Note: Not recorded

Clinical trials 14

1 linked trials carry an injury-indication flag. These flags support record-level exploration and sit alongside the stringent aggregate counts described in Methods.

NCT05133310 ↗Injury indicationPHASE4unknown

Effect of Simvastatin on Sepsis and Febrile Neutropenia in Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia · Sepsis

Enrolment: 108 · Results not recorded

NCT00762164 ↗PHASE4completed

Comparative Efficacy of a Vytorin 10/80 Tablet Split Into 4 (Estimated Dose Ezetimibe 2.5 + Simvastatin 20) Versus Simvastatin 20 Milligrams on LDL Cholesterol

Hypercholesterolemia

Enrolment: 34 · Results not recorded

NCT01282385 ↗PHASE4unknown

Hemodynamic Effect of the Combination of Simvastatin With Non-cardioselective Beta Blockers in Patients With Cirrhosis and Clinically Significant Portal Hypertension

Liver Cirrhosis · Portal Hypertension

Enrolment: 60 · Results not recorded

NCT02305355 ↗PHASE4completed

Efficacy and Safety of Prescription Omega-3 Fatty Acid Added to Stable Statin Therapy in Patients With Type 2 Diabetes and Hypertriglyceridemia

Diabetes Mellitus, Type 2 · Hypertriglycemia

Enrolment: 68 · Results not recorded

NCT03653663 ↗PHASE4unknown

Near Infrared Spectroscopy to Diagnose Statin-Associated Muscle Symptoms

Statin Adverse Reaction · Skeletal Myopathy

Enrolment: 40 · Results not recorded

NCT00906451 ↗PHASE4completed

Effect of Simvastatin Treatment on Inflammatory Response and Endothelial Function After Myocardial Infarction

Myocardial Infarction · Inflammation · Endothelial Dysfunction

Enrolment: 58 · Results not recorded

NCT03084601 ↗PHASE4completed

Postoperative Pain After 3MIX-TATIN Versus Calcium Hydroxide Iodoform Paste In Necrotic Primary Molars

Necrotic Pulp · Postoperative Pain

Enrolment: 100 · Results not recorded

NCT04140201 ↗PHASE4unknown

Evaluation of Lipid Lowering Agents on Diabetic Retinopathy and Cardiovascular Risk of Diabetic Patients

Diabetic Retinopathy

Enrolment: 80 · Results not recorded

NCT00654407 ↗PHASE3completed

Open Label Randomized Multi-Center Phase IIIB Parallel Group Switching Study Comparing Atorvastatin and Simvastatin With Rosuvastatin in High Risk Subjects With Type IIa and IIb Hypercholesterolemia

Hypercholesterolemia

Enrolment: 4875 · Results not recorded

NCT02735707 ↗PHASE3recruiting

REMAP-CAP: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (includes simvastatin and vitamin C domains)

Community-acquired Pneumonia · Influenza · COVID-19

Enrolment: 20000 · Results not recorded

NCT01057758 ↗PHASE3terminated

Effect of Association of a Statin to Antibiotics on Prognosis of Suspected Ventilator-associated Pneumonia

Pneumonia

Enrolment: 300 · Results not recorded

NCT01923077 ↗PHASE2unknown

Early Intensive Statins Improve Left Ventricular Function in Acute Myocardial Infarction

Acute Myocardial Infarction

Enrolment: 140 · Results not recorded

NCT06379958 ↗PHASE1recruiting

Phase 1 Open-label 4-Part Drug-Drug Interaction Study to Evaluate Effects of CYP3A4 Inhibition/Induction on Leramistat PK and Effect of Leramistat on Simvastatin PK

Pharmacokinetics

Enrolment: 48 · Results not recorded

NCT00995670 ↗Phase not recordedcompleted

Ischemia/Reperfusion Injury of Human Endothelium: Role of Glucose and Statins (vitamin C and simvastatin arms)

Hyperglycemia

Enrolment: 59 · Results not recorded

Preclinical evidence 19

15 studies reported at therapy level; 19 evidence entries itemised.

PMID 21087618 ↗2010Mixed findings

Differential efficiency of simvastatin and lipoic acid treatments on Bothrops jararaca envenomation-induced acute kidney injury in mice.

MouseChemical/toxinMaleAfter envenomation

Model: Bothrops jararaca venom-induced acute kidney injury

Both lipoic acid and simvastatin mitigated some venom-induced renal effects, with simvastatin showing broader benefit.

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PMID 20452610 ↗2010Reported benefit

Protective role of simvastatin on lung damage caused by burn and cotton smoke inhalation in rats.

RatBurnUnspecifiedWistarFemalen = 18Orogastric (oral)25 mg/kg/dayAfter injury

Model: 30 percent burn with cotton smoke inhalation

Simvastatin reduced lung and tracheoepithelial damage, oxidative stress and apoptosis after burn and smoke inhalation.

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PMID 21441352 ↗2011Reported benefit

Simvastatin regulates CXC chemokine formation in streptococcal M1 protein-induced neutrophil infiltration in the lung.

MouseOtherC57BL/6Malepretreatment before M1 protein challenge

Model: streptococcal M1 protein-induced acute lung injury

Simvastatin reduced M1 protein-induced neutrophil infiltration and oedema by decreasing pulmonary CXC chemokine formation.

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PMID 21666443 ↗2011Reported benefit

Simvastatin in traumatic brain injury: effect on brain edema mechanisms.

RatTBIFluid percussionSprague-DawleyMaleOral37.5 mg/kg1 h and 6 h after TBI

Model: Lateral fluid percussion traumatic brain injury

Simvastatin reduced post-traumatic brain oedema, neurological deficits and blood-brain barrier permeability after fluid percussion TBI in rats by preserving tight junctions and limiting neutrophil infiltration.

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PMID 33008033 ↗2020Reported benefit

Protective Effects of Simvastatin on Endotoxin-Induced Acute Kidney Injury through Activation of Tubular Epithelial Cells' Survival and Hindering Cytochrome C-Mediated Apoptosis.

RatEndotoxin/LPSWistarn = 30 rats in 5 groups of 6Oral gavage, prepared in 0.5 per cent methylcellulose10, 20 or 40 mg/kgPretreatment: 5 days of dosing before LPS, final dose 1.5 h before LPS

Model: Single non-lethal intraperitoneal lipopolysaccharide (serotype O127:B8) challenge at 0.25 LD50/kg (5.5 mg/kg) inducing sepsis-associated acute kidney injury

Simvastatin dose-dependently reduced LPS-induced renal histopathological injury, with renal damage score falling from 3.58 plus or minus 0.50 with LPS alone to 1.42 plus or minus 0.50 at 40 mg/kg. Tubular apoptotic index fell from 34.8 plus or minus 3.6 per cent to 14.0 plus or minus 3.3 per cent a…

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PMID 29445744 ↗2017Reported benefit

Simvastatin Ameliorates PAK4 Inhibitor-Induced Gut and Lung Injury.

RatChemical/toxinSprague-DawleyMalen = 48 rats randomised into two groups of 24 (PAK4 inhibitor, P…Intraperitoneal injection20 mg/kg/dayImmediately after each oral PAK4 inhibitor administration

Model: Gut mucosal barrier dysfunction and acute lung injury induced by oral administration of the PAK4 inhibitor PF-3758309 at 15 mg/kg/day

The PAK4 inhibitor reduced gut PAK4, ZO-1 and CD11c, raised plasma endotoxin, increased lung wet-to-dry ratio, alveolar wall thickness and circulating endothelial microparticles, and lowered lung PAK4 and CD11c. Simvastatin attenuated all of these changes, with alveolar wall thickness falling from…

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PMID 27406816 ↗2017Reported benefit

Simvastatin Therapy in the Acute Stage of Traumatic Brain Injury Attenuates Brain Trauma-Induced Depression-Like Behavior in Rats by Reducing Neuroinflammation in the Hippocampus.

RatTBIFluid percussionSprague-DawleyMaleIntraperitoneal injection4, 10 or 20 mg/kg0, 24 and 48 h after traumatic brain injury

Model: Fluid percussion traumatic brain injury

Simvastatin 20 mg/kg given for 3 days significantly attenuated the increase in immobility duration on day 15 after injury and significantly reduced neuronal apoptosis, microglial and astrocyte activation and TNF-alpha expression in hippocampal CA3.

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PMID 23543392 ↗2013Reported benefit

Simvastatin reduces VEGF and NO levels in acute stages of experimental traumatic brain injury.

RatTBIUnspecifiedWistar albinoMalen = 40 rats in four groups1 mg/kg3 hours after the injury insult

Model: Experimentally induced traumatic brain injury

Simvastatin significantly reduced histopathological brain injury scores and prevented the trauma-induced rises in serum and brain VEGF and brain nitric oxide at 24 hours.

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PMID 23428876 ↗2013Reported benefit

Simvastatin maintains function and viability of steatotic rat livers procured for transplantation.

RatIschaemia-reperfusionOther / unspecifiedSprague-DawleyMaleDonor pretreatment (route not stated in the abstract)Single dose (amount not stated in the abstract)30 minutes before liver procurement

Model: Steatotic liver grafts from high-fat diet fed donors subjected to 16 hours cold storage and warm reperfusion (0 hours cold storage as control)

Cold-stored steatotic livers showed raised hepatic vascular resistance, endothelial dysfunction, liver damage, oxidative stress and low nitric oxide. Simvastatin donor pretreatment markedly improved liver injury and prevented endothelial dysfunction, with reduced cell death, autophagy induction and…

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PMID 22537532 ↗2012Reported benefit

Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-alpha.

MouseSpinal cord injuryCompressionPPAR-alpha knockout mice on 129S4/SvJae background and wild-type controls, C57BL/6n = 30 mice per experimental groupIntraperitoneal bolus10 mg/kg simvastatin dissolved in saline; PPAR-alpha antago…1 h and 6 h after injury; GW6471 given 30 min before simvastatin, and at 30 min…

Model: Extradural compression of the spinal cord at T6-T7 with an aneurysm clip of 24 g closing force via T5-T8 laminectomy

Simvastatin reduced inflammation, neutrophil infiltration, nitrotyrosine, cytokine expression, NF-kappaB activation, iNOS expression and apoptosis after spinal cord injury. The effect was weaker in PPAR-alpha knockout mice and was abolished by the PPAR-alpha antagonist GW6471, indicating PPAR-alpha…

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PMID 22122302 ↗2011Reported benefit

Simvastatin pretreatment prevents ambient particle-induced lung injury in mice.

MouseChemical/toxinBALB/cMaleIntraperitoneal1 mg/kg body weight per dayPretreatment for 14 days before particulate exposure

Model: Acute intranasal exposure to residual oil fly ash or Buenos Aires urban air particulate matter at 1 mg/kg body weight for 24 hours, producing acute lung injury

Both particulate types produced acute pulmonary injury with increased lavage cell number, neutrophilic influx, superoxide anion generation and TNF-alpha. Simvastatin had no significant effect by itself but prevented the pulmonary cytotoxicity and inflammation induced by both particulate types.

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PMID 31728280 ↗2019Mixed findings

Sexual Dimorphism of Gut Microbiota Dictates Therapeutics Efficacy of Radiation Injuries.

MouseRadiationMale and femalen = n = 30 per group for survival and body weight after 7 Gy; n…Oral gavage for simvastatin; dietary administration for high-fat dietSimvastatin or high-fat diet given following irradiation

Model: Ionising radiation injury: 7 Gy total body irradiation to assess survival, 4 Gy total body irradiation to assess haematopoietic toxicity, and 12 Gy total abdominal irradiation to assess gastrointestinal toxicity. Additional arms used an antibiotic mixture in drinking water to deplete gut microbes and faecal microbiota transplantation from opposite-sex donors for 14 days

Therapeutic efficacy was strictly sex-dependent. Oral simvastatin improved survival and body weight, restored thymus and spleen tissue, lowered peripheral blood IL-6, TNF-alpha and malondialdehyde, preserved colon length, intestinal villi and goblet cells, reduced faecal LCN2 and normalised intesti…

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PMID 25013810 ↗2014Reported benefit

Simvastatin combined with antioxidant attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury.

RatTBIWeight-drop / impact-accelerationSprague-DawleyMalen = 30 rats total, 6 per group across 5 groupsOral, via orogastric tubeSimvastatin 15 mg/kg per day in 1 mL distilled water; vitam…First dose 1 h after injury

Model: Cortical contusion by weight-drop, 20 g brass weight from 40 cm onto a footplate over the left hind paw sensorimotor cortex, 10 repeated impacts

All treatment groups reduced serum ICAM-1 relative to untreated TBI, with the combination significantly lower than the statin-alone group at 24 h and lower than control at 24 h and day 7. No IL-10 effect was detected. All treated groups outperformed controls on grip testing at 24 h, 72 h and 7 days…

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PMID 30668918 ↗2019Reported benefit

Simvastatin With PRP Promotes Chondrogenesis of Bone Marrow Stem Cells In Vitro and Wounded Rat Achilles Tendon-Bone Interface Healing In Vivo.

RatWoundSprague-DawleyFemalen = 12 wounded rat Achilles tendon-bone interfacesLocal application to the wounded tendon-bone interface

Model: Surgically wounded Achilles tendon-bone interface

Wounds treated with simvastatin-containing platelet-rich plasma gel healed faster and showed greater safranin O and collagen I and II staining than saline, platelet-rich plasma alone or simvastatin alone.

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PMID 24105712 ↗2013Reported benefit

Simvastatin attenuates radiation-induced tissue damage in mice.

MouseRadiationC57BL/6JMaleIntragastric20 mg/kg/dayPretreatment for 14 days before irradiation

Model: Total body cobalt gamma irradiation at 4 Gy or 8 Gy, causing gastrointestinal and haematopoietic acute radiation injury

Simvastatin 20 mg/kg/day for 14 days preserved jejunal crypt-villus height and reduced apoptosis after 4 Gy and 8 Gy, restored bone marrow structure and reduced marrow apoptosis, increased red blood cells and haemoglobin after 4 Gy without changing white cells or platelets, increased circulating en…

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PMID 18722369 ↗2008

Statins decrease chondroitin sulfate proteoglycan expression and acute astrocyte activation in central nervous system injury

RatSpinal cord injury

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PMID 16368834 ↗2006

Pretreatment with simvastatin reduces lung injury related to intestinal ischemia-reperfusion in rats

RatIschaemia-reperfusion

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PMID 15665042 ↗2005

Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury

MouseEndotoxin/LPS

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PMID 12588778 ↗2003

Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage

RatTBI

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