Pharmacodynamics
Conditions
Brief summary
A majority of high-risk patients does not achieve their cholesterol target levels and most of these patients do not receive more effective combination therapy, which goes beyond statin monotherapy. Large interindividual differences in treatment outcomes have been observed for patients receiving statins. Statins block cholesterol synthesis and increase cellular low-density lipoprotein (LDL) uptake. Importantly, LDL uptake is highly divergent in individuals.The aim of this trial is to investigate how atorvastatin influences leukocyte readouts of LDL uptake and lipid storage in humans. The trial is a single-arm, open-label, interventional trial. A total of 15 healthy volunteers will receive 40 mg atorvastatin once a day for 4 weeks. The participants will provide blood samples before starting the atorvastatin intervention, each week when taking atorvastatin, and one week after the end of the intervention for the measurement of leukocyte readouts of LDL uptake and lipid storage.
Interventions
DRUGAtorvastatin
one 40 mg atorvastatin tablet once daily for 28 days
Sponsors
University of Helsinki
Mikko Niemi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
1. a signed written informed consent 2. age 18-40 years 3. healthy, and 4. Accepted results from laboratory tests (blood haemoglobin, basic blood count and blood platelets, alanine aminotransferase, alkaline phosphatase, glutamyl transferase, creatinine, plasma potassium and sodium). Negative pregnancy test result (serum human chorionic gonadotropin) for women. 5. Fully vaccinated against COVID-19.
Exclusion criteria
1. significant disease 2. smoking 3. SLCO1B1 poor function genotype 4. oral contraception or other continuous medication 5. pregnancy, planning of pregnancy or breastfeeding 6. participating in a clinical trial less than 3 months ago 7. donating blood less than 3 months ago 8. marked obesity 9. anticipated difficulties in drawing blood samples 10. weight less than 45 kg 11. BMI less than 18.5 kg/m2 or 12. inadequate Finnish language skills
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lipid trafficking score LT-Mo | Baseline and once a week for 5 weeks | The primary outcome measurement is the lipid trafficking score LT-Mo is a combination of LDL uptake and lipid droplet quantifications in monocytes. The participants provide blood samples before starting the atorvastatin intervention, each week when taking atorvastatin (4 times in total), and one week after the end of the intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Leukocyte LDL uptake | Baseline and once a week for 5 weeks | Systematic quantification of leukocyte uptake of low-density lipoprotein (LDL). Leukocytes are exposed to fluorescently labelled LDL particles and internalized LDL particles are quantified with microscopy and automated image analysis. The specific readouts are overall fluorescent LDL intensity and the number of endosomal organelles filled with fluorescent LDL particles for monocyte and lymphocyte subpopulations. |
| Leukocyte lipid storage | Baseline and once a week for 5 weeks | A systematic semi-automated approach is used to quantify cellular lipid droplets, dedicated storage organelles for lipids. Individual lipid droplets, their size and area are quantified in each cell and either used as individual readouts or combined with LDL uptake readouts to derive lipid trafficking scores. |
| Atorvastatin plasma concentration | Once a week during the 4 week atorvastatin treatment | The plasma concentrations of atorvastatin and its metabolites will be quantified with liquid chromatography tandem mass spectrometry (LC-MS/MS) from plasma samples. |
Countries
Finland
Contacts
Primary ContactMikko Niemi, MD, PhD
Backup ContactAnssi Mykkänen, MD
Outcome results
None listed