The Effects of Melatonin on Elevated Liver Enzymes During Statins Treatment

April 19, 2017 updated by: Cezary Chojnacki, Medical University of Lodz
Introduction. Statins are generally well tolerated but not devoid of side effects. Quite often it is manifested by asymptomatic increase in the level of aspartate and alanine aminotransferase. In such cases patients to administer hepatoprotective drugs, but most of them used for this purpose are ineffective. The aim of this study was assess the usefulness of melatonin in counteracting the adverse hepatic events from statins. Methods. The research program included 60 patients(aged 47-65 years, 41 women and 23 men)with hyperlipidemia taking atorvastatin or rosuvastatin in dose 20-40 mg daily. The patients were randomly allocated in two groups. Group I (n=30) was recommended to take the same statin at a standardized daily dose of 20 mg together with melatonin at a dose 2 x 5 mg, at 7:00 and 21:00. In group II (n=30) patients took statins with placebo at the same time of the day. Follow-up laboratory tests (AST, ALT, GGT, ALP, cholesterol, triglycerides) were evaluated after 2,4 and 6 mounts of treatment.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Introduction Statins are widely used in the treatment and prevention of lipid metabolism disorders. They are generally well tolerated but not devoid of side effects. These include, among others, muscular symptoms, arthritis, headaches, gynecomastia. Myositis and rhabdomyolysis associated with increased activity of creatinine kinase and serum creatinine levels are rare but serious adverse events of statin therapy. The risk of these complications is increased in elderly patients with chronic diseases and in alcohol abusers.

Furthermore, statins cause hepatotoxic effect which is observed in several percent of treated patients, usually in the first weeks of the therapy . Most frequently it is manifested by asymptomatic increase in the level of aspartate and alanine aminotransferase. This is usually a temporary increase, but in some patients the level of these enzymes exceeds 3 times the normal limit, which is a matter of concern. In such cases, patients expect the decision to discontinue the treatment or to administer hepatoprotective drugs. Acetylcholine, sylibinin, phospholipids and other drugs used for this purpose are not always effective. Therefore, there is still search for alternative drugs for the protection of liver.

In own study melatonin was used for this purpose because previous experimental studies had demonstrated that it protected liver against harmful effects of many toxic agents as well as the consequences of ischemia-reperfusion model.

The liver is an organ in which there comes to intensive metabolic and detoxification processes. In their course large amounts of reactive oxygen species are generated and they exert a toxic effect on hepatocytes. A complex antioxidant system - in which metabolized there melatonin (pineal and from other sources) is an important part - prevents that.

The main melatonin metabolic pathway in the liver is through hydroxylation pathway at the C-6 position by 6-hydroxylase and P450 cytochromes (CYP1A1, CYP1A2, CYP2P19, CYP1B1 isozymes). The 6-hydroxymelatonin, formed in this process, is conjugated with sulphate and glucuronide to 6-hydroxymelatonin sulphate or glucuronide. In this process melatonin and its metabolites exert high antioxidant activity.

An alternative metabolic pathway includes melatonin oxidation to N-acetyl-formyl-5- methoxykynuramine (AFMK) and N-acetyl-5-methoxykynuramine (AMK). The kynurenine pathway of melatonin metabolism leads to formation of a series of free radical scavengers.

Furthermore, melatonin decreases the production of proinflammatory cytokines and inhibits hepatic fibrogenesis. Owing to its multidirectional action in liver, apoptosis and necrosis decrease, the integrity is protected and regeneration is improved.

The aim of this study was to assess the usefulness of melatonin in counteracting the adverse hepatic events from statins.

Material and Methods Patients and Data Collection The research program included 30 subjects, aged 47-68 years, 41 women and 23 men. All women were I the postpostmenopausal period. Recruitment and diagnostic tests were conducted in the Department of Gastroenterology, Medical University of Lodz and Outpatient Consulting Clinic "Gastro" in Lodz.

The research study was performed in the years 2012-2016. Therapeutic Procedures After inclusion into the study, all patients were recommended the same balanced diet with limited animal fats and simple carbohydrates of caloric content of 1600 kcal. At the same time, they were recommended to continue the treatment with the same statin at a daily dose of 20 mg.

The patients were randomly allocated into two groups. Group I (n=30) was recommended to take statin together with melatonin (LEK-AM, Poland) at a dose of 2x5 mg, at 7:00 a.m. and 9:00 p.m. In Group II (n=30) patients took statin with placebo (LEK-AM, Poland) at the same dose and time of the day.

Follow-up laboratory tests (AST, ALT, GGT, ALP, cholesterol and triglycerides) were evaluated after 2,4 and 6 months of treatment.

Ethical procedures A written consent was obtained from the patients and the Bioethics Committee of the Medical University in Lodz approved the study protocol (RNN/45/12/KB).

Tests were conducted in accordance with the Declaration of Helsinki and with the principles of Good Clinical Practice.

Statistical analysis All parameters were checked for normality using the Shapiro-Wilk test. Wilcoxon's rank sum test was used for the comparison of basal treatment differences between each liver enzyme level. Comparison of parameters in four time series was calculated using ANOVA Friedman test. Mann-Whitney U test was used for nonparametric data to perform the comparison between groups. Calculation were made using Statistical 9.1 Microsoft Co. software, and statistical significance was established at p< 0,05.

Acknowledgments This work was supported by the grant from the Polish Ministry of Science and Higher Education No: NN 402 54 37/40.

Competing Interests The authors declare that they have no competing interests.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
60

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

47 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:- hyperlipidemia treated with statins for minimum 6 months

  • at least 2-fold increase in the level of aspartate and alanine aminotransferase found in two consecutive tests
  • the persistence of increased aminotransferase levels despite the reduction in the statin dose At the time of the inclusion of patients in the study, 38 subjects were taking atorvastatin ( 20 mg), and 26 - rosuvastatin at the dose 40 mg (3 patients), - 20mg (19 patients) and 15 mg (4 patients).

Exclusion Criteria:- history of viral hepatitis

  • cholelithiasis 4
  • body mass index (BMI)>30kg/m2
  • alcohol abuse
  • familial hypercholesterolemia
  • established hypertension
  • thyroid diseases
  • other organic, metabolic or mental diseases
  • hormone replacement therapy
  • taking other medications, especially analgesics and psychotropic drugs

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: melatonin
Melatonin 10mg/d p.o.
Drug: Melatonin 10 mg
melatonin 10mg daily p.o.
Other Names:
  • Melatonin Lek-AM 10mg
Placebo Comparator: placebo
placebo 10mg/d p.o.
Drug: Placebo
Placebo 10mg daily p.o.
Other Names:
  • Placebo 10mg

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
liver enzymes
Time Frame: 6 months
levels
6 months

Collaborators and Investigators

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Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Medical University of Lodz

Study record dates

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Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2012

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 30, 2016

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 15, 2016

Study Registration Dates

First Submitted

First Submitted

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April 13, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 19, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 20, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 20, 2017

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 19, 2017

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NN 402 54 37/40
  • RNN/45/12/KB (Other Identifier: Bioethics Committee of the Medical University in Lodz)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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