Prospective, randomized, double-blinded, placebo-controlled study on safety and tolerability of the krill powder product in overweight subjects with moderately elevated blood pressure.

BACKGROUND: Krill powder is rich in bioactive ingredients such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), phospholipids, protein and astaxanthin. Containing dominantly EPA, it is considered to be effective in lowering lipids, foremost serum triglycerides and LDL cholesterol. Krill-derived protein hydrolysates/peptides may have positive effect on blood pressure and astaxanthin has anti-oxidative and anti-inflammatory properties. Thus, krill powder has a lot of potential in improving lipid and metabolic profile and reinforcing the activity of the antioxidant system. However, randomized clinical trials on krill powder are scarce and systematic data of krill meal on human safety is limited. Some of the earlier studies have reported several, non-serious adverse events, mostly related to gastrointestinal tract, but systematic sufficiently powered study on safety is lacking. The aim of this study was to collect data on safety and tolerability of krill powder in humans and simultaneously gain efficacy data by measuring the risk factors for cardiovascular disease. METHODS: The study was a randomised, double-blinded, placebo-controlled intervention study with 35 overweight subjects with mildly or moderately elevated blood pressure, who took 4 g krill oil powder or 4 g of placebo during an 8-week follow-up period. The study consisted of a pre-screening, screening, day 0 baseline (randomization visit) and three follow-up visits on days 14, 28 and 56. The reported adverse events in the groups were compared as primary endpoint and haematological safety parameters and changes in systolic and diastolic pressure and blood total and lipoprotein lipids were measured as secondary end points. RESULTS: There were in total 80 reported adverse events during the follow-up; 50 in placebo and 30 in krill powder group. Gastrointestinal symptoms (flatulence, heartburn and diarrhea) were the most commonly reported among those probably related to the test products. No serious adverse events were reported. The mean value of all measured hematology variables remained within the reference values in all study subject and no significant changes were observed in blood pressure or lipid values. CONCLUSIONS: The results seem to indicate that using krill powder as a source for EPA and DHA is safe in therapeutic dose and the risk of adverse events, let alone serious ones, is low. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03112083 , retrospectively registered.

Permeability and toxicity characteristics of L-cysteine and 2-methyl-thiazolidine-4-carboxylic acid in Caco-2 cells.

Acetaldehyde is a known mutagenic substance and has been classified as a group-one carcinogen by the WHO. It is possible to bind acetaldehyde locally in the gastrointestinal (GI) tract with the semi-essential amino acid l-cysteine, which reacts covalently with acetaldehyde and forms compound 2-methyl-thiozolidine-4-carboxylic acid (MTCA). The Caco-2 cell line was used to determine the permeation of l-cysteine and MTCA, as well as the possible cell toxicity of both substances. Neither of the substances permeated through the Caco-2 cells at the concentrations used in this study, and only the highest concentration of MTCA affected the viability of the cells in the MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide) test. These results showed that when l-cysteine is administered in formulations releasing it locally in the lower parts of GI tract, it is not absorbed but can react with acetaldehyde, and that neither l-cysteine nor MTCA is harmful to the cells when present locally in the upper parts of GI tract. This study also shows that MTCA is sensitive at a lower pH of 5.5. Since stable MTCA is desired in different parts of the GI tract, this observation raises concern over the influence of lower pH on l-cysteine-containing product ability to bind and eliminate carcinogenic acetaldehyde.

Reducing carcinogenic acetaldehyde exposure in the achlorhydric stomach with cysteine.

BACKGROUND: Acetaldehyde, associated with alcohol consumption, has recently been classified as a group 1 carcinogen in humans. Achlorhydric atrophic gastritis is a well-known risk factor for gastric cancer. Achlorhydria leads to microbial colonization of the stomach. Several of these microbes are able to produce significant amounts of acetaldehyde by oxidation from alcohol. Acetaldehyde can be eliminated from saliva after alcohol intake and during smoking with a semi-essential amino acid, L-cysteine. The aim of this study was to determine whether cysteine can be used to bind acetaldehyde in the achlorhydric stomach after ethanol ingestion. METHODS: Seven volunteers with achlorhydric atrophic gastritis were given either slow-release L-cysteine or placebo capsules in a double-blinded randomized trial. Volunteers served as their own controls. A naso-gastric tube was inserted to each volunteer. The volunteers ingested placebo or 200 mg of L-cysteine capsules, and ethanol 0.3 g/kg body weight (15 vol%) was infused intragastrically through a naso-gastric tube. Five-milliliter samples of gastric contents were aspirated at 5-minute intervals. RESULTS: During the follow-up period, the mean acetaldehyde level of gastric juice was 2.6 times higher with placebo than with L-cysteine (13 vs. 4.7 µM, p < 0.05, n = 7). CONCLUSIONS: L-cysteine can be used to decrease acetaldehyde concentration in the achlorhydric stomach during alcohol exposure. Intervention studies with L-cysteine are needed on reducing acetaldehyde exposure in this important risk group for gastric cancer.

Neutron activation based gamma scintigraphic evaluation of enteric-coated capsules for local treatment in colon.

The fate of two colon-specific formulations developed in our previous study was investigated using a gamma scintigraphic imaging method. The formulations contained paracetamol and samarium oxide (Sm2O3) and either microcrystalline cellulose (MCC) or hypromellose (HPMC K4M) as diluent and were coated with Eudragit S polymer. The gamma scintigraphic evaluation proved that the products remained intact in the stomach and the upper gastrointestinal tract. The gastric residence time was less that 1h. Three to four hours after administration the formulations had reached the ileo-caecal junction, i.e. the small intestine transit time was approximately 3h. The capsules disintegrated in the ileo-caecal junction or in the ascending colon. The capsules containing MCC released the marker momentarily, the capsules containing HPMC K4M gradually spreading it to the whole colon. The gamma images also verified that the HPMC gel disintegrates completely in 12-14 h. While comparing the results to those previously obtained from the bioavailability studies it could be concluded that it is possible to develop colon specific drug products that begin releasing the drug in the ileo-caecal junction or at the beginning of the ascending colon and spread the drug dose to a larger surface area by using enteric coats and hydrophilic polymers.