The pharmacokinetics and the relative bioavailability of Mythocondro® were investigated in a comparative pharmacokinetic open label, randomized, two-way cross-over study in 24 human subjects with bovine CS, following a 2,400 mg single dose.
In this human clinical trial Mythocondro® showed an higher bioavailability of 43%, versus bovine CS, with an increased Area Under the Curve (AUC0-24h). This behavior highlights Mythocondro® capacity to be better absorbed if compared to bovine CS. In particular, 5h after administration, the plasmatic concentration of Mythocondro® remains 89% higher than bovine CS.
Quite similar value of Cmax for both formulations further supports data demonstrating that the different plasmatic behavior is strictly related to the capacity of Mythocondro® to remain for a longer time in the blood compartment with a higher concentration compared to bovine CS.
Mythocondro® was tested for efficacy both in vitro and in vivo with evaluation of:
1. Intestinal epithelial permeability compared to animal Chondroitin Sulfates
Mythocondro® shows an improved intestinal epithelial permeability compared to animal CS samples due to its lower molecular mass, without the need of further hydrolysis by the intestinal flora. The intestinal permeability was tested in the Caco-2 cells line model, one of the tests accepted by the ECVAM (European Center for the Validation of Alternative Methods) for the in vitro evaluation of intestinal absorption and is able to predict the absorption of orally administered drugs and substances.
In this model Mythocondro® permeability coefficient is up to 65 times higher than animal CS.
Coefficients of effective permeability (Peff)
Comparison between animal-derived CS and Mythocondro®: Peff of Mythocondro® appeared to be significantly higher than the rest of the samples. [Surapaneni 2013]
|Permeability Coefficient (Peffx106)|
|Mythocondro® vs Animal CS||Significantly higher than the rest of the samples|
2. Efficacy and activity in an induced adjuvant arthritis (AA) model in rats
Adjuvant induced Arthritis (AA) in rats is widely accepted and considered by the scientific community as the reference experimental model to test arthritis symptoms and their treatments. It allows to monitor the disease processes in the acute phase (days 14 – 21) and in the subchronic phase (day 28) of the disease. The advantages of this model are its many similarities with Rheumatoid Arthritis (RA) and polyarthritis diseases in man, such as symmetrical joint involvement, persistent joint inflammation, synovial hyperplasia and a good response to most therapies effective in RA (Bina and Wilder, 1999).
Arthritic score is a complex index of pathology progression assembling several clinical parameters including periarticular erythema, edema and the local inflammation at the site of injection.
Mythocondro® showed the in vivo ability to improve many parameters. Oral daily administration over four weeks ameliorated the arthritic score, involving inflammation at joint level and hind paw swelling, and prevented the inflammation-related body weight loss. The study included healthy animals, untreated arthritic animals and arthritic animals who received 900 mg/kg daily of bovine CS, and Mythocondro®.
Mythocondro® significantly reduced the arthritic score by up to about 30% from 14 to 28 days.
Reduction in Arthritic Score by CS Molecular Weight
Comparison between percent of reductions of pharmaceutical grade Animal CS and Mythocondro®, administered at 900mg/kg body Weight for 14 days. [Bauerova 2014].
3. Anti-inflammatory effect compared to animal Chondroitin Sulfates (production of pro-inflammatory cytokines and C-reactive protein in plasma)
Anti-inflammatory effect of Mythocondro® has been assessed through the evaluation of plasmatic levels of pro-inflammatory cytokines, IL-1β and IL-6, of γ-glutamyltransferase (GGT) activity in hind paw joint tissue homogenates and plasmatic C-reactive protein (CRP). In particular CRP has recently been proposed as a marker of disease severity in OA.
Mythocondro® showed a greater efficacy in reducing plasmatic levels of pro-inflammatory cytokines, compared with the European pharmacopeia (EP) standard-grade CS of bovine origin. Normal inflammatory cytokine levels were restored as well as oxidative stress and inflammation-related protein levels. The greater effect of Mythocondro® in reducing arthritic parameters may be related to its lower molecular mass and increased bioavailability with respect to animal CS.
|Mythocondro® vs Non treated Animals||% Reduction of Cytokines|
Reduction of pro-inflammatory Cytokines by CS
Comparison between percent of reductions of AA treated animals and Mythocondro®
The results of studies were published in 2014 by Bauerova. [Bauerova K. et al. – Pharmacology 94, 109-114, 2014. Chondroitin sulfate effect on induced arthritis in rats. Osteoarthritis and cartilage, 19(11), 1373-1379].
Mythocondro® underwent in vitro and in vivo toxicity studies, which have fully validated the excellent safety profile of the fermentation-based CS Mythocondro®, with evaluation of:
The results of the subchronic toxicity study supports the no-observed-adverse-effect level (NOAEL) for CS as 1000 mg/kg bw/day, the highest dose tested. The available evidence suggests that recommended daily intake of microbial derived Mythocondro®, is very safe.
All the here above studies described have been published in 2016.[Miraglia, N., Bianchi, D., Trentin, A., Volpi, N., & Soni, M. G. (2016). Safety assessment of non-animal chondroitin sulfate sodium: Subchronic study in rats, genotoxicity tests and human bioavailability. Food and Chemical Toxicology, 93, 89-101]