Artrofort Complex Mechanism of Action

Pharmacology: Pharmacodynamics: ARTROFORT Complex is a medicinal product containing the active ingredients glucosamine sulphate and chondroitin sulphate.
Glucosamine sulfate: The active ingredient glucosamine sulphate is the salt of an amino-monosaccharide glucosamine which is physiologically present in the human body and used, together with sulphates, for the biosynthesis of hyaluronic acid of the synovial fluid and of glycosaminoglycans of the fundamental substance of articular cartilage.
The mechanism of action of glucosamine sulphate is therefore the stimulation of glycosaminoglycans synthesis and thus of the articular proteoglycans. Moreover, glucosamine has anti-inflammatory activities and inhibits the degradation processes of articular cartilages thus supporting from one side the activity on osteoarthritis symptoms, and from the other side the possible delay of the articular structural damage evidenced in the long-term clinical studies.
Short- and medium-term clinical studies have shown that the efficacy of glucosamine sulphate on osteoarthritis symptoms is evident already after 2-3 weeks from the beginning of administration. On the other hand, the symptomatic efficacy of glucosamine sulphate treatment, versus common analgesics and non steroidal anti-inflammatory drugs, is ideal after 6-month continuous cycles, or after 3-month cycles with an evident residual effect of 2 months after withdrawal.
Clinical studies of daily continuous treatment up to 3 years have shown a decrease on the osteoarthritis symptoms and a delay, radiologically determined of structural damage at joint level.
Chondroitin sulphate: Chondroitin sulphate is an important component of most vertebrate tissues. It is predominantly present in the extracellular matrix surrounding cells and is most abundant in those tissues with a large extracellular matrix such as those that form the connective tissues of the body, cartilage, skin, blood vessels and also bone, ligaments and tendons.
Chondroitin sulfate has anti-inflammatory activity and affects cartilage metabolism. Oral administration of chondroitin sulphate has shown to significantly decrease granuloma formation due to cotton, pellet or sponge implantation; to stimulate proteoglycan production of chondrocytes; to inhibit the production of certain proteolytic enzymes (e.g. collagenase, elastase, proteoglycanase, phospholipidase A2, N-acetylic glucosamidase etc.) in in vitro and in vivo models; to inhibit cartilage cytokine production.
When the effects of chondroitin sulphate on induced cartilage injury in rabbits were investigated, it was found that the animals that were given i.m. or oral chondroitin sulphate before injury induction had less proteoglycans loss from the articular cartilage than the control animals. Chondroitin sulphate is an inhibitor of extracellular proteases involved in the metabolism of connective tissues.
The addition of chondroitin sulphate to the medium of a chondrocytes culture from human articular cartilage resulted in an increase of proteoglycans concentration of the pericellular matrix and a dose-dependent decrease in collagenolytic activity.
As far as it is known, no effects on the cardiovascular and respiratory systems, on the CNS, or the autonomic nervous system, have been observed following chondroitin sulphate administration.
Short and long-term clinical trials have demonstrated that chondroitin sulfate is effective in relieving symptoms of osteoarthritis.
Glucosamine and Chondroitin sulphate combination: Glucosamine sulfate and chondroitin sulfate synergistically act to stimulate glycosaminoglycan synthesis. Combining these substances produces, from one site, the up-regulation of the synthetic activities in chondrocytes and, from the other site, the inhibition of degradative enzymes.
When combined in an animal osteoarthritis model, glucosamine and chondroitin sulphate were more effective than the compounds alone.
Clinical studies in animals and man have further indicated that the combination therapy is effective and allows a significant drop in NSAIDs use by osteoarthritis patients.
Analgesics and NSAIDs may be used concomitantly with ARTROFORT Complex, either for rescue analgesia during possible flares of the disease, or in the initial period of treatment, when the symptomatic effects of the product may be delayed for few weeks.
Physical therapy programs can be used concomitantly with ARTROFORT Complex in the overall management of osteoarthritis.
Pharmacokinetics: Glucosamine: Animal and human studies, carried out with ¹⁴C-labelled glucosamine, have shown that, after oral administration glucosamine is rapidly and almost completely absorbed at systemic level (about 90% of the radioactive dose is absorbed).
The steady-state concentrations of glucosamine in plasma and in the synovial fluid after repeated once-a-day doses of 1500 mg are in the range of 10 μM and therefore in line with those which have shown a pharmacological activity in in vitro experimental models, which justify the mechanism of action and the clinical effect of the drug.
After oral absorption, glucosamine is significantly distributed in extra-vascular compartments (including synovial fluid), with an apparent distribution volume 37-fold higher than the total human body water quantity. In humans, Glucosamine has shown to have affinity for joint tissues.
The metabolic profile of glucosamine has not been studied because the drug, being a natural substance present in the human body, is used for the biosynthesis of some components of articular cartilage.
In man, the terminal elimination half-life of glucosamine from plasma has been only estimated because of glucosamine plasmatic levels which are measurable for further 48 h after oral administration. The calculated value was around 15 h. Experimental results show that the kidneys significantly contributes to the elimination of glucosamine and/or of its metabolites.
Chondroitin sulphate: The bioavailability after oral administration is 15-24%. A 10% of absorbed chondroitin sulfate appears in unmetabolized form and 90% as depolymerized derivatives with lower molecular weight, as a result of first-pass effect metabolism.
Distribution volume of chondroitin sulfate is relatively low, approx. 0.3 l/kg. In humans, chondroitin sulfate has shown to have affinity for joint tissues.
At least 90% of chondroitin sulphate dose is first metabolized by lysosomal sulfatases, and after that it is depolymerized by hyaluronidases, i.e. β-glucuronidases and β-N-acetyl hexose amidases. Liver, kidneys and other organs are involved in the depolymerization of chondroitin sulphate.
Systemic elimination of chondroitin sulfate is 30.5 ml/min, i.e. 0.43 ml/min/kg.
On average, chondroitin sulphate remains in the body for 5-15 hours. Main part of chondroitin sulfate and its depolymerized derivatives are eliminated through the kidneys.
Toxicology: Preclinical Safety Data: Glucosamine sulphate: The acute, subchronic, chronic toxicity, embryotoxicity and mutagenic studies performed with glucosamine sulphate did not reveal special hazards for humans and indicate the large safety margin of the drug. The maximum tested doses showed no or minimal effects, these were reversible and there was no detectable target organ toxicity. The doses used in the experimental studies represent a very large multiple of the daily dose currently used in human therapy, which is around 20-25 mg/kg.
Chondroitin sulphate: Data concerning subacute and chronic toxicity, mutagenicity, genotoxicity, carcinogenicity and reproduction toxicity of chondroitin sulfate reveal no special hazard for humans.
Glucosamine and Chondroitin sulfate combination: Experimental toxicity studies on glucosamine and chondroitin sulfate combination are not available. However, no concerns of toxicity hazards for humans should be arisen due to the ascertained toxicological profile and the large safety margin of the single ingredients.