Viartril-S/Viartril-S 500 Mechanism of Action

Viartril-S: Pharmacotherapeutic group: Other anti-inflammatory and anti-rheumatic agents, on-steroidal anti-inflammatory drugs.
Pharmacology: Pharmacodynamics: Mechanism of action: Glucosamine sulfate is the sulfate salt of the endogenous amino-monosaccharide glucosamine, a normal constituent and preferred substrate for the synthesis of glycosaminoglycans and proteoglycans in cartilage matrix and synovial fluid.
Early in vitro studies have shown that glucosamine sulfate stimulates the synthesis of glycosaminoglycans and thus of articular cartilage proteoglycans. However, glucosamine sulfate has been more recently shown to inhibit the interleukin-1 β (IL-1 β) intracellular signaling pathway via blockade of the intracellular activation and nuclear translocation of nuclear factor kappa B (NF-κB) in the cartilage chondrocytes and other relevant cells.
Pharmacodynamic effects: Early in vitro studies have demonstrated that glucosamine sulfate has anabolic and anti-catabolic effects on cartilage metabolism; sulfate ions may contribute to the pharmacological effects exerted by glucosamine by controlling the rate of glycosaminoglycan and proteoglycan synthesis and inhibiting cartilage degrading enzymes.
More recent studies have postulated that glucosamine sulfate decreases IL-1 β mediated effects, thus inhibiting a cascade of events that lead to joint inflammation and cartilage damage, such as the synthesis of metalloproteases, cyclooxygenase-2 and extracellular matrix proteins that are absent in normal cartilage, the release of nitric oxide and of prostaglandin E2, the inhibition of chondrocyte proliferation and the induction of cell death. Differently from NSAIDs, glucosamine does not directly inhibit cyclooxygenase activities. Human chondrocyte cell models have shown that crystalline glucosamine sulfate inhibits IL-1-stimulated gene expression at glucosamine concentrations similar to or lower than those found in plasma and synovial fluid of knee osteoarthritis patients receiving the drug at the therapeutic dose of 1500 mg once daily. Animal models confirmed the potential of glucosamine sulfate at human equivalent doses in delaying the progression of the disease and alleviating its symptoms.
Clinical efficacy and tolerability: The safety and efficacy of glucosamine sulfate have been confirmed in clinical trials for treatment up to three years.
Short- and medium-term clinical studies have shown that the efficacy of glucosamine sulfate on osteoarthritis symptoms is evident already after 2-3 weeks from the beginning of administration. However, differently from NSAIDS, glucosamine sulfate has shown a duration of effect which ranges from 6 months to 3 years.
Clinical studies of daily continuous crystalline glucosamine sulfate treatment up to 3 years have shown a progressive improvement on the symptoms and a delay of the joint structural changes, as determined by plain radiography.
Glucosamine sulfate has demonstrated a good tolerability over both short-term and long-term treatment courses.
Pharmacokinetics: Absorption: After oral administration of ¹⁴C-labelled glucosamine, the radioactivity is rapidly and almost completely (about 90%) absorbed systemically in healthy volunteers. The absolute bioavailability of glucosamine in man after administration of oral glucosamine sulfate was 44%, due to first-pass effect of the liver. After oral administration of daily repeated doses of 1500 mg of glucosamine sulfate in healthy volunteers under fasting conditions, the maximum plasma concentrations at steady-state (C_max,ss) averaged 1602±426 ng/mL between 1.5-4 h (median: 3 h; t_max). At steady-state, the AUC of the plasma concentrations vs. time curve was 14564±4138 ng.h/mL. It is unknown if meals significantly affect the drug oral bioavailability. The pharmacokinetics of glucosamine are linear after once daily repeated administrations in the dose interval 750-1500 mg with deviation from linearity at the dose of 3000 mg due to lower bioavailability. No gender differences were found in man with regard to the absorption and to the bioavailability of glucosamine. The pharmacokinetics of glucosamine was similar between healthy volunteers and patients with osteoarthritis of the knee.
Distribution: 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 body water in humans. Glucosamine does not bind to plasma proteins. It is therefore highly unlikely that glucosamine might produce displacement drug interaction when co-administered with other drugs that are highly bound to plasma proteins.
Metabolism: The metabolic profile of glucosamine has not been studied because being an endogenous substance; it is used as a building block for the biosynthesis of articular cartilage components. Glucosamine is mainly metabolized through the hexosamine pathway and independently of the cytochrome enzyme system.
Crystalline glucosamine sulfate does not act as an inhibitor nor as an inducer of the human CYP450 isoenzymes including CYP 3A4, 1A2, 2E1, 2C9 and 2D6 even when tested at concentrations of glucosamine 300-fold higher than the peak plasma concentrations observed in man after therapeutic doses of crystalline glucosamine sulfate. No clinically relevant metabolic inhibition and/or induction interactions are expected between crystalline glucosamine sulfate and co-administered drugs that are substrates of the human CYP450 isoforms.
Excretion: In man, the terminal elimination half-life of glucosamine from plasma is estimated at 15 h. After oral administration of ¹⁴C-labelled glucosamine to humans, the urinary excretion of radioactivity was 10±9% of the administered dose while fecal excretion was 11.3±0.1%. The mean urinary excretion of unchanged glucosamine after oral administration in man was about 1% of the administered dose suggesting that the kidney and the liver do not significantly contribute to the elimination of glucosamine and/or of its metabolites and/or its degradation products.
Special population: Patients with renal or hepatic impairment: The pharmacokinetics of glucosamine were not investigated in patients with renal or hepatic insufficiency. Studies in renal impaired patient were considered irrelevant due to the limited contribution of the kidney to the elimination of glucosamine.
Similarly, studies in subjects with hepatic impairment were not conducted given glucosamine metabolic fate as an endogenous substance. Therefore, for what described previously and in light of the good safety and tolerability profile of glucosamine, no dose adjustment is considered necessary in subjects with renal or hepatic insufficiency.
Children and adolescents: The pharmacokinetics of glucosamine was not investigated in children and adolescents.
Elderly patients: No specific pharmacokinetic studies were performed in elderly however in the clinical efficacy and safety studies mainly elderly patients were included. Dose adjustment is not required.
Toxicology: Preclinical Safety Data: The toxicity of crystalline glucosamine sulfate in animals was extremely low after single and repeated dosing studies. The maximum tested doses have shown no or minimal effects; these were reversible and there was no detectable target organ toxicity. The highest tested dose in animals corresponds to more than one hundred times the oral dose recommended for human use.
Crystalline glucosamine sulfate was not mutagenic in vitro and in vivo. Studies on carcinogenicity are not available.
In the rat, adverse effects on fertility, embryo/foetal development and postnatal development were not observed. In female rabbits, no teratogenic effects were reported for crystalline glucosamine sulfate.
Results from some in vitro and in vivo studies in animals, have shown that i.v. infusion of glucosamine in suprapharmacological concentrations reduces insulin secretion, probably via inhibition of glucokinase in the beta cells, and induces insulin resistance in peripheral tissues. The relevance in humans is inconclusive.
Experimental studies in humans as well as clinical studies in healthy subjects and in individuals with diabetes, or with impaired glucose tolerance didn't show effects on fasting blood glucose levels, glucose metabolism, or insulin sensitivity.
Viartril-S 500: Glucosamine is the main component of VIARTRIL-S.
This substance has the following therapeutic activities: Arthrotrophic metabolic activity by stimulating the anabolic metabolism of osteo-cartilageneous tissues through: stimulation of the biosynthesis of the mucopolysaccharides (which are the essential components of the cartilage ground substance) and of the bone mesenchymal tissues in general; improvement of the bone calcium uptake.
Lubricant activity through: improvement of synovial fluid viscosity; increase of synovial fluid production.
Glucosamine Sulfate (VIARTRIL-S) is particularly effective in all forms of degenerative osteoarticular disease such as arthrosis and osteoarthritis both subacute and chronic with the following therapeutic effects: disappearance or reduction of articular pains; improvement of articular function; inhibition or regression of the degenerative process.