Viartril-S Mechanism of Action

Pharmacotherapeutic group: other anti-inflammatory and anti-rheumatic agents, non-steroidal anti-inflammatory drugs. ATC code: M01AX05.
Pharmacology: Pharmacodynamics: Mechanism of action: Glucosamine sulphate is the sulphate 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 sulphate stimulates the synthesis of glycosaminoglycans and thus of articular cartilage proteoglycans. However, glucosamine sulphate has been more recently shown to inhibit the interleukin-1 β (IL-β) intracellular signaling pathway via blockade of the intracellular activation and nuclear translocation of nuclear factor kappa B (NF-kB) in the cartilage chondrocytes and other relevant cells.
Pharmacodynamic effects: Early in vitro studies have demonstrated that glucosamine sulphate has anabolic and anti-catabolic effects on cartilage metabolism; sulphate 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 sulphate 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 sulphate 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 1500mg once daily. Animal models confirmed the potential of glucosamine sulphate 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 sulphate 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 sulphate on osteoarthritis symptoms is evident already after 2-3 weeks from the beginning of administration. However, differently from NSAIDS, glucosamine sulphate has shown a duration of effect which ranges from 6 months to 3 years.
Clinical studies of daily continuous crystalline glucosamine sulphate treatment up to 3 years have shown a progressive improvement on the symptoms and a delay of the joint structural changes, as determined by pain radiography.
Glucosamine sulphate 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 systematically in healthy volunteers. The absolute bioavailability of glucosamine in man after administration of oral glucosamine sulphate was 44%, due to first-pass effect of the liver. After oral administration of daily repeated doses of 1500 mg of glucosamine sulphate 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 concentration 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 differenced 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 then 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 metabolite 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 compositions. Glucosamine is mainly metabolized through the hexosamine pathway and independently of the cytochrome enzyme system. Crystalline glucosamine sulphate 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 sulphate.
No clinically relevant metabolic inhibition and/or induction interactions are expected between crystalline glucosamine sulphate 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 liver do not significantly contribute to the elimination 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 impairment 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.