Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Non-steroidal anti-inflammatory/anti-rheumatic drugs.
ATC code: M01AC01.
Mechanism of action
Piroxicam, belonging to the class of benzothiazine-based N-heterocyclic carboxyamides, is the first compound of a new class of NSAIDs, the oxicams.
Piroxicam has an anti-inflammatory, analgesic and antipyretic activity, pharmacological actions similar to those of other non-steroidal anti-inflammatory drugs.

Pharmacodynamic effects
Animal studies have shown that piroxicam affects cell migration to sites of inflammation. Like other NSAIDs, piroxicam interferes with prostaglandin synthesis by inhibiting cyclo-oxygenase.

Unlike indomethacin, piroxicam is a reversible inhibitor of prostaglandin synthesis. In a study performed in 9 patients with active rheumatoid arthritis, piroxicam (20 mg/day for 15 days), the function of polymorphonuclear (PMN) cells, the production of superoxide anions in peripheral blood and in synovial fluid and the concentration of PMN and PMN-elastase in synovial fluid were shown to be markedly lowered.
Modulation of PMN response may contribute to the anti-inflammatory action of piroxicam.
BREXIN is a new formulation of piroxicam where the active compound is complexed with ß-cyclodextrin.
ß-cyclodextrin is a cyclic oligosaccharide derived from enzymatic hydrolysis of common starch. Due to its particular chemical structure, ß-cyclodextrin can form 
inclusion complexes (‘molecular encapsulation’) with various drugs thereby improving their solubility, stability and bioavailability.
Piroxicam-ß-cyclodextrin was found to be very soluble in water and more rapidly absorbed than piroxicam after oral administration.
The improved solubility results in a rapid increase in plasma levels of piroxicam and means the peak value is reached sooner, which is clinically manifested with a quicker onset and greater intensity of the analgesic and anti-inflammatory effect.
As regards piroxicam, the extended plasma half-life of BREXIN is unchanged, thus allowing a once-a-day administration of the product.
The pharmacodynamic and pharmacokinetic properties of BREXIN make it suitable for the treatment of markedly painful rheumatic and/or inflammatory diseases, which seriously compromise the patient’s general condition and normal activity, and where it is necessary to obtain a rapid and intense therapeutic effect.

Efficacy and clinical safety
In the carrageenan-induced footpad oedema test, BREXIN produced an anti- inflammatory activity more quickly than piroxicam; in the first hours after administration, in fact, BREXIN was 2-3 times more active than piroxicam by oral route.
The analgesic activity was assessed in mice with the phenylquinone-induced writhing test by oral route; 5 minutes after treatment, 99% of the maximum inhibitory effect was obtained with BREXIN and 78% was obtained with piroxicam. The activity of both drugs remained constant for two hours after administration.
Therapeutic index values for BREXIN and piroxicam were calculated by comparing the anti-inflammatory effects, evaluated in rats with the carrageenan-induced footpad oedema test, with the gastro-irritant effects in the same animal species.
BREXIN by oral route had a therapeutic index 2.65 times higher than oral piroxicam.
The improved gastrointestinal tolerability of BREXIN was confirmed in humans by means of three double-blind controlled studies, in which the presence of blood in the faeces was assessed using the 51Cr-labelled red-cell method. In all these studies, the treatment duration was 28 days. Two studies showed a significantly lower faecal blood loss with BREXIN towards the end of the 4-week study period, while in the third study a similar trend was seen.
In a further study, a comparison was made of the gastric tolerability of BREXIN, piroxicam, indomethacin and placebo after administration over a 14-day period; the gastric potential difference was also assessed (max GPD). BREXIN produced lesser effects on this parameter than piroxicam or indomethacin, with a positive correlation between the max GPD and endoscopic results.
Therefore, BREXIN shows a more favourable ratio between pharmacodynamic activity and gastrotoxicity than piroxicam.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
After oral administration of BREXIN, only the active substance (piroxicam) is absorbed into the circulation, and not the complex as such.
Studies in healthy volunteers demonstrated that, at equivalent doses of piroxicam (20 mg), the piroxicam plasma peak is reached much earlier with BREXIN (within 30-60 minutes, compared to an average of 2 hours with plain piroxicam by the oral route).

Biotransformation
ß-cyclodextrin is metabolized in the colon by bacterial microflora into linear dextrin, maltose and glucose.

Distribution and elimination
The elimination parameters, Kel and half-life, do not differ from those of piroxicam, as complexation with ß-cyclodextrin affects only absorption kinetics and not elimination kinetics.
Urinary excretion of the active substance over 72 hours, for BREXIN and for plain piroxicam, is about 10% of the administered dose.
After oral administration of the complex, no ß-cyclodextrin was detected in plasma or urine.