piroxicam-beta-cyclodextrin and Pain

Although NSAIDs are very effective drugs, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular (CV) system, skin and gut. Gastrointestinal (GI) side effects are the most common and constitute a wide clinical spectrum ranging from dyspepsia, heartburn and abdominal discomfort to more serious events such as peptic ulcer with life-threatening complications of bleeding and perforation. The appreciation that CV risk is also increased further complicates the choices of physicians prescribing anti-inflammatory therapy. Despite prevention strategies should be implemented in patients at risk, gastroprotection is often underused and adherence to treatment is generally poor. A more appealing approach would be therefore to develop drugs that are devoid of or have reduced GI toxicity. Gastro- duodenal mucosa possesses many defensive mechanisms and NSAIDs have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. NSAIDs cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and systemic inhibition of gastric mucosal protection, through inhibition of cyclooxygenase (COX, PG endoperoxide G/H synthase) activity of the GI mucosa. However, against a background of COX inhibition by anti-inflammatory doses of NSAIDs, their physicochemical properties, in particular their acidity, underlie the topical effect leading to short-term damage. It has been shown that esterification of acidic NSAIDs suppresses their gastrotoxicity without adversely affecting anti-inflammatory activity. Another way to develop NSAIDs with better GI tolerability is to complex these molecules with cyclodextrins (CDs), giving rise to so-called "inclusion complexes" that can have physical, chemical and biological properties very different from either those of the drug or the cyclodextrin. Complexation of NSAIDs with β-cyclodextrin potentially leads to a more rapid onset of action after oral administration and improved GI tolerability because of minimization of the drug gastric effects. One such drug, piroxicam-β-cyclodextrin (PBC), has been used in Europe for 25 years. Preclinical and clinical pharmacology of PBC do show that the β-cyclodextrin inclusion complex of piroxicam is better tolerated from the upper GI tract than free piroxicam, while retaining all the analgesic and anti-inflammatory properties of the parent compound. In addition, the

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Dysmenorrhea; Female; Gastrointestinal Tract; Humans; Models, Molecular; Musculoskeletal Diseases; Pain; Piroxicam

Analgesics continue to be the mainstay of therapy in osteoarthritis. Non-steroidal anti-inflammatory drugs (NSAIDs) play an important role, particularly where there is a significant inflammatory component to the osteoarthritis. Piroxicam-beta-cyclodextrin (PBC) is a new formulation in which piroxicam has been complexed with beta-cyclodextrin, a cyclic oligosaccharide. This results in an increase in the rate of absorption of the active compound and, consequently, in an earlier onset of analgesic action. PBC, like piroxicam, is administered once daily. PBC has been used in the treatment of osteoarthritis. In comparison with piroxicam, PBC showed a more rapid analgesic-anti-inflammatory action after the first administration in patients with active osteoarthritis. Subsequent evaluations at the second, fifth and last day of treatment demonstrated a comparable efficacy of the two drugs. The efficacy and tolerability of PBC was compared with other NSAIDs given intramuscularly, such as diclofenac and ketoprofen. The three compounds provided marked pain relief within thirty minutes and this increased progressively until the third to fourth hour. The efficacy of oral PBC was comparable to that of intramuscular diclofenac or ketoprofen. In comparison with metamisole PBC achieved a more rapid and sustained reduction in pain intensity during the first twelve hours of treatment. This rapid and marked reduction in pain intensity with PBC was also observed in patients with low-back pain when compared with etodolac. In view of its efficacy, tolerability and rapid onset of action, piroxicam-beta-cyclodextrin appears to be an useful analgesic and a prominent progress in the treatment of acute rheumatic pain.

Topics: Acute Disease; Adult; beta-Cyclodextrins; Controlled Clinical Trials as Topic; Cyclodextrins; Diclofenac; Dipyrone; Drug Combinations; Etodolac; Humans; Ketoprofen; Middle Aged; Pain; Piroxicam; Rheumatic Diseases

Piroxicam-beta-cyclodextrin is a novel NSAID; it is a supermolecular inclusion complex designed to improve the risk:benefit ratio of piroxicam. In animal studies it has been shown to be as effective as piroxicam as an anti-inflammatory and analgesic agent but with a more rapid onset of action and reduced gastropathic effects.

Topics: Administration, Oral; Animals; beta-Cyclodextrins; Cyclodextrins; Digestive System; Drug Combinations; Female; Inflammation; Male; Pain; Piroxicam

Piroxicam (Feldene) is indicated for osteoarthritis and rheumatoid arthritis but not analgesia due to its delayed onset of pain relief. Piroxicam-beta-cyclodextrin (PBCD) was developed for pain indication by virtue of the increased absorption rate of piroxicam. Forty-eight patients received a single dose of PBCD or Feldene (10, 20, and 40 mg) in a randomized study, and piroxicam plasma concentration and pain relief were measured. The purpose of the study was to investigate the PK-PD relationship of piroxicam, determine the optimal dose, and evaluate the effect of increased absorption rate on analgesic effect of piroxicam for the pain model studied. The pharmacokinetic data were best described by a two-compartment model with first-order absorption. The absorption rate of PBCD (5/h) was faster than Feldene (1.41/h). Pain relief was found to be increasing with drug concentration in a hypothetical effect compartment (Emax model). The estimated half-life of the equilibration between plasma and effect site was about 2.34 hours. Monte Carlo simulation showed that the time when at least 50% of the patients have a 75% probability of achieving meaningful pain relief (pain intensity difference (PID > or = 1) for PBCD and Feldene at a dose of 20 mg was about 0.5 and 1.5 hours, respectively. PBCD demonstrated an advantage with an onset of pain relief 1 hour earlier than Feldene.

Topics: Absorption; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Cyclodextrins; Dose-Response Relationship, Drug; Drug Combinations; Half-Life; Humans; Pain; Piroxicam

The clinical relevance of piroxicam-beta-cyclodextrin (PBC) in the long-term treatment of osteoarthritis and rheumatoid arthritis is reviewed. Two hundred and twenty-five patients--one hundred with rheumatoid arthritis and one hundred and twenty five with osteoarthritis--were enrolled in a double-blind, randomised, controlled study versus piroxicam. Drugs were administered once-daily, for twelve weeks. The indices of efficacy (pain intensity, severity of inflammation, functional impairment evaluated at 0,2,4,8 and 12 weeks showed the good analgesic effect of piroxicam without significant differences between its two formulations. Tolerance appeared to be better in the group of patients treated with PBC than in the one treated with piroxicam. Both the incidence and severity of side effects were lower for patients treated with PBC. The majority of side effects were related to the gastrointestinal tract. The study suggests that PBC, used in the long term treatment of rheumatic diseases, improves the safety of piroxicam without affecting its efficacy. In another study, thirty patients with chronic osteoarthritis were randomly assigned to receive PBC or tenoxicam daily for eight weeks. Both drugs effectively reduced pain, inflammation, and functional limitation of the affected joints. Endoscopy revealed minor post-treatment mucosal lesions; these tended to be less severe with PBC than with tenoxicam. The clinical experience in the long-term treatment of rheumatic conditions indicates that the microencapsulation of piroxicam as piroxicam-beta-cyclodextrin has provided a new drug with a superior tolerability compared to the parent compound without affecting its high efficacy on the symptoms of the primary disease.

Topics: Adult; Aged; Aged, 80 and over; Antirheumatic Agents; Arthritis, Rheumatoid; beta-Cyclodextrins; Cyclodextrins; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Osteoarthritis; Pain; Piroxicam