Drugs

, Volume 48, Issue 6, pp 907–929

Piroxicam-β-Cyclodextrin

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Rheumatic Diseases and Pain States
  • C. Rhoda Lee
  • Julia A. Balfour
Drug Evaluation

Abstract

Synopsis

Piroxicam-β-cyclodextrin is a complex of the established nonsteroidal antiinflammatory drug (NSAID) piroxicam and an inert cyclic macromolecule, β-cyclodextrin. In clinical trials in patients with rheumatic diseases or pain arising from other conditions, it was as effective an analgesic as standard piroxicam, and showed a faster onset of action on the first day of treatment.

In short term pharmacodynamic studies in healthy volunteers, piroxicam-β-cyclodextrin was equivalent to or tended to show less gastrointestinal mucosal toxicity than standard piroxicam, as assessed by endoscopy and faecal blood loss. However, no data are available on its comparative gastrointestinal mucosal effects from long term clinical trials using similar measures. Preliminary findings from a clinical study suggest piroxicam-β-cyclodextrin caused fewer gas-troduodenal lesions than tenoxicam. As with other NSAIDs, the majority of adverse events associated with piroxicam-β-cyclodextrin in clinical trials were gastrointestinal in origin, with epigastric pain, heartburn and nausea the most common.

Thus, piroxicam-β-cyclodextrin is an effective agent in patients with rheumatic diseases or other pain states. When rapid analgesia is required in the initial treatment of acute pain, the faster onset of action of piroxicam-β-cyclodextrin may be an advantage over the parent compound; however, this is unlikely to be important during long term therapy. The results of further long term trials are awaited before firm conclusions can be reached regarding the gastrointestinal tolerability of piroxicam-β-cyclodextrin compared with that of standard piroxicam and other NSAIDs.

Pharmacodynamic Properties

Piroxicam-β-cyclodextrin is a NSAID with anti-inflammatory, analgesic and antipyretic properties. Limited data available on the analgesic and anti-inflammatory effects of piroxicam-β-cyclodextrin suggest that it is equivalent to piroxicam in animal and human models of pain. The effects of piroxicam-β-cyclodextrin on the gastrointestinal mucosa have been more extensively studied.

Findings from endoscopy and faecal blood loss studies suggest that piroxicam-β-cyclodextrin is equivalent to, or shows a trend to be less toxic than, the parent molecule in healthy volunteers aged 20 to 50 years. However, none of these trends reached statistical significance.

In these studies, total endoscopy scores were similar for both drugs. In 2 studies of 1 month’s duration, piroxicam-β-cyclodextrin 20 mg/day tended to cause less cumulative faecal blood loss than piroxicam 20 mg/day after 2 to 4 weeks’ treatment. In all studies piroxicam-β-cyclodextrin showed a trend towards greater gastric mucosal damage, or significantly more damage, than placebo.

Pharmacokinetic Properties

Administration of piroxicam-β-cyclodextrin as a single dose in fasting volunteers resulted in mean plasma piroxicam concentrations 0.25 and 0.5 hours after administration that were, respectively, 3 to 10 and 1.3 to 3 times higher than after standard piroxicam administration in 2 comparative studies.

Although food slowed the absorption from both products, plasma concentrations of piroxicam were still 2 to 4 and 1.3 to 1.4 times higher 0.5 and 2 hours after administration of piroxicam-β-cyclodextrin than after standard piroxicam. However, after multiple-dose administration the only difference was at 0.25 hours after administration, when the plasma concentration of piroxicam was 1.3 times higher after piroxicam-β-cyclodextrin than piroxicam. The area under the plasma concentration-time curve was similar for piroxicam-β-cyclodextrin 20mg and Piroxicam 20mg, demonstrating a comparable overall extent of absorption.

Post-absorption pharmacokinetic parameters were similar for piroxicam-β-cyclodextrin and piroxicam. The volume of distribution was 0.14 L/kg and the mean terminal elimination half-life was 40 to 63 hours. The main route of elimination of piroxicam is metabolism, with only trace amounts of unchanged drug excreted in the urine.

Therapeutic Potential

In patients with acute pain resulting from arthritis and other rheumatic disease, the analgesic efficacy of piroxicam-β-cyclodextrin was equivalent to that of piroxicam when both were administered once daily at a dose of 20mg for up to 12 weeks. Anti-inflammatory effects of the 2 agents were also equivalent in the study that assessed this. In 2 studies measuring the onset of analgesic effect, piroxicam-β-cyclodextrin was significantly more effective, or showed a trend towards greater efficacy, than piroxicam in the 4 hours after the first dose. In a further 2 studies the analgesic effects of piroxicam-β-cyclodextrin and piroxicam on the second or third day of administration were similar.

In other comparative studies in patients with rheumatic pain, piroxicam-β-cyclodextrin 20 mg/day was superior in analgesic efficacy to dipyrone 500mg 3 times daily, at least as effective as etodolac 200mg twice daily, and equivalent in efficacy to tenoxicam 20 mg/day and nabumetone 1000 mg/day. In studies also investigating the onset of analgesia in the first few hours after the first dose, piroxicam-β-cyclodextrin 20mg appeared to show a faster onset of action than tenoxicam 20mg, nabumetone 1000mg, etodolac 200mg and dipyrone 500mg. Orally administered piroxicam-β-cyclodextrin 20mg as a granule formulation was equivalent in analgesic effect over 12 hours to diclofenac 75mg and ketoprofen 100mg, both administered by deep intramuscular injection.

In patients with postoperative pain or pain arising from acute musculoskeletal disorders, piroxicam-β-cyclodextrin 20 mg/day was equivalent to piroxicam 20 mg/day in relieving pain but the onset of its effect was generally faster in the first hour after the first dose. Piroxicam-β-cyclodextrin has also demonstrated efficacy in the treatment of pain arising from primary dysmenorrhoea, headache or dental extraction.

Tolerability

Piroxicam-β-cyclodextrin would be expected to demonstrate a tolerability profile similar to that of standard piroxicam. However, it has been postulated that reducing the time piroxicam spends in the gastrointestinal tract by complexation with β-cyclodextrin may result in less direct mucosal damage and hence better gastrointestinal tolerability. Short term studies in healthy volunteers suggest a possible trend towards less gastrointestinal toxicity for piroxicam-β-cyclodextrin, but this hypothesis has not been adequately studied in clinical trials. Long term studies comparing piroxicam-β-cyclodextrin with piroxicam in terms of endoscopy score and/or faecal blood loss measurement are awaited.

Data from clinical trials indicate that the principal adverse events involve the gastrointestinal tract. In 2 large short term phase IV studies, 11.3 and 13.5% of patients receiving piroxicam-β-cyclodextrin 20 mg/day reported an adverse event; 67 and 77% of these were gastrointestinal in origin, including epigastric pain, heartburn and nausea. Severe adverse reactions such as gastrointestinal bleeding or gastroduodenal ulcer were seen in 0.2% of 9105 patients. The pattern of adverse events from a longer term trial (3 to 6 months) was broadly similar.

In a double-blind comparative trial in 203 patients with rheumatic disease, the number of gastrointestinal adverse events in piroxicam-β-cyclodextrin recipients was 16 and that in piroxicam recipients was 24; 5 and 8 patients, respectively, withdrew because of the adverse event. In 1 study, piroxicam-β-cyclodextrin 20 mg/day caused fewer upper gastrointestinal tract lesions than tenoxicam 20 mg/day over 8 weeks.

Dosage and Administration

For the treatment of pain and inflammation, the recommended dosage of piroxicam-β-cyclodextrin is 20mg administered once daily as a tablet or granules. Higher dosages of 30 to 40 mg/day may be required in some patients, but these are expected to be associated with a greater incidence of gastrointestinal adverse effects. A maintenance dosage of 10 mg/day may be appropriate in some patients, particularly the elderly.

As with other NSAIDs, the use of piroxicam-β-cyclodextrin is contraindicated in patients with active peptic ulceration, and the drug should be used cautiously in patients with a history of upper gastrointestinal tract disease.

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References

  1. 1.
    Szejtli J. Cyclodextrins: properties and applications. Drag Invest 1990; 2 Suppl.4: 11–21CrossRefGoogle Scholar
  2. 2.
    Rainsford KD. NSAID gastropathy: novel physicochemical approaches for reducing gastric mucosal injury by drug com-plexation with cyclodextrins. Drug Invest 1990; 2 Suppl.4: 3–10CrossRefGoogle Scholar
  3. 3.
    Gerlóczy A, Fónagy A, Keresztes P, et al. Absorption, distribution, excretion and metabolism of orally administered 14C-β-cyclodextrin in rat. Arzneimittel Forschung 1985; 35: 1042–7PubMedGoogle Scholar
  4. 4.
    Cadel S, Bongrani S. Toxicological profile of piroxicam-β-cyclodextrin. Drug Invest 1990; 2 Suppl.4: 37–41CrossRefGoogle Scholar
  5. 5.
    Brogden RN, Heel RC, Speight TM, et al. Piroxicam: a reappraisal of its pharmacology and therapeutic efficacy. Drugs 1984; 28: 292–323PubMedCrossRefGoogle Scholar
  6. 6.
    Cadel S, Bongrani S. β-Cyclodextrin complexation improves absorption and gastric tolerability of piroxicam [abstract]. Acta Physiol Hung 1990; 75 Suppl: 45-6Google Scholar
  7. 7.
    Lister RE, Acerbi D, Cadel S. Supermolecular inclusion of piroxicam with β-cyclodextrin: a review of its pharmacological properties in laboratory animals. Eur J Rheumatol Inflamm 1993; 12(4):6-11Google Scholar
  8. 8.
    Dolci G, Gatto R, Malagnino V. Effetto analgesico piroxicam-β-cyclodestrina sul dolore dentale indotto. Studio controllato in doppio cieco. Odontostomatol Implantoprotesi 1989 (1 Suppl.): 3-6Google Scholar
  9. 9.
    Rainsford KD. Mechanisms of gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. Scand J Gastroenterol 1989; 24 Suppl.163: 9–16CrossRefGoogle Scholar
  10. 10.
    Wallace JL. Pathogenesis of nonsteroidal anti-inflammatory drug gastropathy: recent advances. Eur J Gastroenterol Hepatol 1993; 5: 403–7CrossRefGoogle Scholar
  11. 11.
    Hayllar J, Macpherson A, Bjarnason I. Gastroprotection and nonsteroidal anti-inflammatory drugs (NSAIDs). Rationale and clinical implications. Drug Saf 1992; 7: 86–105Google Scholar
  12. 12.
    Levi S, Shaw-Smith C. Non-steroidal anti-inflammatory drugs: how do they damage the gut?. Br J Rheumatol 1994; 33: 605–12PubMedCrossRefGoogle Scholar
  13. 13.
    Nuutinen LS, Laitinen JO, Salomäki TE. A risk-benefit appraisal of injectable NSAIDs in the management of postoperative pain. Drug Saf 1993; 9: 380–93PubMedCrossRefGoogle Scholar
  14. 14.
    Aabakken L. NSAID-associated gastrointestinal damage: methodological considerations and a review of the experience with enteric coated naproxen. Eur J Rheumatol Inflamm 1992; 12 (2): 9–20PubMedGoogle Scholar
  15. 15.
    Nervetti A, Ambanelli U, Ugolotti G. Assessment of gastric mucosal damage by a new inclusion complex of piroxicam with β-cyclodextrin: a functional study by a scintigraphic method. J Drug Dev 1991; 4 Suppl.1: 39–42Google Scholar
  16. 16.
    Patoia L, Clausi G, Farroni F, et al. Comparison of faecal blood loss, upper gastrointestinal mucosal integrity and symptoms after piroxicam beta-cyclodextrin, piroxicam and placebo administration. Eur J Clin Pharmacol 1989; 36: 599–604PubMedCrossRefGoogle Scholar
  17. 17.
    Santucci L, Fiorucci S, Chiucchiu S, et al. Placebo-controlled comparison of piroxicam-β-cyclodextrin piroxicam and indo-methacin on gastric potential difference and mucosal injury in humans. Dig Dis Sci 1992; 37: 1825–32PubMedCrossRefGoogle Scholar
  18. 18.
    Warrington S, Debbas N, Farthing M, et al. Piroxicam-beta-cyclodextrin: effects on gastrointestinal blood loss and gastric mucosal appearance in healthy men. Int J Tissue React 1991; 13 (5): 243–8PubMedGoogle Scholar
  19. 19.
    Warrington S. Effects of piroxicam-beta-cyclodextrin on the gastrointestinal tract. Eur J Rheumatol Inflamm 1993; 12 (4): 29–37PubMedGoogle Scholar
  20. 20.
    Data on file, Creemers MCW, Van Riel PLCM, et al. Gastro-intestinal toxicity during non-steroidal antiinflammatory drugs in ankylosing spondylitis: increased fecal blood loss, and evidence for gastric adaptation in a 48-week clinical trial. Chiesi Farmaceutici S.p.A, 1993.Google Scholar
  21. 21.
    McCormack K, Brune K. Dissociation between the antinociceptive and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs: a survey of their analgesic efficacy. Drugs 1991; 41: 533–47PubMedCrossRefGoogle Scholar
  22. 22.
    Abramson S, Weissmann G. The mechanism of action of nonsteroidal antiinflammatory drugs. Clin Exp Rheumatol 1989; 7 Suppl.3: 163–70Google Scholar
  23. 23.
    Urquhart E. Central analgesic activity of nonsteroidal antiinflammatory drugs in animal and human pain models. Semin Arthritis Rheum 1993; 23: 198–205PubMedCrossRefGoogle Scholar
  24. 24.
    Bannwarth B, Demotes-Mainard F, Schæverbeke T, et al. Where are peripheral analgesics acting? [leader]. Ann Rheum Dis 1993; 52: 1–4PubMedCrossRefGoogle Scholar
  25. 25.
    Olkkola KT, Brunetto AV, Mattila MJ. Pharmacokinetics of oxicam nonsteroidal anti-inflammatory agents. Clin Phar-macokinet 1994; 26: 107–20CrossRefGoogle Scholar
  26. 26.
    Richardson CJ, Ross SG, Bloka K, et al. High-performance liquid chromatographic analysis of piroxicam and it major metabolite 5′-hydroxypiroxicam in human plasma and urine. J Chromatogr 1986; 382: 382–8PubMedCrossRefGoogle Scholar
  27. 27.
    Woodcock BG, Acerbi D, Merz PG, et al. Supermolecular inclusion of piroxicam with β-cyclodextrin: pharmaokinetic properties in man. Eur J Rheumatol Inflamm 1993; 12: 12–28PubMedGoogle Scholar
  28. 28.
    Piroxicam-β-cyclodextrin prescribing information. Chiesi Farmaceutici SpA, Parma, Italy, 1993.Google Scholar
  29. 29.
    Acerbi D. Pharmacokinetic profile of piroxicam-β-cyclodextrin. Drug Invest 1990; 2 Suppl.4: 42–9CrossRefGoogle Scholar
  30. 30.
    Acerbi D, Bovis G, Carli F, et al. Biopharmaceutical optimisation of β-cyclodextrin inclusion compounds. Drug Invest 1990; 2 Suppl.4: 29–36CrossRefGoogle Scholar
  31. 31.
    Acerbi D, Bonati C, Boscarino G, et al. Pharmacokinetic study on piroxicam at the steady-state in elderly subjects and younger adults after administration of piroxicam beta-cyclo-dextrin. Int J Clin Pharmacol Res 1988; 8: 175–80PubMedGoogle Scholar
  32. 32.
    Acerbi D, Lebacq Jr E, Rondelli I, et al. Rapid oral absorption profile of piroxicam from its β-cyclodextrin complex. Drug Invest 1990; 2 Suppl.4: 50–5CrossRefGoogle Scholar
  33. 33.
    Oral bioavailability of CHF1194, an inclusion complex of piroxicam and β-cyclodextrin, in healthy subjects under single dose and steady-state conditions [editorial]. Eur J Clin Pharmacol. In pressGoogle Scholar
  34. 34.
    Data on file, Biopharma S.A. Bioavailability comparison study of CHF1194 fast-disintegration tablets and Feldene capsules (20mg piroxicam) in 12 healthy volunteers. Study reference 88.129. Data on file. Chiesi Farmaceutici S.p.A, Italy, 1988.Google Scholar
  35. 35.
    Michelacci M, Boscarino G, Acerbi D, et al. Analgesic effect and pharmacokinetics of a piroxicam beta-cyclodextrin oral formulation in post-surgical pain. A controlled study vs. an injectable piroxicam formulation. Clin Trials J 1990; 27 (3): 176–86Google Scholar
  36. 36.
    Netter P, Bannwarth B, Royer-Morrot M-J. Recent findings on the pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid. Clin Pharmacokinet 1989; 17: 145–62PubMedCrossRefGoogle Scholar
  37. 37.
    Woolf TF, Radulovic LL. Oxicams: metabolic disposition in man and animals. Drug Metab Rev 1989; 21: 255–76PubMedCrossRefGoogle Scholar
  38. 38.
    Bufalino L, Oliani C, Gardini F, et al. Studio multicentrico sugli effetti di piroxicam-beta-ciclodestrina nel trattamento delgi stati dolorosi acuti a diversa etiologia. Basi Raz Ter 1990; 20: 227–39Google Scholar
  39. 39.
    Ambanelli U, Nervetti A, Colombo B, et al. Piroxicam-beta-cyclodextrin in the treatment of rheumatic diseases: a prospective study. Curr Ther Res 1990; 48: 58–68Google Scholar
  40. 40.
    Giungi F. Tollerabilità ed efficacia di un trattamento a base di piroxicam beta-ciclodestrina in patologie osteoartrosiche con elevata risposta algica studio controllato contro piroxicam. Med Praxis 1987; 8 (2): 1–12Google Scholar
  41. 41.
    Manzini CU, Mascia MT, Oliani C, et al. Analgesic activity of piroxicam-beta-cyclodextrin complex (granulate formulation) in the treatment of osteoarthritic pain [in Italian]. Arch Med Interna 1989; 41: 189–99Google Scholar
  42. 42.
    Minisola G, Dardano B. Valutazione dell’attività antalgica e delia tollerabilità del piroxicam nel dolore crónico da cervicoartrosi e da lombartrosi. Clin Ter 1989; 131: 73–82PubMedGoogle Scholar
  43. 43.
    Reginster JY, Franchimont P. Piroxicam-beta-cyclodextrin in the treatment of acute pain of rheumatic disease. Eur J Rheumatol Inflamm 1990; 12 (4): 38–46Google Scholar
  44. 44.
    Data on file, Nardelli P, Marino G, et al. Piroxicam-β-cyclodextrin in the treatment of rheumatic pain. A controlled trial vs piroxicam capsules. Data on file. Cheisi Farmacuetici S.p.A, 1990.Google Scholar
  45. 45.
    Abate G, Zito M, Guarino F, et al. Il dolore osteoartritico: terapia con oxicam-derivati. Eur Rev Med Pharmacol Sci 1990; 12: 273–81Google Scholar
  46. 46.
    Bonardelli P, Oliani C, Preti PAM, et al. Efficacy and gastrointestinal tolerability of beta-cyclodextrin-piroxicam and ten-oxicam in the treatment of chronic osteoarthritis. Clin Ther 1990; 12: 547–55PubMedGoogle Scholar
  47. 47.
    Ghirardini M, Betelemme L, Fatti F. Studio di confronto tra droxicam e β-ciclodestrina-piroxicam nel trattamento dell’osteoartrosi e del reumatismo extra-articolare. Reumatologo 1993; 14: 145–7Google Scholar
  48. 48.
    Casale G, Oricchio P, Alfonsi A. Attività antalgica del complesso β-ciclodestrina-Piroxicam nelle forme croniche. Arch Med Interna 1991; 43: 157–64Google Scholar
  49. 49.
    Davoli L, Ciotti G, Biondi M, et al. Piroxicam-beta-cyclodextrin in the treatment of low-back pain. Curr Ther Res 1989; 46: 940–7Google Scholar
  50. 50.
    Gospodinoff A, Minisola G. β-Ciclodestrina-piroxicam vs meclofenamato sódico nel dolore osteoartrosico. Algos 1990; 7 (4): 49–55Google Scholar
  51. 51.
    La Montagna G, Parenti M, Oliani C, et al. Beta-ciclodestrina-piroxicam nel trattamento delle fasi attive della patologia osteoartrosica. Eur Rev Med Pharmacol Sci 1990; 12: 265–72Google Scholar
  52. 52.
    Portioli RI, Casoli P, Tumiati B. II complesso piroxicam-beta-ciclodestrina nel trattamento dell’osteoartrosi e del reumatismo extra-articolare: studio clinico controllato. Reumatologo 1989; 10: 104–7Google Scholar
  53. 53.
    Riccieri V, Spadaro A, Zoppini A. Utilizzo del complesso beta-ciclodestrina piroxicam nella patologia osteoartrosica: studio controllato vs diclofenac sódico. Arch Med Interna 1990; 42: 189–99Google Scholar
  54. 54.
    Rossetti A, Musiari L, Bonati PL, et al. Trattamento del dolore osteoartrosico con PBC. Studio clinico controllato verso metamizolo. Algos 1988; 5 (4): 30–5Google Scholar
  55. 55.
    Tamburro P, Galasso G. Studio clinico controllato sull’effetto antalgico del complesso piroxicam-beta-ciclodestrina nel dolore acuto muscolo-scheletrico e/o articulare. Reumatologo 1989; 10: 237–41Google Scholar
  56. 56.
    Simone C, Oliani C. Beta-cyclodextrin-piroxicam: efficacy and tolerability in the treatment of pain after bone and joint surgery. Curr Ther Res 1990; 47: 541–7Google Scholar
  57. 57.
    Zezza AR, Cosco Mazzuca R, Giuntini C, et al. Valutazione dell’effetto analgesico del piroxicam-betaciclodestrina per os nel trattamento del dolore traumatologico e post-operatorio in ortopedia. Studio controllato vs piroxicam iniettabile. Orto-ped Traumatol Oggi 1988; 8: 255–61Google Scholar
  58. 58.
    Di Matteo L, Fratelli V, Oliani C, et al. Shoulder rotator cuff tendinitis: efficacy and tolerability of piroxicam-beta-cyclodextrin complex [in Italian]. Arch Med Interna 1989; 41: 261–72Google Scholar
  59. 59.
    Galasso G, Tamburro P, Vecchiet L. Analgesic activity of beta-cyclodextrin-piroxicam and tenoxicam in acute soft tissue injuries. Adv Ther 1990; 7: 43–50Google Scholar
  60. 60.
    Tamburro P, Galasso G. Efficacia e tollerabilità del piroxicam-beta-ciclodestrina nel trattamento del dolore muscolo-scheletrico. Reumatologo 1989; 10: 104–7Google Scholar
  61. 61.
    Tamburro P, Galasso G. A controlled trial of β-cyclodextrin-piroxicam versus tiaprofenic acid in the treatment of painful states from inflammation or trauma of periarticular soft-tissues [in Italian]. Arch Med Interna 1990; 42: 73–82Google Scholar
  62. 62.
    Zarotti F, Boscarino G, Serra G, et al. Trattamento del dolore muscolo-scheletrico a diversa etiologia con complesso piroxicam beta-ciclodestrina. Ortoped Traumatol Oggi 1988; 8: 305–12Google Scholar
  63. 63.
    Costa S, Mioli M, Ravaioli R, et al. Prostaglandin synthetase inhibitor piroxicam beta-cyclodextrin in the treatment of primary dysmenorrhea. Curr Ther Res 1987; 42: 156–64Google Scholar
  64. 64.
    Data on file, Di Renzo GC, Gori F, et al. Efficacy and tolerability of piroxicam-beta-cyclodextrin in the treatment of primary dysmenorrhea. Report 20.00/CT/01/90. Data on file. Cheisi Farmaceutici S.p.A, 1990.Google Scholar
  65. 65.
    Gualdi F, Pagliani A, Dessanti L, et al. Trattamento della dismenorrea primaria con il complesso piroxicam-betaciclodestrina. Giorn It Ost Gin 1989; 11: 77–82Google Scholar
  66. 66.
    Zinelli G, Dessanti L, Ventura A, et al. It trattamento farmacológico della dismenorrea primaria: studio clinico controllato con piroxicam beta-ciclodestrina. Giorn It Ost Gin 1986; 8: 679–87Google Scholar
  67. 67.
    Bruno E, Porcellini A, Farronato GP, et al. Il dolore post-es-trattivo, trattamento analgesico con piroxicam. Dental Cadmos 1987; 14: 61–8Google Scholar
  68. 68.
    Data on file, Umile A, Monici Preti PA, et al. Double-blind parallel comparison of single oral doses of piroxicam-β-cyclodextrin, piroxicam, paracetamol and placebo with moderate to severe pain following oral surgery (3rd molar extraction). Clinical trial no. 20.00/CT/06/91. Chiesi Farmaceutici S.p.A., 1993.Google Scholar
  69. 69.
    Dolci G, Ripari M, Pacifici L, et al. Analgesic efficacy and tolerability of piroxicam-β-cyclodextrin in comparison with piroxicam, paracetamol and placebo in the treatment of postsurgical dental pain [in Italian]. Minerva Stomatol 1993; 42: 235–41PubMedGoogle Scholar
  70. 70.
    Marcucci M, Panelli G, Cambini S. Clinical experience in the treatment of dental pain. Clin J Pain 1991; 7 Suppl. 1: S72-6Google Scholar
  71. 71.
    Giacovazzo M, Martelletti P, Zaurito V, et al. Effetto antalgico acuto del complesso piroxicam-beta-ciclodestrina nel trattamento della cefalea. G Neuropsicofarmacol 1989; 11: 31–55Google Scholar
  72. 72.
    Giacovazzo M, Martelletti P, Zaurito V. Piroxicam-beta-ciclodestrina nel trattamento della cefalea: effetto antalgico acuto e prevenzione dell’insorgenza delle crisi cefalalgiche. G Neuropsicofarmacol 1990; 12: 27–33Google Scholar
  73. 73.
    Granella F, Dadatti A, Bizzi P, et al. Trattamento dell’emicrania comune con il complesso piroxicam-beta-ciclodestrina. G Neuropsicofarmacol 1989; 11: 253–8Google Scholar
  74. 74.
    Micieli C, Iannacchero R, Tassorelli C, et al. Effetto antalgico del complesso piroxicam-beta-ciclodestrina nel trattamento dell’emicrania comune. G Neuropsicofarmacol 1989; 11: 170–3Google Scholar
  75. 75.
    Lemmel EM. Gastrointestinal tolerability of piroxicam-β-cyclodextrin in the treatment of painful joint and spine complaints due to osteoarthritis or inflammatory rheumatism [abstract no. V9]. Klinische Pharmakologie aktuell 1993 (2): 39Google Scholar
  76. 76.
    Data on file, Dreiser RL, Umile A, et al. Piroxicam-beta-cyclodextrin in the treatment of rheumatic disease. A multicentric, long-term (6 months), open study in Belgium, France and The Netherlands. Clinical trial no. 20.00/CT/09/90. Chiesi Farmaceutici S.p.A. 1993.Google Scholar
  77. 77.
    Piroxicam prescribing information. Pfizer Ltd, UK, 1993.Google Scholar
  78. 78.
    Del Favero A. Anti-inflammatory analgesics and drugs used in rheumatiod arthritis and gout. In: Dukes MNG, Beeley L, editors. Side effects of drugs annual, v. 12. Amsterdam: Elsevier Science Publishers B.V., 1988: 91-100Google Scholar
  79. 79.
    Laporte J-R, Carne X, Vidal X, et al. Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Lancet 1991; 337: 85–9PubMedCrossRefGoogle Scholar
  80. 80.
    Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med 1991; 115: 787–96PubMedGoogle Scholar
  81. 81.
    Savage RL, Moller PW, Ballantyne CL, et al. Variation in the risk of peptic ulcer complications with nonsteroidal antiinflammatory drug therapy. Arthritis Rheum 1993; 36: 84–90PubMedCrossRefGoogle Scholar
  82. 82.
    Kaufman DW, Kelly JP, Sheehan JE, et al. Nonsteroidal anti-inflammatory drug use in relation to major upper gastrointestinal bleeding. Clin Pharmacol Ther 1993; 53: 485–94PubMedCrossRefGoogle Scholar
  83. 83.
    García Rodríguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 769–72PubMedCrossRefGoogle Scholar
  84. 84.
    Langman MJS, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steriodal anti-inflammatory drugs. Lancet 1994; 343: 1075–8PubMedCrossRefGoogle Scholar
  85. 85.
    Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic ulcers. Facts and figures multiply but do they add up. BMJ 1990; 300: 278–84Google Scholar
  86. 86.
    Barradell LB, Whittington R, Benfield P. Misoprostol: pharmacoeconomics of its use as prophylaxis against gastroduodenal damage induced by nonsteroidal anti-inflammatory drugs. PharmacoEconomics 1993; 3: 140–70PubMedCrossRefGoogle Scholar
  87. 87.
    Friedel HA, Langtry HD, Buckley MM. Nabumetone: a reappraisal of its pharmacology and therapeutic use in rheumatic diseases. Drugs 1993; 45: 131–56PubMedCrossRefGoogle Scholar
  88. 88.
    Balfour JA, Buckley MM-T. Etodolac: a reappraisal of its pharmacology and therapeutic use in rheumatic diseases and pain states. Drugs 1991; 42: 274–99PubMedCrossRefGoogle Scholar
  89. 89.
    Lanza FL. Gastrointestinal toxicity of newer NSAIDs. Am J Gastroenterol 1993; 88: 1318–23PubMedGoogle Scholar
  90. 90.
    Skeith KJ, Wright M, Davis P. Differences in NSAID tolerability profiles: fact or fiction?. Drug Saf 1994; 10: 183–95PubMedCrossRefGoogle Scholar
  91. 91.
    Rees Willet L, Carson JL, Strom BL. Epidemiology of gastrointestinal damage associated with nonsteroidal anti-inflammatory drugs. Drug Saf 1994; 10: 170–81CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • C. Rhoda Lee
    • 1
  • Julia A. Balfour
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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