title: Piroxicam-β-cyclodextrin: a GI safer piroxicam.
abstract: 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 drug is endowed with a quick absorption rate, which translates into a faster onset of analgesic activity, an effect confirmed in several clinical studies. An analysis of the available trials show that PBC has a GI safety profile, which is better than that displayed by uncomplexed piroxicam. Being an inclusion complex of piroxicam, whose CV safety has been pointed out by several observational studies, PBC should be viewed as a CV safe anti-inflmmatory compound and a GI safer alternative to piroxicam. As a consequence, it should be considered as a useful addition to our therapeutic armamentarium.
authors: Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Italy. scarpi@tin.it
authors: C
authors: C
authors: Scarpignato
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004412:Dysmenorrhea / Q000188:drug therapy; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D009140:Musculoskeletal Diseases / Q000188:drug therapy; D010146:Pain / Q000188:drug therapy; D010894:Piroxicam / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047392:beta-Cyclodextrins / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047392:beta-Cyclodextrins; D010894:Piroxicam; C061072:piroxicam-beta-cyclodextrin
references: Scand J Gastroenterol. 1975;10(2):155-60
references: 1091965
references: Cochrane Database Syst Rev. 2002;(4):CD002296
references: 12519573
references: Anesthesiology. 2005 Dec;103(6):1296-304
references: 16306743
references: Eur J Gastroenterol Hepatol. 2011 Oct;23(10):876-80
references: 21900785
references: J Clin Pharmacol. 2000 Feb;40(2):124-32
references: 10664917
references: BMJ. 1992 Oct 10;305(6858):865-8
references: 1422399
references: Aliment Pharmacol Ther. 2004 Feb;19 Suppl 1:9-16
references: 14725573
references: Arthritis Res Ther. 2008;10(1):R7
references: 18201374
references: Eur J Rheumatol Inflamm. 1993;12(4):3-5
references: 7805702
references: J Pharm Sci. 1997 Feb;86(2):147-62
references: 9040088
references: J Rheumatol. 1986 Aug;13(4):789-96
references: 3490574
references: Pharm Res. 1997 May;14(5):556-67
references: 9165524
references: Gen Pharmacol. 1995 Jul;26(4):809-13
references: 7635256
references: Anesthesiology. 2006 Jan;104(1):152-7
references: 16394701
references: Crit Rev Ther Drug Carrier Syst. 1988;4(3):221-63
references: 3276406
references: Science. 1988 May 6;240(4853):760-7
references: 3283937
references: Best Pract Res Clin Gastroenterol. 2001 Oct;15(5):691-703
references: 11566035
references: Dig Dis Sci. 1990 Dec;35(12):1494-9
references: 2253535
references: J Clin Pharmacol. 1974 Apr;14(4):176-82
references: 4595984
references: Aliment Pharmacol Ther. 2009 Mar 1;29(5):481-96
references: 19053986
references: Science. 1985 Feb 22;227(4689):849-56
references: 17821215
references: Gastroenterol Clin North Am. 2009 Jun;38(2):305-14
references: 19446260
references: Toxicol Pathol. 2008 Jan;36(1):30-42
references: 18337219
references: Circulation. 2007 Mar 27;115(12):1634-42
references: 17325246
references: Dig Dis. 1990;8 Suppl 1:60-70
references: 2225521
references: Arch Intern Med. 2000 Jul 24;160(14):2093-9
references: 10904451
references: Am J Gastroenterol. 2005 May;100(5):1028-36
references: 15842575
references: Can Fam Physician. 2007 Jul;53(7):1177-84
references: 17872814
references: Drug Metab Rev. 1989;21(2):255-76
references: 2517627
references: Arzneimittelforschung. 1985;35(7):1042-7
references: 4052138
references: J Clin Pharm Ther. 2008 Oct;33(5):495-506
references: 18834364
references: J R Soc Med. 2007;100 Suppl 48:7-10
references: 18335847
references: Gastroenterology. 2000 Sep;119(3):706-14
references: 10982765
references: BMC Cardiovasc Disord. 2012 Feb 02;12:4
references: 22297085
references: Arch Intern Med. 1994 Feb 14;154(3):311-6
references: 8297198
references: Biol Pharm Bull. 2002 Feb;25(2):149-64
references: 11853157
references: BMC Musculoskelet Disord. 2006 Oct 20;7:79
references: 17054784
references: Clin Gastroenterol Hepatol. 2007 Jul;5(7):818-28, 828.e1-5; quiz 768
references: 17556027
references: Adv Prostaglandin Thromboxane Leukot Res. 1991;21A:153-6
references: 1825533
references: Circulation. 2006 Mar 28;113(12):1578-87
references: 16534006
references: N Engl J Med. 1991 Jun 13;324(24):1716-25
references: 2034249
references: Eur J Rheumatol Inflamm. 1993;12(4):12-28
references: 7805700
references: Pharm Acta Helv. 1988;63(11):299-302
references: 3237722
references: Ann Med. 2006;38(6):415-28
references: 17008305
references: BMJ. 2006 Jun 3;332(7553):1302-8
references: 16740558
references: Reg Anesth. 1997 May-Jun;22(3):243-8
references: 9168216
references: J Gastroenterol Hepatol. 1994 Jul-Aug;9(4):412-5
references: 7948825
references: Int J Clin Pharmacol Res. 1994;14(5-6):185-91
references: 7672875
references: Paediatr Drugs. 2008;10(1):1-7
references: 18162003
references: J Allergy Clin Immunol. 1986 Oct;78(4 Pt 2):689-94
references: 3534051
references: Curr Med Res Opin. 2009 Oct;25(10):2471-7
references: 19678751
references: Int J Clin Pharmacol Ther. 2001 Jan;39(1):33-6
references: 11204935
references: Z Rheumatol. 1997 Mar-Apr;56(2):76-9
references: 9235813
references: Cochrane Database Syst Rev. 2000;(4):CD002762
references: 11034755
references: Riv Eur Sci Med Farmacol. 1990 Aug-Oct;12(4-5):265-72
references: 2103967
references: Curr Med Res Opin. 2007 Aug;23(8):1859-66
references: 17605893
references: Expert Opin Drug Deliv. 2005 Mar;2(2):335-51
references: 16296758
references: Drugs Aging. 2007;24(2):121-31
references: 17313200
references: Anesthesiology. 2006 May;104(5):1033-9
references: 16645456
references: Br J Clin Pharmacol. 2002 Sep;54(3):320-6
references: 12236853
references: Clin Pharmacol Ther. 1976 Aug;20(2):241-50
references: 780041
references: Eur J Gastroenterol Hepatol. 2003 Feb;15(2):173-8
references: 12560762
references: Eur J Rheumatol Inflamm. 1983;6(1):3-23
references: 6345166
references: Am J Cardiol. 2007 Jan 1;99(1):91-8
references: 17196469
references: Arch Intern Med. 1992 Jun;152(6):1289-95
references: 1534651
references: Aliment Pharmacol Ther. 2007 Jul 1;26(1):95-106
references: 17555426
references: Dig Liver Dis. 2002 Feb;34(2):89-94
references: 11926564
references: Acta Physiol Hung. 1990;75 Suppl:45-6
references: 2371898
references: BMJ. 2003 Jul 5;327(7405):18-22
references: 12842950
references: Arch Intern Med. 2007 Feb 26;167(4):394-9
references: 17325302
references: BMJ. 1996 Jun 22;312(7046):1563-6
references: 8664664
references: Pharmacol Res. 2009 Oct;60(4):254-63
references: 19467328
references: Ann N Y Acad Sci. 2008;1135:185-95
references: 18574224
references: Ann Rheum Dis. 2003 Dec;62(12):1145-55
references: 14644851
references: Drug Saf. 2004;27(6):411-20
references: 15144234
references: Anaesthesia. 1998 May;53(5):424-30
references: 9659013
references: Am J Gastroenterol. 2008 Nov;103(11):2908-18
references: 18853980
references: Ann Med. 2009;41(6):423-37
references: 19430988
references: J Pharmacol Toxicol Methods. 1995 Oct;34(2):63-72
references: 8563034
references: FASEB J. 2008 Feb;22(2):383-90
references: 17884974
references: JAMA. 2006 Oct 4;296(13):1633-44
references: 16968831
references: Chem Rev. 1998 Jul 30;98(5):1743-1754
references: 11848947
references: Basic Clin Pharmacol Toxicol. 2006 Mar;98(3):297-303
references: 16611205
references: Curr Med Res Opin. 2009 Jan;25(1):195-204
references: 19210152
references: Cardiovasc Hematol Disord Drug Targets. 2010 Mar;10(1):53-65
references: 20092437
references: Drugs Today (Barc). 2009 Dec;45(12):877-90
references: 20135022
references: Pain. 2001 Jan;89(2-3):175-80
references: 11166473
references: Int J Tissue React. 1991;13(5):243-8
references: 1806546
references: Clin J Pain. 2004 May-Jun;20(3):123-32
references: 15100587
references: Drugs. 1984 Oct;28(4):292-323
references: 6386426
references: Am J Cardiovasc Drugs. 2010;10(2):125-41
references: 20334450
references: Scand J Haematol. 1984 Aug;33(2):155-9
references: 6474093
references: Agents Actions. 1994 Nov;43(1-2):48-52
references: 7741041
references: Eur Heart J. 2006 Jul;27(14):1657-63
references: 16731535
references: Dig Dis. 1995 Jan;13 Suppl 1:9-39
references: 7697906
references: Ann Rheum Dis. 2004 Aug;63(8):901-7
references: 15020311
references: Dig Dis Sci. 1992 Dec;37(12):1825-32
references: 1473431
references: Drugs. 1994 Dec;48(6):907-29
references: 7533698
references: Scand J Gastroenterol. 1992 Dec;27(12):1049-54
references: 1475622
references: Clin Pharmacokinet. 1994 Feb;26(2):107-20
references: 8162655
references: Pharmacol Res. 2009 Feb;59(2):90-100
references: 19073262
references: Annu Rev Pharmacol Toxicol. 2002;42:553-83
references: 11807183
references: Aliment Pharmacol Ther. 2007 Apr 1;25(7):813-21
references: 17373920
references: Am J Gastroenterol. 2009 Mar;104(3):728-38
references: 19240698
references: Int J Clin Pharmacol Res. 1988;8(3):175-80
references: 3403105
references: Pharmazie. 2007 Apr;62(4):284-6
references: 17484284
references: Food Chem Toxicol. 1997 Mar-Apr;35(3-4):331-6
references: 9207895
references: Am J Med. 1999 Dec 13;107(6A):27S-35S; discussion 35S-36S
references: 10628591
references: Curr Med Chem. 2009;16(16):2042-63
references: 19519380
references: J Clin Pharmacol. 2000 Nov;40(11):1257-66
references: 11075311
references: Digestion. 2006;73 Suppl 1:136-50
references: 16498262
references: Clin Exp Rheumatol. 1998 Jan-Feb;16(1):49-54
references: 9543561
references: Chem Pharm Bull (Tokyo). 1975 Dec;23(12):3062-8
references: 1218446
references: Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001751
references: 20091521
references: J Physiol Paris. 2001 Jan-Dec;95(1-6):21-7
references: 11595414
references: Semin Arthritis Rheum. 1997 Jun;26(6 Suppl 1):16-20
references: 9219315
references: Med Res Rev. 1994 May;14(3):353-86
references: 8007740
references: Expert Opin Drug Deliv. 2010 Aug;7(8):967-76
references: 20586705
references: Ann Rheum Dis. 2011 May;70(5):818-22
references: 20833736
references: Curr Pharm Des. 2002;8(12):1077-89
references: 11945152
references: Gut. 2006 Dec;55(12):1731-8
references: 16687434
references: Clin Rheumatol. 1986 Sep;5(3):389-98
references: 3536263
references: Gastroenterol Clin North Am. 2009 Jun;38(2):315-32
references: 19446261
references: Pharm Res. 1998 Jun;15(6):925-30
references: 9647360
references: Clin J Pain. 1991;7 Suppl 1:S72-6
references: 1810525
references: Arthritis Rheum. 2008 Apr 15;59(4):568-74
references: 18383398
references: Best Pract Res Clin Gastroenterol. 2001 Dec;15(6):919-41
references: 11866485
references: Ann Rheum Dis. 2004 Jul;63(7):759-66
references: 15194568
references: PLoS Med. 2011 Sep;8(9):e1001098
references: 21980265
references: Nucl Med Commun. 1987 May;8(5):327-34
references: 3317160
references: Arch Intern Med. 2002 Oct 28;162(19):2204-8
references: 12390063
references: Pharmacoepidemiol Drug Saf. 2006 Dec;15(12):861-72
references: 17086563
references: Arthritis Rheum. 2000 Sep;43(9):1905-15
references: 11014340
references: Laryngoscope. 2002 Apr;112(4):589-602
references: 12150508
references: Eur J Clin Pharmacol. 1989;36(6):599-604
references: 2673795
references: Br J Clin Pharmacol. 1999 Dec;48(6):839-46
references: 10594488
references: Gastroenterol Clin North Am. 2010 Sep;39(3):433-64
references: 20951911
references: J Physiol Paris. 2001 Jan-Dec;95(1-6):3-9
references: 11595412
references: Ital J Gastroenterol Hepatol. 1999;31 Suppl 1:S63-72
references: 10379472
references: J Dent Res. 1987 Mar;66(3):799-801
references: 3475312
references: Int J Med Sci. 2010 Jul 05;7(4):232-9
references: 20617127
references: Eur J Rheumatol Inflamm. 1993;12(4):6-11
references: 7805705
references: Eur J Med Chem. 2005 Jul;40(7):624-31
references: 15935897
references: Rheumatology (Oxford). 2008 Sep;47(9):1342-7
references: 18477642
references: Clin Ther. 1990 Nov-Dec;12(6):547-55
references: 2289222
references: Contraception. 2010 Mar;81(3):185-96
references: 20159173
references: Int J Clin Pract Suppl. 2003 Apr;(135):43-9
references: 12723747
references: Lancet. 2007 Dec 22;370(9605):2138-51
references: 18156036
references: J Pharm Sci. 1996 Nov;85(11):1142-69
references: 8923319
references: BMJ. 2011 Jan 11;342:c7086
references: 21224324
references: Inflammopharmacology. 2010 Apr;18(2):47-55
references: 20213329
references: Experientia. 1979 Jun 15;35(6):797-8
references: 467595
references: FASEB J. 2004 May;18(7):790-804
references: 15117884
references: Am J Gastroenterol. 2006 Apr;101(4):701-10
references: 16494585
references: Pharm Res. 1999 Dec;16(12):1864-70
references: 10644075
references: Arch Intern Med. 1993 Feb 22;153(4):477-84
references: 8435027
references: J Clin Pharmacol. 2000 Oct;40(10):1109-20
references: 11028250