Rheumatoid Arthritis: Karim A

Yuan JJ, Yang DC, Zhang JY, Bible R, Karim A, Findlay JW. · Global Drug Metabolism, Pharmacia, 4901 Searle Parkway, Skokie, Illinois 60077, USA. · Drug Metab Dispos. · Pubmed #12167567 links to  free full text

Abstract: Valdecoxib is a potent and specific inhibitor of cyclooxygenase-2, which is used for the treatment of rheumatoid arthritis, osteoarthritis, and the dysmenorrhea pain. Eight male human subjects each received a single 50-mg oral dose of [(14)C]valdecoxib. Urine, feces, and blood samples were collected after administration of the radioactive dose. Most of the radioactivity in plasma was associated with valdecoxib and the hydroxylated metabolite of valdecoxib (M1). The estimated terminal half-life for valdecoxib was about 7 h. About 76.1% of the radioactive dose was recovered in urine and 18% of the radioactive dose was recovered in feces. Valdecoxib was extensively metabolized in human, and nine phase I metabolites were identified. The primary oxidative metabolic pathways of valdecoxib involved hydroxylation at either the methyl group to form M1 or N-hydroxylation at the sulfonamide moiety to form M2. Further oxidation of M1 led to the formation of several other phase I metabolites. Oxidative breakdown of the N-hydroxy sulfonamide function group in M2 led to the formation of corresponding sulfinic acid and sulfonic acid metabolites. The O-glucuronide conjugate of M1 and N-glucuronide conjugate of valdecoxib were the major urinary metabolites, which accounted for 23.3 and 19.5% of the total administered dose, respectively. The remaining urinary metabolites were glucuronide conjugates of other phase I metabolites. Only 3% of the administered dose was recovered in urine as unchanged parent, suggesting that renal clearance is insignificant for valdecoxib. Absorption of valdecoxib was excellent since the recovery of unchanged valdecoxib in feces was <1% of the administered dose.

Karim A, Tolbert DS, Hunt TL, Hubbard RC, Harper KM, Geis GS. · Searle Research and Development, Skokie, Illinois 60077, USA. · J Rheumatol. · Pubmed #10606360 No free full text.

Abstract: OBJECTIVE: To determine the effects of celecoxib, a specific inhibitor of cyclooxygenase 2 (COX-2) on the renal clearance and plasma pharmacokinetic profile of stable methotrexate (MTX) doses in patients with rheumatoid arthritis (RA). METHODS: Fourteen adult female patients with RA taking a stable weekly dose of MTX (5 to 15 mg/wk) for a minimum of 3 months were randomized to receive concomitantly either celecoxib (200 mg BID) or placebo for a period of 7 days in a single blind, 2 period crossover study of MTX pharmacokinetics and renal clearance. RESULTS: The plasma pharmacokinetic profile of MTX did not change significantly when celecoxib or a placebo was coadministered. The mean renal clearance of MTX alone, 7.98+/-2.18 l/h, was virtually unchanged by coadministration of celecoxib (7.94+/-1.61 l/h) or placebo (7.97+/-1.19 l/h). CONCLUSION: Celecoxib has no significant effect on the pharmacokinetics or renal clearance of MTX in patients with RA, although these results should be confirmed in prospective studies of elderly and renally impaired patients.

Karim A, Ahmed S, Siddiqui R, Marder GS, Mattana J. · Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA. · Chest. · Pubmed #11888989 links to  free full text

Abstract: Upper airway obstruction due to laryngeal involvement is a known complication of systemic lupus erythematosus (SLE). Laryngeal involvement typically accompanies inflammatory activity involving other sites and varies from mild mucosal inflammation to bilateral vocal cord immobility. Cricoarytenoid arthropathy is a rare cause of severe airway obstruction in patients with SLE and almost always occurs in the presence of other associated symptoms. Furthermore, in contrast to patients with rheumatoid arthritis, in whom chronic involvement of cricoarytenoid joints occurs more commonly and often requires surgical intervention, patients with SLE typically present with acute arthritis of cricoarytenoid joints and respond to corticosteroid therapy alone. We describe a patient with known SLE who presented with severe acute upper airway obstruction as the sole manifestation of active SLE after several years of quiescence. The laryngeal involvement progressed from mucosal inflammation to acute cricoarytenoiditis, despite the administration of high-dose corticosteroid therapy, necessitating emergent intubation and tracheostomy. This case illustrates the importance of considering SLE in the differential diagnosis of patients presenting with acute upper airway obstruction.