Los inhibidores de la Ciclooxigenasa 2 (COX-2) y sus efectos adversos !!!   

Data-Medicos 
Dermagic/Express No. 3-(109) 
27 Octubre 2.001 / 27 October 2.001 


EDITORIAL ESPANOL 
================= 
Hola amigos de la red DERMAGIC con su edicion ANIVERSARIA sobre LOS INHIBIDORES 
DE LA CICLOOXIGENASA 2 (COX-2) Y SUS EFECTOS ADVERSOS. 

Se revisaron 4 moleculas: NIMESULIDE, (AULIN) MELOXICAM (MOBIC) , CELECOXIB 
(CELEBREX) y ROFECOXIB (VIOXX), existen otras moleculas que inhiben la ciclooxigenasa 2, 
pero me concentre en las mas populares. 

CELEBREX Y VIOXX consideradas LA NUEVA GENERACION DE LOS 
ANTIINFLAMATORIOS NO ESTEROIDEOS (AINES) con UNA INHIBICION SELECTIVA 
SOBRE LA CICLOOXIGENASA 2 (COX-2), en los procesos inflamatorios. 

NIMESULIDE Y MELOXICAM considerados INHIBIDORES "PREFERENCIALES" SOBRE 
LA CICLOOXIGENASA 2 (COX-2). 

LOS INHIBIDORES SELECTIVOS de la ciclooxigenasa 2 se introdujeron en el mercado en 
1.999, CELECOXIB, REFECOXIB Y MELOXICAM APROBADOS POR LA FDA desde esa 
epoca. 

NIMESULE LA mas vieja de estas MOLECULAS introducida desde LOS AÑOS 80, con mas de 
10 años en el MERCADO AUN NO ESTA APROBADA POR LA FDA, se comercializa en 
LATINOAMERICA Y EUROPA., no en Estados Unidos de America. 

HALLAZGOS DE LA REVISION: 
----------------------------------------------- 

1.) Para agosto de 2.001 se publica un articulo en la web (JAMA) donde se demuestra 
estadisticamente que las NUEVAS MOLECULAS VIOXX (REFECOXIB) Y CELEBREX 
(CELECOXIB) CONSIDERADAS LAS NUEVAS "SUPERASPIRINAS" estan involucradas en 
eventos CARDIACOS, al producir un EFECTO PROTROMBOTICO A NIVEL sanguineo. 

2.) Para septiembre 2.001 se siguen reportando CASOS DE HEPATITIS MEDICAMENTOSA 
PROVOCADOS POR NIMESULIDE. 

3.) TODAS ESTAS 4 MOLECULAS ESTAN involucradas en TOXICIDAD HEPATICA, 
RENAL Y SANGRAMIENTO GASTRICO. 

4.) Las MOLECULAS NIMESULIDE Y MELOXICAM NO ESTAN INVOLUCRADAS EN 
EVENTOS CARDIACOS, se necesitan estudios POSTERIORES PARA COMPROBAR ESTE 
HECHO RECIENTEMENTE DESCRITO. 

5.) LA MOLECULA DE MAYOR TOXICIDAD HEPATICA SEGUN EVENTOS 
REPORTADOS FUE EL NIMESULIDE. 

6.) CELECOXIB ademas de hepatitis ESTA INVOLUCRADA EN PANCREATITIS. 

7.) NINGUNA DE ESTAS MOLECULAS DEBE SER USADA EN MUJERES 
EMBARAZADAS como RELAJANTE DEL UTERO, sobre todo el NIMESULIDE, Pues esta 
involucrado en hepatitis, Oligohidramnios,  daño renal fetal y muerte. 

8.) Las de MENORES EFECTOS secundarios ENCONTRADOS fueron el ROFECOXIB 
(VIOXX) y MELOXICAM (MOBIC) 

9.) LAS MAS RIESGOSAS PARA EL CORAZON FUERON ROFECOXIB (VIOXX) Y 
CELECOXIB (CELEBREX). 

10.) NIMESULIDE CON MAS DE 10 AñOS EN EL MERCADO NO HA SIDO AUN 
APROBADO POR LA FDA, PROBABLEMENTE por la GRAN CANTIDAD DE EFECTOS 
ADVERSOS que se le han descrito y se siguen describiendo. 

CONCLUSIONES: 
---------------------------- 

1.) DE SER VERDAD EL EFECTO PROTROMBOTICO RECIEN DESCRITO DE LAS 
MOLECULAS CELECOXIB (CELEBREX) Y ROFECOXIB (VIOXX) PROVOCANDO 
AUMENTO DE RIESGO CARDIACO, tienen sus dias contados en el mercado. 

"La razon: tu no vas a prescribir una droga como antiinflamatorio 
corriendo el riesgo de que el paciente muera de un evento cardiaco ".....

2.) LA MAS TOXICA DE ESTAS MOLECULAS FUE EL NIMESULIDE CON EL MAYOR 
NUMERO DE EFECTOS ADVERSOS ENCONTRADOS, esta molecula tambien se encuentra 
actualmente bajo estricta OBSERVACION en ALGUNOS PAISES EUROPEOS. De seguir 
reportandose EFECTOS ADVERSOS, tambien tiene sus dias contados. 

" La razon: Tu no vas a prescribir una droga antiinflamatoria en un 
paciente corriendo el riesgo de provocar la "muerte" de su higado......."

Una vez mas con DOCUMENTOS REALES DERMAGIC DEMUESTRA que TODA 
MOLECULA TIENE VENTAJAS Y DESVENTAJAS, Y ESTAS DEBEN SER TOMADAS 
EN CUENTA al momento de prescribirlas en nuestros pacientes. 

En las referencias los hechos... 

Saludos a todos 

Dr. Jose Lapenta R. 

EDITORIAL ENGLISH 
================= 
Hello friends of the net DERMAGIC with their ANNIVERSARY edition on THE INHIBITORS 
OF THE CYCLOOXYGENASE 2 (COX-2) AND THEIR ADVERSE EFFECTS. 

4 molecules were revised: NIMESULIDE, (AULIN) MELOXICAM (MOBIC), CELECOXIB 
(CELEBREX) and ROFECOXIB (VIOXX), other molecules that inhibit the cyclooxygenase 2, 
exist but let us concentrate on those but popular. 

CELEBREX (CELECOXIB) AND VIOXX (ROFECOXIB) THE NEW GENERATION OF 
THE NONSTEROIDAL ANTIINFLAMMATORY DRUGS( NSAIDs) with A SELECTIVE 
INHIBITION ON THE CYCLOOXYGENASE 2 (COX-2), in the inflammatory processes. 

NIMESULIDE AND MELOXICAM considered "PREFERENTIAL" INHIBITORS ON THE 
CYCLOOXYGENASE 2 (COX-2). 

THE SELECTIVE INHIBITORS of the cyclooxygenase 2 were introduced in the market in 1.999, 
CELECOXIB, REFECOXIB AND MELOXICAM APPROVED FOR THE FDA from that 
time. 

NIMESULE THE but old of these MOLECULES introduced from THE eighties, with but of 10 
years in the MARKET not yet THIS APPROVED FOR THE FDA, it is marketed in LATIN 
AMERICA AND EUROPE, not in United States of America. 

DISCOVERIES OF THE REVISION: 
--------------------------------------------------- 

1.) For August of 2.001 it is published a I article in the web (JAMA) where is statistically 
demonstrated that the NEW MOLECULES VIOXX (REFECOXIB) AND CELEBREX 
(CELECOXIB) CONSIDERED THE NEW "SUPERASPIRINS" are involved in HEART events, 
when producing a PROTHROMBOTIC EFFECT AT sanguine LEVEL. 

2.) For September 2.001 they are continued reporting CASES OF HEPATITIS BY DRUGS 
CAUSED FOR NIMESULIDE. 

3.) ALL THESE 4 MOLECULES are involved in HEPATIC, RENAL TOXICITY And 
GASTRIC BLEEDING. 

4.) The MOLECULE NIMESULIDE AND MELOXICAM are not INVOLVED IN HEART 
EVENTS, LATER studies are needed to CHECK THIS RECENTLY DESCRIBED FACT. 

5.) THE MOLECULE OF more HEPATIC TOXICITY ACCORDING TO REPORTED 
EVENTS was THE NIMESULIDE. 

6.) CELECOXIB besides hepatitis IS INVOLVED IN PANCREATITIS. 

7.) NONE OF THESE MOLECULES should BE USED IN PREGNANT WOMEN as 
RELAXANTS OF THE UTERUS, mainly the NIMESULIDE, Because is involved in 
hepatitis, Oligohydramnios, and fetal renal damage and death. 

8.) Those of SMALLER secondary EFFECTS were the ROFECOXIB (VIOXX) and 
MELOXICAM (MOBIC) 

9.) THOSE BUT RISKY FOR THE HEART they were ROFECOXIB (VIOXX) AND 
CELECOXIB (CELEBREX). 

10.) NIMESULIDE WITH MORE THAN 10 years old IN THE MARKET has not EVEN BEEN 
APPROVED BY THE FDA, PROBABLY for the GREAT QUANTITY OF ADVERSE 
EFFECTS that have been described and they are continued describing. 

CONCLUSIONS: 
------------------------ 

1.) OF being TRUE THE PROTHROMBOTIC EFFECT RECENTLY DESCRIBED OF THE 
MOLECULES CELECOXIB (CELEBREX) AND ROFECOXIB (VIOXX) CAUSING 
INCREASE OF HEART RISK, they have their days counted in the market. 

"The reason:  You won't prescribe a drug like antiinflammatory 
running the risk that patient dies from a heart event....."

2.) THE BUT TOXIC OF THESE MOLECULES it was THE NIMESULIDE WITH THE 
MAJOR I NUMBER OF ADVERSE EFFECTS, this molecule is also at the moment under strict 
OBSERVATION in SOME EUROPEAN COUNTRIES. Of continuing being reported 
ADVERSE EFFECTS, he also has their counted days. 

"The reason:  You won't prescribe an antiinflammatory drug in a 
patient running the risk of causing the "death" of their liver...."

Once but with REAL DOCUMENTS DERMAGIC DEMONSTRATES that ALL MOLECULE 
HAS ADVANTAGES AND DISADVANTAGES, AND THESE they should BE TAKEN INTO 
ACCOUNT to the moment to prescribe them in our patients. 

in the references the facts... 

greetings to all 

Dr. Jose Lapenta R. 

============================================================= 
1.) NIMESULIDE ADVERSE EFFECTS -(AULIN) (SHERING-PLOUGH) 
============================================================= 
Source: The bibliographic references in this text, more than 400 articles on the web 

1.) Hepatitis. 
2.) Increased hepatic enzyme levels. 
3.) Hepatocellular necrosis. 
4.) Cholestasis 
5.) Fatal liver damage./ Fulminant hepatic failure and death. 
6.) Gastrointestinal tract ulcers. /Bleeding gastric ulcers. 
7.) Hepatic insufficiency. 
8.) Renal failure./ Renal impairment. 
9.) Urticaria. 
10.) Jaundice. 
11.) Neonatal chronic kidney failure./Neonatal end-stage renal failure./ Perinatal vasoconstrictive 
renal insufficiency. 
12.) Purpura. 
13.) synergistic effect with use of cetirizine with nimesulide. 
14.) Fixed drug eruptions. 
15.) Toxic hepatitis in pregnancy. 
16.) Hypothermia. 
17.) Bullous and erosive stomatitis. 
18.) Oligohydramnios. 
19.) Cross reaction with acetaminophen in alergic patients 
20.) Esophagitis. 
21.) anorexia. 
22.) nausea. 
23.) vomiting. 
============================================================= 
2.) CELECOXIB ADVERSE EFFECTS -CELEBREX (SEARLE-PFIZER) 
============================================================= 
Source: The Bibliographics references on this text, more than 400 articles on the web 

1.) Risk of Cardiovascular events: Myocardial infarction, unstable angina, Cardiac Thrombus, 
resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic 
attacks: 
2.) Atherothrombosis. 
3.) Cholestatic hepatitis. 
4.) Acute pancreatitis. 
5.) Visual disturbance. 
6.) Hallucinations. 
7.) Elevation of blood pressure. / Hypertension. 
8.) leukocyte adherence promotion. 
9.) Acute hepatitis. 
11.) Gastroduodenal ulceration. /Gastrointestinal damage 
12.) Increased insulin sensitivity in healthy subjects. 
13.) Gastropathy and hypoprothrombinemia. 
14.) Delirium. 
15.) Renal impairment. 
============================================================= 
MELOXICAM (MOBIC) BOEHRINGER INGELHEIM PHARMACEUTICALS INC 
============================================================= 
Source: The Bibliographics references on this text, more than 400 articles on the web 

1.) Liver toxicity. 
2.) Cholestasis. 
3.) Erythema multiforme. 
4.) Upper digestive hemorrhage. 
6.) Gastrointestinal complications. 
7.) Alterations in platelet function. 
8.) Rash. 
9.) Eosinophilia. 
10.) Renal impairment. 
11.) Anemia. 
12.) Fluid retention and edema 
13.) premature closure of the ductus arteriosus 

============================================================= 
ROFECOXIB ADVERSE EFFECTS -VIOXX (MERCK S. and D.) 
============================================================= 
Source The Bibliographical references in this text, and more than 350 articles on the web. 

1.) Risk of Cardiovascular events: Myocardial infarction, unstable angina, Cardiac Thrombus, 
resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic 
attacks: 
2.) Atherothrombosis. 
3.) Acute tubulointerstitial nephritis. 
4.) Upper gastrointestinal bleeding. / Gastrointestinal damage 
5.) Delirium. 
6.) Renal dysfunction. 
7.) Elevation of blood pressure. / Hypertension. 
============================================================= 
============================================================= 
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES 
============================================================= 
CYCLOOXYGENASE 2 (COX-2) INHIBITORS 
============================================================= 
1.) Risk of Cardiovascular Events Associated With Selective COX-2 lnhibitors 
2.) Cyclo-oxygenase products and atherothrombosis. 
3.) Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 
inhibitors. A report of four cases. 
4.) Cyclooxygenase 2 inhibition and thrombosis comment on the article by Crofford et al. 
5.) Cyclooxygenase 2 inhibitors and thrombogenicity production: comment on the article by Crofford 
et al. 
6.) COX-2 inhibition and thrombotic tendency: a need for surveillance. 
7.) Uterine relaxant effects of cyclooxygenase-2 inhibitors in vitro. 
8.) Inhibition of both COX-1 and COX-2 is required for development of gastric damage in response 
to nonsteroidal antiinflammatory drugs. 
9.) COX-2 inhibitors and renal failure: the triple whammy revisited. 
10.) Renal side-effects of cyclo-oxygenase-type-2 inhibitor use. 
11.) Clinical experience with cyclooxygenase-2 inhibitors. 
Inflamm Res 1999 May;48(5):247-54 
12.) [Preferential COX-2 inhibition: its clinical relevance for gastrointestinal non-steroidal 
anti-inflammatory rheumatic drug toxicity.] 
13.) Mechanism of action of aspirin-like drugs. 
============================================================= 
CELECOXIB (CELEBREX) SEARLE-PFIZER 
============================================================= 
1.) Cholestatic hepatitis in association with celecoxib 
2.) Acute pancreatitis associated with celecoxib. 
3.) Visual disturbance associated with celecoxib. 
4.) Acute onset of auditory hallucinations after initiation of celecoxib therapy. 
5.) Effect of cyclooxygenase-2 inhibitor (celecoxib) on the infarcted heart in situ. 
6.) Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on 
COX-2 versus COX-1 in healthy volunteers. 
7.) Selective cyclo-oxygenase-2 inhibition with celecoxib elevates blood pressure and promotes 
leukocyte adherence. 
8.) Celecoxib-induced acute pancreatitis and hepatitis: a case report. 
9.) Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine 
coronary arteries. 
10.) Nonsteroidal Anti-Inflammatory Drugs and Hypertension. 
11.) Possible celecoxib-induced gastroduodenal ulceration. 
12.) Inhibition of cyclooxygenase-1 or -2 on insulin sensitivity in healthy subjects. 
13.) Cyclooxygenase-2 inhibitor celecoxib: a possible cause of gastropathy and 
hypoprothrombinemia. 
============================================================= 
NIMESULIDE (SHERING-PLOUGH) 
============================================================= 
1.) Nimesulide 
2.)COX 2 inhibitor and fulminant hepatic failure. 
3.) CASE REPORT Fatal hepatitis and renal failure during treatment with nimesulide 
4.) Nimesulide and renal impairment. 
5.) Aspirin and paracetamol tolerance in patients with nimesulide-induced urticaria. 
6.) Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID-induced skin 
disorders. 
7.) Neonatal chronic kidney failure associated to cyclo-oxygenase inhibitors administered during 
pregnancy. 
8.) Nimesulide aggravates kainic acid-induced seizures in the rat. 
9.) Nimesulide-induced hepatitis and acute liver failure. 
10.) Nimeulide and neonatal renal failure. 
11.) Fatal hepatitis associated with nimesulide. 
12.) Neonatal end-stage renal failure associated with maternal ingestion of cyclo-oxygenase-type-1 
selective inhibitor nimesulide as tocolytic. 
13.) [Nimesulide acute hepatitis: description of 3 cases]. 
14.) Analgesics for pediatric use. 
15.) Nimesulide, clavulanic acid and hepatitis. 
16.) Nimesulide-induced hepatitis and acute liver failure. 
17.) [Toxic hepatitis caused by nimesulide, presentation of a new case and review of the literature]. 
18.) [Bleeding gastric ulcers and acute hepatitis: 2 simultaneous adverse reactions due to nimesulide 
in a case]. 
19.) Nimesulide-induced acute hepatitis: evidence from six cases. 
20.) Nimesulide-induced purpura. 
21.) Modification of antihistaminic activity of cetirizine by nimesulide. 
22.) Perinatal vasoconstrictive renal insufficiency associated with maternal nimesulide use. 
23.) Acute renal failure induced by nimesulide in a patient suffering from temporal arteritis. 
24.) Drug-induced cholestasis. 
25.) Adverse drug reactions postal survey-bronchial asthma and angioedema with nimesulide. 
26.) Hypothermia with nimesulide. 
27.) [Nimesulide-induced acute hepatitis]. 
28.) [Nimesulide toxic hepatitis in pregnancy]. 
29.) Positive lesional patch tests in fixed drug eruptions from nimesulide. 
30.) Nimesulide-induced acute hepatitis. 
31.) [Severe acute hepatitis probably induced by nimesulide]. 
32.) Bullous and erosive stomatitis induced by nimesulide. 
33.) The uncoupling effect of the nonsteroidal anti-inflammatory drug nimesulide in liver mitochondria 
from adjuvant-induced arthritic rats. 
34.) Can a cyclo-oxygenase type-2 selective tocolytic agent avoid the fetal side effects of 
indomethacin? 
============================================================= 
ROFECOXIB (VIOXX) MERCK SHARP AND DOHME 
============================================================= 
1.) Tolerability to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions. 
2.) FDA warns Merck over its promotion of rofecoxib. 
3.) Nephrotoxicity of selective COX-2 inhibitors. 
4.) [Upper gastrointestinal bleeding secundary to rofecoxib]. 
5.) Celecoxib- and rofecoxib-induced delirium. 
6.) Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, 
rofecoxib. 
7.) Rofecoxib-induced renal dysfunction in a patient with compensated cirrhosis and heart failure. 
8.) Gastrointestinal damage induced by celecoxib and rofecoxib in rats. 
9.) FDA refuses companies' request to drop ulcer warning 
10.) Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on 
cyclooxygenase-2-selective inhibition. 
============================================================= 
MELOXICAM (MOBIC) BOEHRINGER INGELHEIM PHARMACEUTICALS INC 
============================================================= 
1.) Meloxicam-induced liver toxicity. 
2.) [Meloxican-induced cholestasis]. 
3.) Meloxicam-induced erythema multiforme. 
4.) Meloxicam, 15 mg/day, spares platelet function in healthy volunteers. 
5.) [Upper digestive hemorrhage caused by meloxicam.] 
6.) Gastrointestinal complications and meloxicam. 
7.) MELOXICAM ADVERSE EFFECTS 
============================================================= 
============================================================= 
CYCLOOXYGENASE 2 (COX-2) INHIBITORS 
============================================================= 
1.) Risk of Cardiovascular Events Associated With Selective COX-2 lnhibitors 
============================================================= 
Source: JAMA august 2.001 Vol. 286 No. 8 

Debabrata Mukherjee, MD; Steven E. Nissen, MD; Eric J Topol, MD 

Atherosclerosis is a process with infiammatory features and selective cyclooxygenase 2 (COX-2> 
inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, 
by decreasing vasodilatory and antiaggregatory prostacyclin production, COx-2 antagonists may 
lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors 
when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we 
performed a MEDLINE search to identifv al English-Ianguage articles on use of COX-2 inhibitors 
published between 1998 and February 2001. We also reviewed relevant submissions to the US 
Food and Drug Administration by pharmaceutical companies. 


Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study 
(VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 
patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR 
showed that the reí ative risk of developing a confirmed adjudicated thrombotic cardiovascular event 
(myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or 
unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment 
compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P = .002). There was no 
significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between 
celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction 
rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the 
placebo group of a recent metaana Iysis of 23 407 patients in primary prevention trials (0.52%): 
0.74% with rofecoxib (P = .04 com pared with the placebo group of the meta-analysis) and 0.80% 
with celecoxib (P = .02 compared with the placebo group of the meta-analysis). 

The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 
inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the 
risk. 

Aspirin and nonsteroidal anti-infiammatory agents (NSAIDs) have proven analgesic, 
anti-infiammatory, and antithrombotic properties but also have significant gastric toxicity. The 
gastrointestinal toxi city appears to be related to cyclooxygenase 1 (COX-1) inhibition.1 In 1990, 
Fu et al2 detected a novel COX protein in monocytes stimulated by interleukin, and a year later 
Kujubu et al3 identified a gene with considerable homology to COX-1. 
identification of this COX-2 protein rekindled the efforts of the pharmaceutical industry to produce a 
safer analgesic and anti-infiammatory drug via selective inhibition of COX-2, and this class of agents 
was introduced in 1999. By October 2000, celecoxib and rofecoxib had sales exceeding $3 billion 
in the United States, and a prescription volume in excess of 100 million for the 12-month period 
ending in July 2000.~ 


The development of COX-2 inhibitors as anti-inflammatory agents without gastric toxicity is based 
on the premise that COX-1 predominates in the gastric mucosa and yields protective prostaglandins, 
whereas COX-2 is induced in inflammation and leads to pain, swelling, and discomfort. However, 
selective COX-2 inhibitors decrease vascular prostacyclin (PGI2) production and may affect the 
balance between prothrombotic and antithrombotic eicosanoids. Unlike the platelet inhibition 
afforded by COX1 inhibitors, COX-2 inhibitors do not share this salutary antithrombotic property. 
In contrast, by decreasing vasodilatory and antiaggregatory PGI2 production, COX-2 antagonists 
may tip the balance in favor of prothrombotic eicosanoids (eg, thromboxane A2) and may lead to 
increased cardiovascular thrombotic events.6 However, atherosclerosis is a process with 
inflammatory features7 and selective COX-2 inhibitors may potentially have antiatherogenic effects 
by virtue of inhibiting inflammation. Herein,we analyze the randomized trials that have been 
performed to determine whether COX-2 inhibitors are associated with a protective or hazardous 
effect on the risk of cardiovascular events. 

METHODS 
------- 
We used MEDLINE to identify all published, English-language, randomized, double-blind trials of 
COX-2 inhibitors from January 1998 to February 2001. Keywords used for our search included 
COX-2, cyclooxygenase, rofecoxib, and celecoxib. We also searched the World Wide Web using 
the same keywords A number of studies8-17 focused only on the gastrointestinal effects of COX-2 
inhibitors and did not assess cardiovascular events, most likely because investigators were unaware 
of any cardiovascular adverse effects at that time. These studies were not included in our analysis 
because there was no reporting of cardiovascular adverse effects. 


COX-2 inhibitors were approved in 1998 and there have been 2 major postmarketing multicenter 
trials with these agents. These include the Vioxx Gastrointestinal Outcomes Research study 
(VIGOR)18 and the Celecoxib Arthritis Safety Study <CLASS).19 We also reviewed 
cardiovascular event rates from Study 085 and Study 090, both submitted to the US Food and Drug 
Administration (FDA).20 Table 1 summarizes the design of these trials. We also compared the 
annualized myocardial infarction (Ml) rates in the placebo group of a recent meta-analysis of 4 
aspirin primary prevention trials with Ml rates in the VIGOR and CLASS trials. 

An October 12, 2000, Adverse Events Reporting System search limited to the United States was 
conducted for rofecoxib and celecoxib using the following MedDRA terms: central nervous system 
hemorrhages and cerebral accidents, coronary artery occlusion, coronaartery embolism, myocardial 
infarctíon, gastrointestinal arterial occlusion and infartion, and embolísm, thrombosis, and stenosis.21 


Time-to-event analysis of cardiovascular events was penformed based on Kaplan-Meier estimates 
of cumulative event incidences. The relative risk <RR) of rofecoxib with respect to naproxen was 
derived from an unstratified Cox model in which the number of events was at least 11; othenvise, RR 
¡5 the ratio of rates and the P value was calculated from a discrete log-rank 
distribution. Event rates in the CLASS trial were expressed as percentages of patients, with end 
points. Frequency of MIs across the trials was compared using the Fisher exact test. Statistical 
analysis was performed using Statistica version 5.5 (StatSoft Inc, Tulsa, OkIa). 

RESULTS 
------- 

VIGOR Trial 
------------ 

The VIGOR trial16 was a doubíe-blind, randomized, stratified, paralíel group trial of 8076 patients 
comparing the occurrence of gastrointestinal toxicity with rofecoxib (50 mgld) or naproxen (1000 
mg/d) during Iong-term treatment for patients with rheumatoid arthritis. Aspirin use was not 
permitted in the study. Although not fully published, cardiovascular event data from the VIGOR trial 
sponsor was recentíy submitted to the FDA.22 The baseline characteristics between the treatment 
groups in the VIGOR trial demonstrated no meaningful or significant differences. Patients requiring 
aspirin for cardiac reasons were excluded from this trial. 


Based on excessive cardiovascular adverse effects in one group in an interim analysis, the data and 
safety monitoring board recommended blinded adjudication of cardiovascular events.22 Ninety-eight 
cases (65/4047 from the rofecoxib group, 33/4029 from the naproxen group) were sent for 
adjudication of vascular events. Of these, 45 patients (46 events) in the rofecoxib group and 20 
patients (20 events) in the naproxen group were adjudicated to have serious thrombotic 
cardiovascular adverse events (MI, unstable angina, cardiac thrombus, resuscitated cardiac arrest, 
sudden or unexplained death, ischemic stroke, and transient ischemic attacks). Eventfree survival ana 
Iysis of these 66 patients showed that the RR (95% confidence interval [CI]) of developing a 
cardiovascular event in the rofecoxib treatment group was 2.38 (1 .39~.00), p<.00i 22 (Figurel). 

A subgroup analysis was performed for patients cíassified as either 'aspinn indicated~' or "aspinn not 
indicated." In the VIGOR trial, aspirin-indicated patients were defined as those with past medical 
history of stroke, transient ischemic aftack, MI, unstable angina, angina pectoris, coronary artery 
bypass graft surgery, or percutaneous coronary interventions. OnIy 321 (3.9%) patients were 
aspirin-indicated patients (170 in the rofecoxib group; 151 in the naproxen group), because the need 
for aspirin was an exclusion criterion. The RR of developing serious cardiovascular events among 
aspirin-indicated patients between the rofecoxib group and the naproxen group was 4.89 (95% CI, 
1.41-16.88), P = .01, and the RR for aspirin not indicated patients was 1.89 (95% CI, 1.03-3.45), 
P = 04.22 Of note, no patient in the aspirin indicated group sustained an MI. 


lf al cardiovascular events from the adverse event data sets that were termed ."serious" in the FDA 
medical reviewer's opinion were compared, there were 111 patients in the rofecoxib group and 50 
patients in the naproxen group with serious cardiovascular events. Event-free survival analysis 
showed the risk of serious cardiovascular events in the rofecoxib group was 2.2 times higher (95% 
CI, 1.62-3.21; P<.001) than in the naproxen group.22 


CLASS Trial 
----------- 
CLASS was a doubíe-blind, randomized controlíed trial in which 8059 patients were randomized to 
receive 400 mg of ceíecoxib twice per day, 800 mg of ibuprofen 3 times per day, or 75 mg of 
diclofenac twice per day.19 Aspirin use (<325 mgld) was permitted in this study. Although not 
published, cardiovascular event data from the CLASS study submitted to 
the FDA were included in our review.23 The CLASS trial with celecoxib demonstrated no 
significant difference in cardiovascular events compared with the NSAIDs. Figure 2 shows the 
thrombotic event rates in the CLAS~ trial. The event rates are stratified by patients receiving aspirin 
and those not receiving aspirin. 

Study 085 and Study 090 
------------------------ 

Study 085 (N = 1042) was a randomized, double-bíind, parallel-group, placebo-controlled trial of 
the efficacy and safety of rofecoxib (12.5 mgld) nabumetone (1000 mgld) vs píacebo after 6 weeks 
of treatment for osteoarthritis of the knee. Patients were allowed to take Iow-dose aspirin 1 
cardioprotection.2Q There were 3 total cardiovascular events in this trial: 1 event (0.2%) in the 
rofecoxib group, 2 events (0.4%) in the nabumetone group, and no events in the píacebo group. 

Study 090 (N = 978) was a randomized, placebo-controlled, paralIeI-grou~ double-blind trial of 
the efficacy and safety of rofecoxib (12.5 mg/d) vs nabumetone (1000 mgld) vs placebo in patients 
with osteoarthritis of the knee. Low-dose aspirin for cardioprotection was also aííowed in this study 
Study 090 reported a total of 9 serious cardiovascular events: 6 (1.5%) events in the rofecoxib 
group, 2 (0.5 %) in the nabumetone group, and 1 (0.5%) in the placebo group. 

Adverse Event Reporting System 
------------------------------ 

An Adverse Event Reporting System search revealed 144 unduplicated thrombotic or embolic cases 
for celecoxib and 159 cases for rofecoxib.21 Forty-two celecoxib cases and 60 rofecoxib cases 
were excíuded for a Iac of documented event or for hemorrhagic stroke in which the prothrombin 
time, partial thromboplastin time, or international normalized ratio was above the normal range; also 
excluded were secondhand reports with no confirmed diagnosis. Ninety-nine thrombotic or embolic 
events were attributed to rofecoxib and 102 cases to ceíecoxib. Table2 summarizes th thrombotic 
events reported with each agent. 

Comparison With Contemporary Meta-anaíysis 
------------------------------------------- 

The meta-anaíysis of the US Physicians' Health Study, the UK Doctors Study, the Thrombosis 
Prevention Trial, and the Hypertension Opti mal Treatment trials included 48 540 patients, of whom 
25 133 were treated with aspirin and 23 407 were given píacebo.24 The annualized MI rate in ti 
placebo group in this meta-analysis was 0.52%. The annualized MI rates 1 both the VIGOR and the 
CLASS trials were higher: 0.74% with rofecoxib = .04, compared with the placebo group 
of the meta-analysis) and 0.80% with celecoxib (P = .02, compared with the placebo group of the 
metaanalysis) 

COMMENT 
-------- 

Aspirin and NSAIDs inhibit prostaglandin synthesis via a cyclooxygenase enzyme. This action is the 
key to both their therapeutic and toxic effects. The COX-1 isoform is constitutively expressed in 
most cells, which results in the production of homeostatic prostaglandins that maintain gastrointestinal 
mucosal integrity and renal blood flow. The COX-1 isoform is also expressed in platelets and 
mediates production of thromboxane A2 a potent píatelet activator and aggregator. The COX-2 
isoform produces prostaglandins at infiammatory sites as well as PGI2, which is a vasodilator and 
inhibitor of platelet aggregation. Nonselective NSAIDs inhibit the production of both thromboxane 
and PGI2. Selective COX-2 inhibitors have no effect on thromboxane A2 production, but by 
decreasing PGI2 productior may tip the natural balance between prothrombotic thromboxane A2 
and antithrombotic PGI2, potentiaíly leading to an increase in thrombotic cardiovascular events.25. 
26 

We reviewed the cardiovascular event rates in the 2 major triaís with selective COX-2 inhibitors and 
in 2 smaller trials. The VIGOR trial demonstrated significantly increased risk of cardiovascular event 
rates with use of rofecoxib although the study enrolled patients who did not require aspi rin for 
protection from ischemic events. Patients with angina, congestive heart failure, MI, coronary artery 
bypass graft surgery within 1 year, stroke or transient ischemic attacks within 2 years, and 
uncontrolled hypertension were excluded from this trial. However, these criteria can be viewed as 
too stringent, given data from trials that support more liberal use of aspirin for primary prevention. 

The results of the VIGOR study can be expía ined by either a significant prothrombotic effect from 
rofecoxib or an antithrombotic effect from naproxen (or conceivabíy both). There are differential 
effects of NSAIDs and COX-2 inhibitors on ex vivo píatelet aggregation to 1 mM arachidonic acid. 
Naproxen has significant antiplatelet effects, with mean platelet aggregation inhibition of 93% compa 
red with píatelet aggregation inhibition of 92% for those taking aspi rin (81 mg).22 Thus naproxen, 
but not ibuprofen (platelet aggregation of approximately 80%) or diclofenac (platelet aggregation of 
approximately 40%), resulted in a high leve of plateíet aggregation inhibition similar to that achieved 
with aspi rin.22 There 5 dinical evidence that flurbiprofen, 50 mg twice daily for 6 months, reduced 
the incidence of MI by 70% compared with placebo.27 Indobufen, another NSAID, was as 
effective as aspirin in preventing saphenous vein graft occlusion alter coronary artery bypass graft 
surgery.26 


Because of the evidence for an antiplatelet effect of naproxen, it is difficult to assess whether the 
difference in cardiovascular event rates in VIGOR was due to a benefit from naproxen or to a 
prothrombotic effect from rofecoxib. Therefore, we examined results from a meta-analysis of 4 
aspirin primary prevention trials24 to evaluate whether the cardiovascular event rates observed with 
rofecoxib were similar in VIGOR to a placebo-treated population with similar cardiac risk factors. 
While acknowíedging that comparison of patient popuíations in 2 different trials is always 
probíematic, the results of this meta-analysis may further demonstrate the prothrombotic potential of 
rofecoxib and celecoxib and suggest that increased event rates with COX-2 inhibitors are possibly 
due to a prothrombotic effect, not merely a failure to offer the protection of aspirin-like NSAIDs. 
However, it is important to point out that rheumatoid arthritis increases risk of Ml, making intertrial 
comparisons difficult.29 

In contrast to the VIGOR study, the CLASS study with celecoxib did not show a significant increase 
in cardiovascular event rates compared with NSAIDs, possibly due to the use of low-dose aspirin in 
the CLASS trial or to pharmacological differences in the NSAID agents used as controls in the 2 
studies. Diclofenac and ibuprofen have significantly less antiplatelet effects compared with 
naproxen.22 To have a vascular protective effect, nearcomplete inhibition of thromboxane over time 
is needed3~ and the degree o thromboxane inhibition with didofenac and ibuprofen may not afford 
cardioprotection. Furthermore, diclofenac exhibits more effect on PGI2 inhibition than does 
naproxen. Van Hecken et a131 demonstrated that diclofenac causes 94% inhibition of COX-2 
compared with 71% inhibition o COX-2 for naproxen. Thus, diclofenac not only has less antiplateíet 
effect, but may have some intrinsic prothrombotic effect among NSAIDs due to inhibition of 
vasodiíatory PGI2 and this may have masked the increase in event rates with celecoxib. 
Furthermore, the MI rate with celecoxib (0.80%) was similar to that reported with rofecoxib 
(0.74%) when rates were recalculated as an annualized percentage rate to enable direct comparison 

Shinmura et a132 recently demonstrated that up-regulation of COX-2 plays an essential role in the 
cardioprotection afforded by the late phase of ischemic preconditioning. Administration of selective 
COX-2 inhibitors 24 hours alter ischemic preconditioning abolished the cardioprotective effect o late 
ischemic preconditioning against myocardial stunning and MI.32 These data would further suggest 
potential deleterious cardiac effects of COX-2 inhibitors. 

The availabiiity of selective COX-2 inhibitors has raised several important clinical questions. These 
concern the prothrombotic potential of COX-2 inhibitors, differences in the antithrombotic effect of 
various NSAIDs, the mandatory use of aspirin with selective COX-2 inhibitors, and whether 
simuitaneous use of aspirin negates the gastrointestinal protective effect of selective COX-2 
inhibitors. 

Current data would suggest that use of selective COX-2 inhibitors might lead to increased 
cardiovascular events. Two smaller studies (Study 085 and Study 090) of rofecoxib that both 
allowed the use of low-dose aspinn did not demonstrate the significant increase in cardiovascular 
event rate noted in VIGOR. However, these studies had smaller sampie sizes, used only 25% of the 
dose of rofecoxib used in VIGOR, and had few events for meaningful comparison. Thus the 
prothrombotic effect seen with rofecoxib may potentiaiiy be dose dependent. Also, the use of 
low-dose aspirin in these protocols may negate some of the gastrointestinal benefits of selective 
COX-2 inhibition. There is evidence that gastrointestinal bleeding from aspirin is not dose related.33 


COX-2 inhibitors also have been shown to increase biood pressure,34 and more patients in the 
VIGOR trial developed hypertension in the rofecoxib group compared with the naproxen group. For 
rofecoxib, the mean increase in systolic blood pressure in the VIGOR trial was 4.6 mm Hg and the 
mean increase in diastolic blood pressure was 1.7 mm Hg, compared with a 1.0-mm Hg increase in 
systoiic blood pressure and a 0.1-mm Hg increase in diastolic blood pressure with naproxen. 
Changes in blood pressure in the CLASS trial were not reported. Previous work has shown that a 
2-mm Hg reduction in diastolic blood pressure results in about a 40% reduction in the rate of stroke 
and a 25% reduction in the rate of MI.35 The Heart Outcomes Prevention Evaluation study 
demonstrated significant reduction in cardiovascular events with a 3- 4-mm Hg reduction in biood 
pressure.36 Moreover, a recent reanaiysis of 20 years of blood pressure data from the Fra mingham 
Heart Study37 suggests that the degree of benefit expected from a decrease in blood pressure may 
have been underestimated. Thus, the elevation in blood pressure reported with use of COX-2 
¡nhibitors may also play an important role in adverse cardiovascular outcomes. 

Based on this review, it is useful to consider nonselective and selective COX inhibitors as possessing 
a spectrum of biological effects, both favorable and unfavorabie. At one end of the spectrum, 
COX-2 inhibitors show less propensity for gastrointestinal toxicity but greater prothrombotic 
potential. At the other end of the spectrum, aspirin and naproxen show greater potential for 
gastrointestinal toxicity but have a cardioprotective effect. Other agents fail along intermediate points 
in this spectrum. Clinicians may want to consider these pafferns of riskk and benefit in selecting the 
most appropriate agent for individual patients. 

Our analysis has several significant limitations. The increase in cardiovascular events in these trials 
was unexpected and evaluation of these end points was not prespecified. There remains 
considerable uncertainty in any post hoc anaiysis. The patient populations in these triais were 
heterogeneous, and it has been established that patients w¡th meumatoid arthrit¡s have a higher risk 
of MI.29 This leads to difficulty in assessing risk in a more representative sampling of patients. Also, 
the trial< we examined only addressed continuous use of COX-2 inhibitors. Currentl~ no data exist 
on cardiovascular safety for the sporadic, intermittent use of these agents by individuais for 
musculoskeietal pain, which appears to be the most frequent pattern of use. 

Our findings suggest a potential increase in cardiovascular event rates for the prsently availabie 
COX-2 inhibitors. It is possible that concomitant use of aspirin may not fully offset the risk of 
selective COX-2 inhibitors. However, definitive evidence of such an adverse effect will require a 
prospective randomized clinical trial. On the other hand, the inflammaton component of 
atherosclerosis has recently been emphasized7. ?8, 39 and may be suppressible by COX-2 
inhibitors. Given the remarkable exposur and popularity of this new class of medications, we believe 
that it is mandatory to conduct a trial specifically assessing cardiovascular risk an benefit of these 
agents. Until then, we urge caution in prescribing these agents to patients at risk for cardiovascular 
morbdity. 


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3. Kujubu DA, Fietcher BS, Varnum BC, Lim RW, Herschman HR. 
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4.IMS Health. 
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5. Schmedtje JF, Ji YS, Liu WL, DuBois RN, Runge MS. 
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6. Beiton O, Byrne D, Kearney D, Leahy A, Fitzgerald DJ. 
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10.) Ehrich EW, Davies GM, Watson DJ, Bolognese JA, Seidenberg BC,Bellamy N.Minimal 
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11. Lipsky PE, lsakson PC. 
Outcome of specific COX-2 inhibition in rheumatoid arthritis. 
J Rheumatol.1997;24(suppl 49):9-14. 


12. Megeff CE, Strayer SM. 
Celecoxib for rheumatoid arthritis.J Fam Pract.2000;49:108-109. 

13. Bensen WG, Zhao SZ, Burke TA, et al. 
Upper gastrointestinal toierability of ceiecoxib, a COX-2 specific inhibitor, compared to naproxen 
and placebo. 
J Rheumatol. 2000;27:1876-1883. 

14. Chen BH. 
COX-2 inhibitors and renal function in eiderly peopie. 
CMAJ 2000; 163:604. 

15. Day R, Morrison B, Luza A, et al, for the Rofecoxibilbuprofen Comparator Study Group. 
A randomized trial of the efficacy and toierabiiity of the COX-2 inhibitor rofecoxib vs ibuprofen in 
patients with osteoarthritis. Arch lntem Med. 2000;160:1781-1787. 

16. Goldstein JL, Silverstein FE, Agrawai NM, et al. 
Reduced risk of upper gastrointestinal ulcer complications with ceiecoxib, a novel COX-2 inhibitor. 
Am J Gastroenterol. 2000;95:1681-1690. 


17. Langman MJ, Jensen DM, Watson DJ, et al. 
Adverse upper gastrointestinal effects of rofecoxib compa red with NSAIDs. JAMA. 
1999;282:1929-1933. 

18. Bombardier C, Lame L, Reicin A, et al. 
Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid 
arthritis. 
N Engí J Med.2000;343: 1520-1528. 

19.SiIverstein FE, Faich G, Goldstein JL, et al, for the Ceiecoxib Long-term Arthritis Safety Study. 
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and 
rheumatoid arthritis: the CLASS study: a randomized controlled trial. 
JAMA. 2000;284: 1247-1255. 

20. Food and Drug Administration. 
Cardiovascular Safety Review. 
Rockville, Md: Food and Drug Administration; 2001. Availabie at: 
Http://www.fda.gov/ohíms/dockets/ac/01 /briefing/ 
3677b2_06_cardio.pdf. Accessibiiity verified July 2, 2001. 

21. Food and Drug Administration. 
OPDRA Postmarketing Safety Revíew. 
Rockv¡lle, Md: Food and Drug Administration/Center for Drug Evaluation and Research; 2001. 
Available at: 
http://www.fda .gov/ohrms/docketslac/0 1 /b~iefing/ 
3677b1_11_thrombo.doc. Access¡b¡Iity verified JuIy 2, 2001. 


22. FDA Advisory Committee. Cardiovascular Safety Review of Rofecoxib.Rockviiie, Md: Food 
and Drug Administration; 2001. Availabie at: 
http://www.fda .gov/ohrms/dockets/ac/01 /briefing/ 
3677b2_06_cardio.pdf. Accessibiiity verified July 2, 2001. 


23. FDA CLASS Ad¡sory Committee. 
CLASS Advísory Comm¡ttee Brieflng DocumenL 
Rockvi líe, Md: Food and Drug Administration; 2001. Available at:http:I/www.fda 
.gov/ohrms/dockets/ac/01 /briefing/ 
3677b1_Ol_searie.pdf. Accessib¡lity verified JuIy 2, 2001. 


24. Sanmuganathan PS, Ghahramani P, Jackson PR, WalIis EJ, Ramsay LE. Aspirin for primary 
prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived 
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Heart. 200185:265-271. 

25. M~dam BF, Cateila-Lawson F, Mardin¡ lA, Kapoor 5, Lawson JA, FitzGerald GA. 
Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a 
selective inhibitor of COX-2. Pmc Natí Acad Sci U SA. 1 999;96:272-277. 


26. Cateila-Lawson F, M~dam B, Morrison BW, et al. 
Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive 
eicosanoids. 
J Phannacol Exp Ther 1999;289:735-741. 

27. Brochier ML, for the Flurbiprofen French Trial. 
Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thromboiysis 
or angioplasty in acute myocardial infarction. Eur Hean J 1993;14:951-957. 

28. Cataido G, Heiman F, Lavezzari M, Marubini E. 
Indobufen compa red with aspirin and dipyridamole on graft patency after coronary artery bypass 
surgery: results of a combined anaiysis. Conon Artery Dis. 1998;9:21 7-222. 

29.Waliberg-Jonsson 5, Johansson H, Ohman ML, Rantapaa-Dahiqvist 5. Extent of inflammation 
predicts cardiovascular disease and overall mortaiity in seropositive rheumatoid arthritis: a 
retrospective cohort study from disease onset.J Rheumatol 1 999;26:2562-2571. 

30.ReiIly lA, FitzGerald GA. 
Inhibition of thromboxane formation in vivo and ex vivo: implcations for therapy with piatelet 
inhibitory drugs. 
Blood. 1987;69:180-186. 

31. Van Hecken A, Schwartz JI, Depre M, et al. 
Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on 
COX-2 versus COX-1 in heaithy voiunteers. J Clin Phannacol.2000;40:1 109-1120. 


32. Shinmura K, Tang XL, Wang Y, et al. 
Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic 
preconditioning in conscious rabbits. 
Proc Natí Acad Sc¡ U SA.2000;97: 10197-10202. 

33. Tayior DW, Barnett HJ, Haynes RB, et al, for the ASA and Carotid Endarterectomy (ACE) 
Trial Coilaborators. 
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34. Muscara MN, Vergnolle N, Lovren F, et al. 
Selective cyclo-oxygenase-2 inhibition with ceiecoxib elevates bloodpressure and promotes 
leukocyte adherence. 
Br J PharmacoL 2000;129: 1423-1430. 

35. Collins R, Peto R, MacMahon 5, et al. 
Blood pressure, stroke, and coronary heart disease, II: short-term reductions in bloed pressure: 
overview of randomised drug triais in their epidemiological context. 
Lancet. 1 990;335:827-838. 

36. Yusuf 5, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G, for the Heart Outcomes Prevention 
Evaluation Study lnvestigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on 
cardiovascular events in high-risk patients. 
N Engí J Med. 2000;342: 145-153. 

37. Clarke R, Shipiey M, Lewington 5, et al. 
Underestimation of risk associations due to regression dilution in Iong-term foliow-up of prospective 
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Am J Epidemiol. 
1999;150:341-353. 


38. Libby P, Simon Dl. 
lnflammation and thrombosis: the ciot th¡ckens. Circulation. 
2001;103:1718-1720. 


39. Jahn J, Dalhoff K, Katus HA. 
Coronary artery disease: an infiammatory or infectious process. Basic Res Cardiol. 2000;95(suppl 1 
):159-164. 

============================================================= 
2.) Cyclo-oxygenase products and atherothrombosis. 
============================================================= 
Ann Med 2000 Dec;32 Suppl 1:21-6 

FitzGerald GA, Austin S, Egan K, Cheng Y, Pratico D. 

Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia 19104, USA. 
[email protected] 

The advent of selective inhibitors of the cyclo-oxygenase (COX)-2 enzyme has afforded the 
opportunity to reduce the incidence of gastrointestinal complications of traditional nonsteroidal 
anti-inflammatory drugs (NSAIDs). The widespread use of these drugs has increased interest in their 
role in the cardiovascular system. Although deletion of the prostacyclin receptor (the IP) accelerates 
atherogenesis in the mouse, retention of one copy of the IP is atheroprotective. This is consistent 
with the failure of biochemically defined, selective doses of a COX-2 inhibitor to accelerate 
atherogenesis in the mouse, despite suppressing prostacyclin biosynthesis by roughly 60%. Inhibition 
of both COX isozymes, by contrast, markedly retards atherogenesis. Consistent with these 
observations, antagonism of the thromboxane receptor (the TP) retards atherogenesis and diminishes 
the proliferative response to vascular injury in the mouse. Even partial suppression of prostacyclin 
(without coincident inhibition of platelet COX-1-dependent thromboxane formation) by COX-2 
inhibitors may be undesirable in acute vascular occlusive syndromes. However, these drugs are 
unlikely to accelerate progression of the underlying vascular disease. By contrast, the effects of TP 
antagonists, aspirin, and even traditional NSAIDs on atherosclerotic plaque progression merit further 
evaluation in humans. 

============================================================= 
3.) Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 
inhibitors. A report of four cases. 
============================================================= 
Arthritis Rheum 2000 Aug;43(8):1891-6 

Comment in: 
Arthritis Rheum. 2001 Apr;44(4):984 

Crofford LJ, Oates JC, McCune WJ, Gupta S, Kaplan MJ, Catella-Lawson F, Morrow JD, 
McDonagh KT, Schmaier AH. 

University of Michigan, Ann Arbor, USA. 

Specific inhibitors of cyclooxygenase 2 (COX-2) have been approved for the treatment of 
osteoarthritis and rheumatoid arthritis. Unlike nonsteroidal anti-inflammatory drugs, specific COX-2 
inhibitors do not inhibit platelet activation. However, these agents significantly reduce systemic 
production of prostacyclin. As a result, theoretical concerns have been raised that specific COX-2 
inhibitors could shift the hemostatic balance toward a prothrombotic state. Patients with connective 
tissue diseases (CTD), who may be predisposed to vasculopathy and thrombosis, often have arthritis 
or pain syndromes requiring treatment with antiinflammatory agents. Herein we describe 4 patients 
with CTD who developed ischemic complications after receiving celecoxib. All patients had a history 
of Raynaud's phenomenon, as well as elevated anticardiolipin antibodies, lupus anticoagulant, or a 
history compatible with antiphospholipid syndrome. It was possible to measure a urinary metabolite 
of thromboxane A2 in 2 of the patients as an indicator of in vivo platelet activation, and this was 
markedly elevated in both. In addition, the patients had evidence of ongoing inflammation as 
indicated by elevated erythrocyte sedimentation rate, hypocomplementemia, and/or elevated levels 
of anti-DNA antibodies. The findings in these 4 patients suggest that COX-2 inhibitor-treated 
patients with diseases that predispose to thrombosis should be monitored carefully for this 
complication. 

============================================================= 
4.) Cyclooxygenase 2 inhibition and thrombosiscomment on the article by Crofford et al. 
============================================================= 
Arthritis Rheum 2001 Apr;44(4):984 

Comment on: 
Arthritis Rheum. 2000 Aug;43(8):1891-6 

McMurray R. 

Publication Types: 
Comment 
Letter 
============================================================= 
============================================================= 
5.) Cyclooxygenase 2 inhibitors and thrombogenicity production: comment on the article by Crofford 
et al. 
============================================================= 
Arthritis Rheum 2001 May;44(5):1229-30 

Sperling R, Braunstein N, Melin J, Reicin A. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
6.) COX-2 inhibition and thrombotic tendency: a need for surveillance. 
============================================================= 
Med J Aust 2001 Aug 20;175(4):214-7 

Cleland LG, James MJ, Stamp LK, Penglis PS. 

Rheumatology Unit, Royal Adelaide Hospital, SA. [email protected] 

Cyclooxygenase-2 (COX-2) inhibitors belong to a new class of drugs which have anti-inflammatory 
efficacy similar to that of traditional non-steroidal anti-inflammatory drugs (NSAIDs), but are 
associated with a reduced incidence of adverse upper gastrointestinal events. Biochemical evidence 
that COX-2 inhibitors could promote or exacerbate a tendency to thrombosis is supported by recent 
results from clinical trials and case reports. Two agents in this class, celecoxib and rofecoxib, have 
been listed on the Pharmaceutical Benefits Scheme (PBS) for very broad indications in chronic 
arthropathies, suggesting that they will move into widespread community use. It is important to 
canvass the possibility that use of these agents could be associated with thrombotic events. 

============================================================= 
7.) Uterine relaxant effects of cyclooxygenase-2 inhibitors in vitro. 
============================================================= 
Obstet Gynecol 2001 Oct;98(4):563-9 

Slattery MM, Friel AM, Healy DG, Morrison JJ. 

Department of Obstetrics and Gynaecology, National University of Ireland Galway, Clinical Science 
Institute, University College Hospital Galway, Galway, Ireland. 

OBJECTIVE: To compare the effects of three cyclooxygenase-2 (COX-2) inhibitors: nimesulide, 
meloxicam, and celecoxib, which exhibit varying COX-2 selectivity, on contractile activity in 
pregnant (before and after labor) and nonpregnant human myometrial tissue in vitro. METHODS: 
Isometric tension recording was performed under physiologic conditions in isolated myometrial strips 
obtained from 33 women undergoing hysterectomy or either elective or emergency cesarean section. 
The effects of cumulative additions of nimesulide, meloxicam, and celecoxib (between 1 nmol/L and 
100 micromol/L) on myometrial contractility were measured, and values for -log(10) EC(50) and 
mean maximal inhibition were compared. RESULTS: Nimesulide, meloxicam, and celecoxib exerted 
significant relaxant effects on contractility in nonpregnant, pregnant nonlabor, and pregnant labor 
myometrial strips. Values for -log(10) EC(50) values (+/- standard error of the mean) were as 
follows: nimesulide (nonpregnant) 5.14 +/- 0.93 (n = 6), (pregnant nonlabor) 4.91 +/- 0.75 (n = 6), 
and (pregnant labor) 5.84 +/- 0.35 (n = 6); meloxicam (nonpregnant) 6.53 +/- 0.57 (n = 6), 
(pregnant nonlabor) 4.80 +/- 0.71 (n = 6), and (pregnant labor) 5.62 +/- 0.21 (n = 6); celecoxib 
(nonpregnant) 6.15 +/- 0.99 (n = 6), (pregnant nonlabor) 7.08 +/- 0.98 (n = 6), and (pregnant 
labor) 7.25 +/- 0.99 (n = 3). Celecoxib exhibited greater potency than nimesulide or meloxicam (P 
< .01). The range of maximal relaxation values achieved in the three tissue types were as follows: 
nimesulide 68-70% (n = 18; P < .01), meloxicam 69-84% (n = 18; P < .01), and celecoxib 
69-77% (n = 15; P < .01). CONCLUSION: COX-2 inhibitors exert significant relaxation in human 
myometrium with a similar potency in nonpregnant and pregnant (before and after labor onset) 
tissues. Celecoxib, a COX-2 specific inhibitor, was more potent than nimesulide or meloxicam, 
COX-2 preferential inhibitors. 

============================================================= 
8.) Inhibition of both COX-1 and COX-2 is required for development of gastric damage in response 
to nonsteroidal antiinflammatory drugs. 
============================================================= 
J Physiol Paris 2001 Jan;95(1-6):21-7 

Tanaka A, Araki H, Komoike Y, Hase S, Takeuchi K. 

Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, 
Misasagi, Yamashina, 607-8414, Kyoto, Japan 

We examined the gastric ulcerogenic property of selective COX-1 and/or COX-2 inhibitors in rats, 
and investigated whether COX-1 inhibition is by itself sufficient for induction of gastric damage. 
Animals fasted for 18 h were given various COX inhibitors p.o., either alone or in combination, and 
they were killed 8 h later. The nonselective COX inhibitors such as indomethacin, naproxen and 
dicrofenac inhibited PG production, increased gastric motility, and provoked severe gastric lesions. 
In contrast, the selective COX-2 inhibitor rofecoxib did not induce any damage in the stomach, with 
no effect on the mucosal PGE(2) contents and gastric motility. Likewise, the selective COX-1 
inhibitor SC-560 also did not cause gastric damage, despite causing a significant decrease in PGE(2) 
contents. The combined administration of SC-560 and rofecoxib, however, provoked gross damage 
in the gastric mucosa, in a dose-dependent manner. SC-560 also caused a marked gastric 
hypermotility, whereas rofecoxib had no effect on basal gastric motor activity. On the other hand, the 
COX-2 mRNA was expressed in the stomach after administration of SC-560, while the normal 
gastric mucosa expressed only COX-1 mRNA but not COX-2 mRNA. These results suggest that 
the gastric ulcerogenic property of conventional NSAIDs is not accounted for solely by COX-1 
inhibition and requires the inhibition of both COX-1 and COX-2. The inhibition of COX-1 
up-regulates the COX-2 expression, and this may counteract the deleterious influences, such as 
gastric hypermotility and the subsequent events, due to a PG deficiency caused by COX-1 
inhibition. 

============================================================= 
9.) COX-2 inhibitors and renal failure: the triple whammy revisited. 
============================================================= 
Med J Aust 2000 Sep;173(5):274 
Erratum in: 
Med J Aust 2000 Nov 6;173(9):504 

Boyd IW, Mathew TH, Thomas MC. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
10.) Renal side-effects of cyclo-oxygenase-type-2 inhibitor use. 
============================================================= 
Lancet 2000 Feb 26;355(9205):753 

Comment on: 
Lancet. 1999 Dec 18-25;354(9196):2106-11 

Stubanus M, Riegger GA, Kammerl MC, Fischereder M, Kramer BK. 

Publication Types: 
Comment 
Letter 
============================================================= 
============================================================= 
11.) Clinical experience with cyclooxygenase-2 inhibitors. 
Inflamm Res 1999 May;48(5):247-54 
============================================================= 
van Ryn J, Pairet M. 

Department of Pulmonary Research, Boehringer Ingelheim Pharma KG, Biberach an der Riss, 
Germany. [email protected] 

Increasing amounts of experimental and clinical data support the role of selective cyclooxygenase 
(COX)-2 inhibition in anti-inflammatory processes and the role of COX-1 inhibition in increasing the 
frequency of side effects. This article reviews the regulation of COX-2 in inflammatory processes 
based on in vitro and in vivo work. In addition, it summarizes the various in vitro assays used to 
classify the new generation of selective and highly selective inhibitors of COX-2, since prior 
categorization of NSAIDs does not satisfactorily encompass the COX-2 concept. Finally, the latest 
published clinical data of new selective and highly selective inhibitors of COX-2 (meloxicam, 
nimesulide, etodolac, celecoxib and MK966) are discussed. 

============================================================= 
12.) [Preferential COX-2 inhibition: its clinical relevance for gastrointestinal non-steroidal 
anti-inflammatory rheumatic drug toxicity.] 
============================================================= 
Z Gastroenterol 1999 Jan;37(1):45-58 

[Article in German] 

Dammann HG. 

Klinische Forschung Hamburg, Wissenschaftliches Institut, Hamburg. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and 
pain. These drugs tend to cause significant side effects, however, including gastric and intestinal 
toxicity. The mechanism of action of NSAIDs is through their inhibition of the key enzyme of 
prostaglandin biosynthesis, the cyclooxygenase. Recently, two forms of cyclooxygenase have been 
found to exist: COX-1 and COX-2, the constitutive and inducible forms, respectively. COX-1 exists 
in the stomach, intestine, kidneys and platelets, while COX-2, the inducible form, is expressed during 
inflammation. The therapeutic effects of NSAIDs are largely the result of inhibition of the enzyme 
cyclooxygenase-2 (COX-2), whereas the toxic effects (e.g., gastrointestinal, renal and platelet 
effects) are primarily due to the inhibition of COX-1. Individual NSAIDs show different potencies 
against COX-1 compared with COX-2 and this explains the variations in the side effects of 
NSAIDs at their anti-inflammatory doses. Drugs with high potency against COX-2 and a better 
COX-2-/COX-1 activity ratio will have anti-inflammatory activity with fewer gastrointestinal side 
effects. In contrast piroxicam and indomethacin, which drugs have a much higher potency against 
COX-1 than against COX-2, are amongst those with the highest gastrointestinal toxicity. Based on 
these findings, COX-2 seems to be an ideal target for the development of new anti-inflammatory 
drugs. Several compounds with preferential or specific COX-2 inhibiting properties have been 
synthesized and evaluated in pre-clinical and clinical studies i.e. Meloxicam, Celecoxib, MK-966, 
Flusolid and L-745, 337. The COX-2 selectivity of these novel NSAIDs relate well to their 
favorable gastrointestinal tolerability profile. Clinical trials have shown meloxicam and celecoxib to 
be as effective as currently available NSAIDs, but with an improved gastrointestinal tolerability 
profile. Further clinical trials and large-scale postmarketing surveillance programs are needed, 
however, to confirm the potential therapeutic benefits of these novel preferential or specific COX-2 
inhibitors. 

============================================================= 
13.) Mechanism of action of aspirin-like drugs. 
============================================================= 
Semin Arthritis Rheum 1997 Jun;26(6 Suppl 1):2-10 

Vane JR, Botting RM. 

William Harvey Research Institute, St Bartholomew's, London, UK. 

Nonsteroid antiinflammatory drugs (NSAIDs) or aspirin-like drugs act by inhibiting the activity of the 
cyclooxygenase (COX) enzyme. Two isoforms of COX exist, COX-1, which is constitutively 
expressed, and COX-2, which is an inducible isoform. Prostaglandins synthesized by the 
constitutively expressed COX-1 are implicated in the maintenance of normal physiological function 
and have a 'cytoprotective' action in the stomach. COX-2 expression is normally low but is induced 
by inflammatory stimuli and cytokines. It is thought that the antiinflammatory actions of NSAIDs are 
caused by the inhibition of COX-2, whereas the unwanted side effects, such as gastrointestinal and 
renal toxicity, are caused by the inhibition of the constitutively expressed COX-1. Individual 
NSAIDs show different selectivities against the COX-1 and COX-2 isoforms. NSAIDs that are 
selective towards COX-2, such as meloxicam, may have an improved side-effect profile over 
current NSAIDs. In addition to their use as antiinflammatory agents in the treatment of rheumatoid 
arthritis and osteoarthritis, selective COX-2 inhibitors may also be beneficial in inhibiting colorectal 
tumor cell growth and in delaying premature labor. 

============================================================= 
============================================================= 
CELECOXIB (CELEBREX) SEARLE-PFIZER 
============================================================= 
============================================================= 
1.) Cholestatic hepatitis in association with celecoxib 
============================================================= 
BMJ 2001;323:23 ( 7 July ) 
Drug points 

J P O'Beirne, S R Cairns. 

Digestive Disease Centre, Royal Sussex County Hospital, Brighton BN2 5BE 

Non-steroidal anti-inflammatory drugs, particularly diclofenac sodium, have been associated with 
serious hepatotoxicity.1 Recently, cyclo-oxygenase-2 selective non-steroidal anti-inflammatory drug 
inhibitors have become popular for the treatment of arthritic conditions, mainly because of their safer 
profile for gastrointestinal side effects.2 Celecoxib (Celebrex; Searle) is one such drug, licensed for 
the treatment of rheumatoid arthritis and osteoarthritis. We report a case of serious hepatotoxicity 
associated with celecoxib. 

A 54 year old woman developed sacroiliac pain. She consulted her general practitioner, who 
prescribed celecoxib 200 mg daily. After four days her pain resolved and she developed generalised 
pruritus. When celecoxib was discontinued the pruritus resolved. 

A week later the pain returned and celecoxib was restarted. Two days later the patient developed 
dark urine and increasing pruritus. Five days later she developed jaundice, and blood tests showed 
an aspartate transaminase concentration of 1650 IU/l (reference range 10-40 IU/l), alkaline 
phosphatase 232 IU/l (25-115 IU/l), and bilirubin 123 µmol/l (5-20 µmol/l). She was also taking 
isphagula husk (Fybogel; Reckitt and Colman) and alverine citrate (Spasmonal; Norgine), which she 
had taken for many months, and hormone replacement therapy (six monthly implants of oestradiol 
with 100 mg of testosterone), which she had received for four years. She was referred to us for 
further management. 

She had no risk factors for viral hepatitis, and examination was normal apart from noticeable icterus. 
All drugs were withdrawn and relevant blood tests were performed. We excluded viral and 
autoimmune hepatitis by blood tests. Her eosinophil count was raised at 0.8×106/l. A hepatic 
ultrasonogram appeared normal. 

On withdrawal of celecoxib her liver function tests improved (figure) and her symptoms resolved. 
The temporal relation between ingestion of the drug and hepatotoxicity strongly suggested an 
association between celecoxib and liver damage. A yellow card was submitted to the Committee on 
Safety of Medicines. 

In a review of controlled clinical trials involving 7400 patients, hepatic dysfunction occurred in 0.8% 
of those treated with celecoxib compared with 0.9% treated with placebo and 3.7% treated with 
diclofenac sodium. No patient treated with celecoxib, however, had increases of alkaline 
phosphatase concentrations greater than eight times normal.3 

Nimesulide, another non-steroidal anti-inflammatory drug with cyclo-oxygenase-2 selectivity, has 
been reported to cause fulminant hepatic failure,4 and celecoxib has been associated with hepatitis 
and pancreatitis.5 To our knowledge severe cholestatic hepatitis has not been reported in association 
with celecoxib. 

Physicians should be aware that, despite a better safety profile for gastrointestinal side effects than 
conventional non-steroidal anti-inflammatory drugs, celecoxib may still be associated with severe 
hepatotoxicity. Celecoxib should be stopped if the results of liver function tests are abnormal. 


References 
1. Iveson TJ, Ryley NG, Kelly PM, Trowell JM, McGee JO, Chapman RW. Diclofenac associated 
hepatitis. J Hepatol 1990; 10: 85-89[Medline]. 
2. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal 
toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid 
arthritis: the CLASS study: a randomized controlled trial. Celecoxib long-term arthritis safety study. 
JAMA 2000; 284: 1247-1255[Medline]. 
3. Maddrey WC, Maurath CJ, Verburg KM, Geis GS. The hepatic safety of and tolerability of the 
novel cyclooxygenase-2 inhibitor celecoxib. Am J Ther 2000; 7: 153-158[Medline]. 
4. McCormick PA, Kennedy F, Curry M, Traynor O. COX-2 inhibitor and fulminant hepatic 
failure. Lancet 1999; 352: 353. 
5. Carrillo-Jimenez R, Nurnberger M. Celecoxib-induced acute pancreatitis and hepatitis. Arch 
Intern Med 2000; 170: 553-554[Medline]. 

============================================================= 
2.) Acute pancreatitis associated with celecoxib. 
============================================================= 
Ann Intern Med 2000 Apr 18;132(8):680 

Baciewicz AM, Sokos DR, King TJ. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
3.) Visual disturbance associated with celecoxib. 
============================================================= 
Pharmacotherapy 2001 Jan;21(1):114-5 

Lund BC, Neiman RF. 

Clinical and Administrative Division, College of Pharmacy Iowa City, IA 52242-1112, USA. 
[email protected] 

Celecoxib, a specific inhibitor of cyclooxygenase-2, is used to treat the symptoms of arthritis. A 
79-year-old woman developed an atypical visual disturbance associated with this agent that resolved 
on discontinuation of celecoxib. Similar visual disturbances described with the traditional nonsteroidal 
antiinflammatory drugs are discussed. 

============================================================= 
4.) Acute onset of auditory hallucinations after initiation of celecoxib therapy. 
============================================================= 
Am J Psychiatry 2000 Jun;157(6):1022-3 

Lantz MS, Giambanco V. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
5.) Effect of cyclooxygenase-2 inhibitor (celecoxib) on the infarcted heart in situ. 
============================================================= 
Pharmacology 2001 Jul;63(1):28-33 

Yamamoto T, Kakar NR, Vina ER, Johnson PE, Bing RJ. 

Huntington Medical Research Institutes, Department of Experimental Cardiology, Pasadena, Calif 
91101, USA. 

Several attempts have been made to replace aspirin with compounds without gastric toxicity; a 
cyclooxygenase-2 (COX-2) inhibitor, celecoxib, and a nitric oxide-aspirin, NCX-4016, have been 
developed for this purpose. This paper compares effects of celecoxib, NCX-4016 and aspirin on 
production of prostacyclin (PGI2) and thromboxane A2 (TXA2) and activation of the inducible form 
of nitric oxide synthase (iNOS) in infarcted heart in situ. Aspirin was most effective in reducing 
myocardial PGI2 synthesis and formation of TXA2. Myocardial effects of celecoxib resemble those 
of NCX-4016, although the two compounds have different modes of action. 

============================================================= 
6.) Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on 
COX-2 versus COX-1 in healthy volunteers. 
============================================================= 
J Clin Pharmacol 2000 Oct;40(10):1109-20 

Van Hecken A, Schwartz JI, Depre M, De Lepeleire I, Dallob A, Tanaka W, Wynants K, Buntinx 
A, Arnout J, Wong PH, Ebel DL, Gertz BJ, De Schepper PJ. 

Center for Clinical Pharmacology, UZ Gasthuisberg, Leuven, Belgium. 

Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with 
that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers 
randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 
800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the 
high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine 
the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. 
Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of 
lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 
66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 
mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean 
inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 
6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion 
of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib 
is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1. 

============================================================= 
7.) Selective cyclo-oxygenase-2 inhibition with celecoxib elevates blood pressure and promotes 
leukocyte adherence. 
============================================================= 
Br J Pharmacol 2000 Apr;129(7):1423-30 

Muscara MN, Vergnolle N, Lovren F, Triggle CR, Elliott SN, Asfaha S, Wallace JL. 

Department of Pharmacology & Therapeutics, University of Calgary, 3330 Hospital Drive NW, 
Calgary, Alberta, T2N 4N1, Canada. 

1. Selective inhibitors of cyclo-oxygenase-2 have been shown to be effective anti-inflammatory 
drugs with reduced gastrointestinal toxicity relative to conventional nonsteroidal anti-inflammatory 
drugs (NSAIDs). In the present study, we examined the possibility that selective COX-2 inhibition, 
by blocking prostacyclin synthesis, would increase blood pressure and cause leukocyte adherence 
and platelet aggregation. 2. Normal rats and rats with hypertension induced by chronic administration 
of Nomega-nitro-L-arginine methylester were given celecoxib (10 mg kg(-1)) daily for 3 weeks. 
Celecoxib significantly elevated of blood pressure in both the normal and hypertensive rats (mean 
increase of >33 mm Hg after 3 weeks). 3. In normal rats, celecoxib had no effect on serum 6-keto 
prostaglandin (PG)F(1alpha) levels. Hypertensive rats exhibited a significant increase (82%) in serum 
6-keto PGF(1alpha) levels, and this was reduced to the levels of normal rats by treatment with 
celecoxib. 4. Rats treated with celecoxib exhibited significant increases in weight gain (20%), plasma 
arginine-vasopressin levels (148%) and plasma urea (69%) relative to vehicle-treated controls. 
Plasma creatinine levels were unaffected by treatment with celecoxib, while plasma renin levels were 
significantly decreased (30%) relative to controls. 5. Superfusion of mesenteric venules with 
celecoxib (3 microM) in vivo resulted in significant increases in leukocyte adherence to the 
endothelium in both normal and hypertensive rats. 6. These studies suggest that suppression of 
COX-2 significantly influences vascular and/or renal function, leading to elevated blood pressure and 
leukocyte adherence. 

============================================================= 
8.) Celecoxib-induced acute pancreatitis and hepatitis: a case report. 
============================================================= 
Arch Intern Med 2000 Feb 28;160(4):553-4 

Carrillo-Jimenez R, Nurnberger M. 

Publication Types: 
Letter 
============================================================= 
9.) Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine 
coronary arteries. 
============================================================= 
Circulation 2001 Aug 14;104(7):820-5 

Hennan JK, Huang J, Barrett TD, Driscoll EM, Willens DE, Park AM, Crofford LJ, Lucchesi BR. 

University of Michigan Medical School, Department of Pharmacology, Ann Arbor 48109-0632, 
USA. 

BACKGROUND: Prostanoid synthesis via the action of cyclooxygenase-2 (COX-2) is a 
component of the inflammatory response. Prostacyclin, a product of COX-2 in vascular 
endothelium, has important physiological roles, such as increasing blood flow to injured tissues, 
reducing leukocyte adherence, and inhibiting platelet aggregation. We examined the possibility that 
selective COX-2 inhibition could suppress the protective effects of prostacyclin, resulting in an 
alteration of the hemostatic balance and vascular tone. METHODS AND RESULTS: Circumflex 
coronary artery thrombosis was induced in dogs by vascular electrolytic injury. Orally administered 
celecoxib (COX-2 inhibition) or high-dose aspirin (HDA) (COX-1 and COX-2 inhibition) did not 
alter time to occlusive thrombus formation compared with controls (celecoxib 77.7+/-7.2 minutes, 
HDA 72.0+/-18.5 minutes, control 93.0+/-21.8 minutes). Oral HDA with an endothelial recovery 
period (HDA-ER) (COX-1 inhibition) produced a significant increase in time to vessel occlusion 
(257.0+/-41.6 minutes). The observed increase in time to occlusion was abolished when celecoxib 
was administered to animals dosed with HDA-ER (80.7+/-20.6 minutes). The vasomotor effect of 
endothelium-derived prostacyclin was examined by monitoring coronary flow during intracoronary 
administration of arachidonic acid or acetylcholine. In celecoxib-treated animals, vasodilation in 
response to arachidonic acid was reduced significantly compared with controls. CONCLUSIONS: 
The results indicate important physiological roles for COX-2-derived prostacyclin and raise 
concerns regarding an increased risk of acute vascular events in patients receiving COX-2 inhibitors. 
The risk may be increased in individuals with underlying inflammatory disorders, including coronary 
artery disease. 

============================================================= 
10.) Nonsteroidal Anti-Inflammatory Drugs and Hypertension. 
============================================================= 
J Clin Hypertens (Greenwich) 2000 Oct;2(5):319-323 

Brook RD, Kramer MB, Blaxall BC, Bisognano JD. 

Department of Internal Medicine, Division of Hypertension, University of Michigan Health Center, 
Ann Arbor, MI. 

Nonsteroidal anti-inflammatory drugs are among the most widely prescribed medications. Their 
effect on blood pressure has been monitored, and many small studies have determined a potential 
relationship between their use and elevation of blood pressure. These drugs may affect blood 
pressure by inhibiting prostaglandin synthesis, which may affect arteriolar smooth muscle tone and 
natriuresis. Since many patients with conditions such as osteoarthritis require treatment and also have 
hypertension, even modest elevations in blood pressure or inhibition of antihypertensive medication 
efficacy resulting from non steroidal anti-inflammatory drugs can be of significant clinical and public 
health importance. This review finds that certain drugs (e.g., indomethicin, piroxicam, and naproxen) 
may cause clinically relevant elevations in blood pressure in hypertensive patients. Aspirin and 
sulindac do not appear to elevate blood pressure significantly, even in hypertensive patients. 
Ibuprofen and other nonsteroidal anti-inflammatory drugs appear to have an intermediate blood 
pressure effect. Cyclo-oxygenase-2 inhibitors such as refecoxib and celecoxib have been shown to 
cause mild elevations in blood pressure, but further studies are needed to evaluate the full magnitude 
and population distribution of this effect. (c)2000 by Le Jacq Communications, Inc. 

============================================================= 
11.) Possible celecoxib-induced gastroduodenal ulceration. 
============================================================= 
Ann Pharmacother 2001 Jun;35(6):782-3 

Bates DE, Lemaire JB. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
12.) Inhibition of cyclooxygenase-1 or -2 on insulin sensitivity in healthy subjects. 
============================================================= 
Horm Metab Res 2001 Apr;33(4):250-3 

Gonzalez-Ortiz M, Martinez-Abundis E, Balcazar-Munoz BR, Robles-Cervantes JA. 

Medical Research Unit in Clinical Epidemiology, West National Medical Center, Mexican Institute 
of Social Security, Guadalajara City. [email protected] 

The aim of this study was to identify the effects of cyclooxygenase (COX)-1 and -2 inhibition each 
on insulin sensitivity in healthy subjects. A randomized, double-blind, controlled clinical trial was 
carried out in 21 young, healthy, non-obese male volunteers. Pharmacological COX-1 inhibition was 
performed with the prescription of acetylsalicylic acid (ASA) at a low dose, and COX-2 selective 
inhibition was performed with celecoxib. After randomization, all subjects received an oral morning 
dose of ASA 100 mg (n = 7), celecoxib 200 mg (n = 7), or placebo for the control group (n = 7) 
during a period of 15 days. Before and after of the study period, a metabolic profile was measured 
in all participants. An insulin tolerance test (ITT) was performed to assess insulin sensitivity, and the 
constant for the serum glucose disappearance rate (K ITT) was calculated. Clinical and metabolic 
characteristics were similar between groups. The K ITT calculated with the ITT was higher after 
celecoxib than at baseline (4.8 +/- 0.9 vs. 4.3 +/- 0.6%/min, p = 0.04), indicating improvement in 
insulin sensitivity. Neither ASA nor placebo administrations modified insulin sensitivity. In conclusion, 
COX-2-selective inhibitor at a celecoxib dose of 200 mg daily increased insulin sensitivity in healthy 
subjects. 

============================================================= 
13.) Cyclooxygenase-2 inhibitor celecoxib: a possible cause of gastropathy and 
hypoprothrombinemia. 
============================================================= 
South Med J 2000 Sep;93(9):930-2 

Linder JD, Monkemuller KE, Davis JV, Wilcox CM. 

Department of Medicine, University of Alabama at Birmingham, 35294, USA. 

Gastrointestinal side effects from nonsteroidal anti-inflammatory drugs (NSAIDs) result mainly from 
inhibition of the enzyme cyclooxygenase (COX)-1; it is responsible for the synthesis of prostaglandin 
E2, which leads to increased mucosal blood flow, increased bicarbonate secretion, and mucus 
production, thus protecting the gastrointestinal mucosa. In inflammation, COX-2 is induced, causing 
synthesis of the prostaglandins in conditions such as osteoarthritis and rheumatoid arthritis. Two 
NSAIDs (celecoxib and rofecoxib) with very high specificity for COX-2 and virtually no activity 
against COX-1 at therapeutic doses have been approved for clinical use. In trials of celecoxib and 
rofecoxib, only 0.02% of patients had clinically significant gastrointestinal bleeding, compared to a 
1% to 2% yearly incidence of severe gastrointestinal side effects with NSAIDs. Our patient had 
arthritis of the hips and chronic atrial fibrillation and was on warfarin therapy for stroke prevention; 
less than a week after starting celecoxib therapy, gastrointestinal bleeding and hypoprothrombinemia 
occurred. 

============================================================= 
NIMESULIDE (SHERING-PLOUGH) 
============================================================= 
1.) Nimesulide 
2.)COX 2 inhibitor and fulminant hepatic failure. 
3.) CASE REPORT Fatal hepatitis and renal failure during treatment with nimesulide 
4.) Nimesulide and renal impairment. 
5.) Aspirin and paracetamol tolerance in patients with nimesulide-induced urticaria. 
6.) Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID-induced skin 
disorders. 
7.) Neonatal chronic kidney failure associated to cyclo-oxygenase inhibitors administered during 
pregnancy. 
8.) Nimesulide aggravates kainic acid-induced seizures in the rat. 
9.) Nimesulide-induced hepatitis and acute liver failure. 
10.) Nimeulide and neonatal renal failure. 
11.) Fatal hepatitis associated with nimesulide. 
12.) Neonatal end-stage renal failure associated with maternal ingestion of cyclo-oxygenase-type-1 
selective inhibitor nimesulide as tocolytic. 
13.) [Nimesulide acute hepatitis: description of 3 cases]. 
14.) Analgesics for pediatric use. 
15.) Nimesulide, clavulanic acid and hepatitis. 
16.) Nimesulide-induced hepatitis and acute liver failure. 
17.) [Toxic hepatitis caused by nimesulide, presentation of a new case and review of the literature]. 
18.) [Bleeding gastric ulcers and acute hepatitis: 2 simultaneous adverse reactions due to nimesulide 
in a case]. 
19.) Nimesulide-induced acute hepatitis: evidence from six cases. 
20.) Nimesulide-induced purpura. 
21.) Modification of antihistaminic activity of cetirizine by nimesulide. 
22.) Perinatal vasoconstrictive renal insufficiency associated with maternal nimesulide use. 
23.) Acute renal failure induced by nimesulide in a patient suffering from temporal arteritis. 
24.) Drug-induced cholestasis. 
25.) Adverse drug reactions postal survey-bronchial asthma and angioedema with nimesulide. 
26.) Hypothermia with nimesulide. 
27.) [Nimesulide-induced acute hepatitis]. 
28.) [Nimesulide toxic hepatitis in pregnancy]. 
29.) Positive lesional patch tests in fixed drug eruptions from nimesulide. 
30.) Nimesulide-induced acute hepatitis. 
31.) [Severe acute hepatitis probably induced by nimesulide]. 
32.) Bullous and erosive stomatitis induced by nimesulide. 
33.) The uncoupling effect of the nonsteroidal anti-inflammatory drug nimesulide in liver mitochondria 
from adjuvant-induced arthritic rats. 
34.) Can a cyclo-oxygenase type-2 selective tocolytic agent avoid the fetal side effects of 
indomethacin? 
35.) NIMESULIDE ADVERSE EFFECTS. 
============================================================= 
============================================================= 
1.) Nimesulide 
============================================================= 
SOURCE: THE WHO. /Organizacion Mundial de la SALUD 
WHO PHARMACEUTICALS NEWSLETTER 

Nimesulide 

A total of 17 of the reports on adverse effects on the liver were linked with the use of nimesulide. 
Eight of these cases involved hepatitis and 9 increased hepatic enzyme levels. The majority of 
patients (14) were women. The average age was 61 years (ranging between 23 and 88 years), and 
9 of the patients were over 60 years of age. The symptoms or findings of liver effects usually 
appeared after 1-6 weeks of treatment. In 11 patients the laboratory values had returned to normal 
at the follow-up after nimesulide was stopped. Six patients had still not recovered 2-8 weeks after 
withdrawal of medication, when the report on the adverse effect was made. Five patients were using 
concomitant drugs which have been reported to have hepatic reactions. According to published case 
reports, nimesulide can cause both hepatocellular necrosis and pure cholestasis. Individual cases of 
fatal liver damage have also been reported. 

Nimesulide is a relatively new drug, introduced on the Finnish market in January 1998. However, it 
is widely used and the number of daily doses (0.2 g) by September 2000 totalled over 14 million. 
One reason for the popularity of nimesulide is probably its selectivity – which, as a COX-2 inhibitor, 
is claimed to be higher than that of older anti-inflammatory analgesics – and the fewer cases of 
gastrointestinal tract ulcers it causes. 

Due to its adverse effects on the liver, the product information on nimesulide was updated at the 
beginning of 2000. Hepatic insufficiency was added to the contraindications and additional text was 
included in the section on warnings according to which patients with abnormal values in their liver 
function tests and/or patients with symptoms indicative of liver damage (anorexia, nausea, vomiting, 
jaundice) during nimesulide therapy must be closely monitored and medication stopped. These 
patients should not be re-exposed to nimesulide. Increased hepatic enzyme values were included in 
the section on rare adverse effects in the SPC, and cholestasis and rapidly developing hepatitis were 
included in the list of very rare adverse effects. 

============================================================= 
2.)COX 2 inhibitor and fulminant hepatic failure. 
============================================================= 
McCormick PA, Kennedy F, Curry M, Traynor O. 
Lancet. 1999 Jan 2;353(9146):40-1. 

This article reports on the case of a patient who developed fulminant hepatic failure from treatment 
with the selective COX2 inhibitor Nimesulide. 
============================================================= 

============================================================= 
3.) CASE REPORT 
Fatal hepatitis and renal failure during treatment with nimesulide 
============================================================= 
A. Schattner1, 3, N. Sokolovskaya2 & J. Cohen2, 3 

Schattner A, Sokolovskaya N, Cohen J (Kaplan Medical Center, Rehovot, and the Hebrew 
University-Hadassah School of Medicine, Jerusalem, Israel). Fatal hepatitis and renal failure during 
treatment with nimesulide (Case Report). J Intern Med 2000; 247: 153–155. 

A healthy 70-year-old woman who took nimesulide for 5 days, presented 2 weeks later with 
jaundice for which no other cause was found. Laboratory evidence of coagulopathy, 
hypoalbuminaemia and hypoglycaemia were present on admission, and liver biopsy showed massive 
necrosis of hepatocytes and severe inflammatory infiltrate. Despite supportive and corticosteroid 
treatment, her jaundice deepened and progressive acute renal failure developed, characterized by a 
‘prerenal’ profile changing into irreversible acute tubular necrosis pattern, coma, occult 
Gram-negative sepsis and death. Although rare, nimesulide-associated hepatotoxicity and 
nephrotoxicity may occur and should be recognized as early as possible, to ensure immediate drug 
withdrawal and treatment. 

============================================================= 
4.) Nimesulide and renal impairment. 
============================================================= 
Eur J Clin Pharmacol 1999 Apr;55(2):151-4 Related Articles, Books, LinkOut 

Leone R, Conforti A, Ghiotto E, Moretti U, Valvo E, Velo GP. 

Clinical Pharmacology Unit, Institute of Pharmacology, Policlinico B.go Roma, University of Verona, 
Italy. [email protected] 

OBJECTIVES: To analyse from spontaneous reporting data the renal adverse reactions associated 
with the use of nimesulide. METHODS: Case reports were obtained from a Northern Italian 
Regional database (Veneto Pharmacovigilance System), containing all the spontaneous reports filed 
between 1988 and 1997. The Veneto Region is the principal contributor to the Italian spontaneous 
reporting system, with an annual report rate of approximately 17 per 100,000 inhabitants. The 
clinical records of hospitalized patients were also analysed. RESULTS: Of the 120 reports 
associated with oral nimesulide, 11 referred to suspected renal adverse reactions. The drug was 
taken by ten patients for a short period. All the patients discontinued the therapy and hospitalization 
was required in six cases. Other risk factors were identified in six cases. DISCUSSION: Together 
with the new insights into the possible consequences of renal cyclooxygenase-2 (COX-2) inhibition, 
the reported cases should draw the attention of doctors and patients to the importance of recognizing 
any possible signs of renal impairment during nimesulide therapy, although only extensive 
epidemiological data can define the real impact of its renal toxicity. 

============================================================= 
5.) Aspirin and paracetamol tolerance in patients with nimesulide-induced urticaria. 
============================================================= 
Ann Allergy Asthma Immunol 1998 Sep;81(3):237-8 Related Articles, Books, LinkOut 

Asero R. 

Ambulatorio di Allergologia, Ospedale Caduti Bollatesi, Bollate (MI), Italy. 

BACKGROUND: The administration of aspirin and other nonsteroidal anti-inflammatory drugs in 
patients sensitive to nimesulide might be hazardous. OBJECTIVE: To assess the tolerance to both 
acetaminophen (paracetamol) and aspirin in patients with a history of urticaria induced by nimesulide. 
METHODS: Nine patients with a history of nimesulide intolerance were submitted to single-blind, 
placebo-controlled peroral challenges with increasing doses of acetaminophen and aspirin. 
RESULTS: Acetaminophen was tolerated by all patients, whereas two experienced immediate 
systemic urticaria after the administration of 125 mg of aspirin. CONCLUSION: Acetaminophen 
and aspirin are well tolerated by most nimesulide-sensitive patients. Since a minority of patients show 
aspirin sensitivity, tolerance of this agent should always be ascertained by properly performed 
peroral challenges. 

============================================================= 
6.) Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID-induced skin 
disorders. 
============================================================= 
Ann Allergy Asthma Immunol 1999 Jun;82(6):554-8 Related Articles, Books, LinkOut 

Asero R. 

Allergy Clinic, Caduti Bollatesi Hospital, Bollate, Italy. 

BACKGROUND: Previous studies show skin reactions after exposure to acetaminophen and/or 
nimesulide to occur in about 10% of patients with a history of urticaria induced by aspirin or other 
nonsteroidal anti-inflammatory drugs (NSAIDs). This fact is surprising since cross-reactivity among 
different NSAIDs should not occur among subjects without a history of chronic urticaria. 
OBJECTIVE: To detect risk factors for intolerance to alternative drugs such as acetaminophen and 
nimesulide in different groups of patients with a history of adverse skin reactions 
(urticaria/angioedema, or anaphylaxis) after the ingestion of aspirin and other NSAIDs. METHODS: 
Two hundred fifty-six patients with a history of recent pseudoallergic skin reactions caused by 
NSAIDs underwent elective oral challenges with increasing doses of both acetaminophen and 
nimesulide. Patients were divided into three groups: A = 69 subjects with chronic urticaria, B = 163 
otherwise normal subjects with a history of urticaria after the ingestion of aspirin, and C = 24 
otherwise normal subjects with a history of urticaria after the ingestion of pyrazolones but 
aspirin-tolerant. RESULTS: Forty-eight (19%) patients reacted to acetaminophen and/or nimesulide. 
Similar numbers of patients with chronic urticaria (23%) and of normal subjects with a history of 
aspirin-induced urticaria (19%) did not tolerate one of the alternative drugs challenged. 
Pyrazolones-intolerant patients showed the lowest number of reactors (4%). Aspirin intolerance 
represented a risk factor for acetaminophen- and/or nimesulide-induced urticaria (RR = 5.4). A 
history of anaphylactoid reactions induced by NSAID represented a risk factor for urticaria after the 
ingestion of the alternative study drugs (RR = 5.7). Atopic status was associated with a higher risk of 
reactivity to nimesulide: this drug induced urticaria in 11/47 (23%) atopics versus 18/209 (9%) 
non-atopics (P < .005; RR = 3.2). A history of intolerance to antibacterial drugs was not associated 
with a higher prevalence of reactivity against acetaminophen and/or nimesulide. CONCLUSIONS: 
In at least 20% of patients with a history of urticaria/angioedema or anaphylaxis induced by aspirin 
or other NSAIDs, but without a history of chronic urticaria, cross-reactivity with other NSAIDs 
occurs. Atopy as well as a history of aspirin-induced anapylactoid reactions seem to represent 
relevant risk factors for intolerance to alternative NSAIDs. In view of these findings, 
aspirin-intolerant patients with such clinical features should be submitted to peroral tolerance tests 
with at least two alternative substances in order to avoid potentially severe reactions. 

============================================================= 
7.) Neonatal chronic kidney failure associated to cyclo-oxygenase inhibitors administered during 
pregnancy. 
============================================================= 
Minerva Urol Nefrol 2001 Jun;53(2):113-6 

Peruzzi L, Gianoglio B, Porcellini G, Conti G, Amore A, Coppo R. 

Nefrologia e Dialisi, Ospedale Infantile Regina Margherita, Turin, Italy. 

Non-steroidal anti-inflammatory drugs (NSAID) are used since years as tocolytic due to their 
capacity to inhibit cyclo-oxygenase (COX) expressed in uterus and fetal membranes, fundamental 
for labour initiation and maintenance. The use of nimesulide, a COX-2 selective NSAID, has been 
recently proposed due to its capacity to selectively inhibit the enzyme expressed in the myometrium 
and endometrium. A case of neonatal irreversible end stage renal failure after maternal assumption of 
nimesulide as tocolytic for 6 week is reported. Cesarean section at the 32nd week due to 
oligohydramnios gave birth to a baby girl of 2090 g, in good general conditions, without signs of 
respiratory distress and of visible abnormalities. From birth she displayed oligo-anuria which 
required dialytic substitutive therapy from the second day of life. At US scan both kidneys had 
normal diameters for gestational age slightly increased echogenicity and a reduced cortico-medullary 
differentiation. On the 20th day of life she had a surgical renal biopsy for the persistence of 
oligo-anuria, showing fetal glomeruli, without lymphocytic interstitial infiltrate, and normal tubuli 
without evidence of necrosis. She is now 16 months old and under automated peritoneal dialysis on 
a home dialysis program. The occurrence of chronic renal failure in strict relationship with maternal 
nimesulide assumption in this case is strongly suggestive for a pharmacological damage, either direct 
or mediated by renin angiotensin inhibition, and possibly modulated by genetic factors, likely to 
account for the different outcome of similarly treated patients. A cautious use of this drug as long 
term tocolytic should be recommended while waiting for ad hoc experimental and clinical evidences 
of safeness. 

============================================================= 
8.) Nimesulide aggravates kainic acid-induced seizures in the rat. 
============================================================= 
Pharmacol Toxicol 2001 May;88(5):271-6 
Kunz T, Oliw EH. 

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala Biomedical Centre, 
Sweden. [email protected] 

Treatment of rats with kainic acid (10 mg/kg, intraperitoneally) triggers limbic seizures. 
Cyclooxygenase-2 mRNA is expressed in the hippocampus and cortex after 8 hr and marked cell 
loss occurs after 72 hr in the CA1-CA3 areas of the hippocampus. We examined the effect of the 
cyclooxygenase-2 inhibitor, nimesulide (N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide), on 
kainate-induced seizures and delayed neurotoxicity. Nimesulide (10 mg/kg, intraperitoneally) was 
well tolerated given alone or 6-8 hr after kainate. However, pretreatment with nimesulide augmented 
seizures and increased the mortality rate from approximately 10% to 69%. We examined the effect 
of nimesulide on delayed cell loss after 72 hr in the surviving animals with histological staining. Cell 
loss did not seem to be reduced in animals treated with nimesulide 6-8 hr after kainate, but in the 
surviving animals pretreated with nimesulide less cell loss occurred. We conclude that nimesulide 
should be used with caution as an antiinflammatory drug in patients with convulsive disorders. 

============================================================= 
9.) Nimesulide-induced hepatitis and acute liver failure. 
============================================================= 
Isr Med Assoc J 1999 Oct;1(2):89-91 

Comment in: 
Isr Med Assoc J. 1999 Nov;1(3):221 
Isr Med Assoc J. 1999 Oct;1(2):98-9 

Weiss P, Mouallem M, Bruck R, Hassin D, Tanay A, Brickman CM, Farfel Z, Bar-Meir S. 

Department of Gastroenterology, Sheba Medical Center, Tel-Hashomer, Israel. 

BACKGROUND: Nimesulide is a relatively new non-steroidal anti-inflammatory drug that is gaining 
popularity in many countries because it is a selective cyclooxygenase 2 inhibitor. Occasionally, 
treatment is associated with mild elevation of liver enzymes, which return to normal upon 
discontinuation of the drug. Several cases of nimesulide-induced symptomatic hepatitis were also 
recently reported, but these patients all recovered. OBJECTIVES: To report the characteristics of 
liver injury induced by nimesulide. PATIENTS AND METHODS: We report retrospectively six 
patients, five of them females with a median age of 59 years, whose aminotransferase levels rose 
after they took nimesulide for joint pains. In all patients nimesulide was discontinued, laboratory tests 
for viral and autoimmune causes of hepatitis were performed, and sufficient follow-up was available. 
RESULTS: One patient remained asymptomatic. Four patients presented with symptoms, including 
fatigue, nausea and vomiting, which had developed several weeks after they began taking nimesulide 
(median 10 weeks, range 2-13). Hepatocellular injury was observed with median peak serum 
alanine aminotransferase 15 times the upper limit of normal (range 4-35), reversing to normal 2-4 
months after discontinuation of the drug. The remaining patient developed symptoms, but continued 
taking the drug for another 2 weeks. She subsequently developed acute hepatic failure with 
encephalopathy and hepatorenal syndrome and died 6 weeks after hospitalization. In none of the 
cases did serological tests for hepatitis A, B and C, Epstein-Barr virus and cytomegalovirus, as well 
as autoimmune hepatitis reveal findings. CONCLUSIONS: Nimesulide may cause liver damage. The 
clinical presentation may vary from abnormal liver enzyme levels with no symptoms, to fatal hepatic 
failure. Therefore, monitoring liver enzymes after initiating therapy with nimesulide seems prudent. 

============================================================= 
10.) Nimeulide and neonatal renal failure. 
============================================================= 
Lancet 2000 Feb 12;355(9203):575 

Comment on: 
Lancet. 1999 Nov 6;354(9190):1615 


Balasubramaniam J. 

Publication Types: 
Comment 
Letter 
============================================================= 
============================================================= 
11.) Fatal hepatitis associated with nimesulide. 
============================================================= 
J Hepatol 2000 Jan;32(1):174 

Comment on: 
J Hepatol. 1998 Jul;29(1):135-41 

Andrade RJ, Lucena MI, Fernandez MC, Gonzalez M. 

Publication Types: 
Comment 
Letter 
============================================================= 

============================================================= 
12.) Neonatal end-stage renal failure associated with maternal ingestion of cyclo-oxygenase-type-1 
selective inhibitor nimesulide as tocolytic. 
============================================================= 
Lancet 1999 Nov 6;354(9190):1615 

Comment in: 
Lancet. 2000 Feb 12;355(9203):575 
Lancet. 2000 Jan 15;355(9199):236-7 

Comment on: 
Lancet. 1997 Jul 26;350(9073):265-6 

Peruzzi L, Gianoglio B, Porcellini MG, Coppo R. 

Cyclo-oxygenase-type-2 (COX-2) enzyme is fundamental for nephrogenesis, upregulated on fetal 
membranes and myometrium at parturition. Fetal COX-2 inhibition, due to maternal nimesulide 
assumption, can be responsible for neonatal chronic renal failure. 

============================================================= 
13.) [Nimesulide acute hepatitis: description of 3 cases]. 
============================================================= 
Med Clin (Barc) 1999 Sep 25;113(9):357-8 

[Article in Spanish] 

Romero Gomez M, Nevado Santos M, Fobelo MJ, Castro Fernandez M. 

Publication Types: 
Letter 
============================================================= 

============================================================= 
14.) Analgesics for pediatric use. 
============================================================= 
Indian J Pediatr 2000 Aug;67(8):589-90 

Malhotra S, Pandhi P. 

Department of Clinical Pharmacology, PGIMER, Chandigarh. 

The use of nimesulide is increasing and recently, concerns have been raised regarding its 
hepatotoxicity, especially in children. At least two deaths due to fulminant hepatic failure have been 
attributed to nimesulide. In India, nimesulide has been approved and about twelve pediatric 
preparations are available. Lack of effective postmarketing surveillance means that adverse drug 
reactions may not be picked or reported. Therefore, quick approval of those drugs for which 
substitutes are available may not be desirable in India and in other developing countries. 

============================================================= 
15.) Nimesulide, clavulanic acid and hepatitis. 
============================================================= 
J Intern Med 2000 Aug;248(2):168-9 

Comment on: 
J Intern Med. 2000 Jan;247(1):153-5 

Elmalem E. 

Publication Types: 
Comment 
Letter 
============================================================= 

============================================================= 
16.) Nimesulide-induced hepatitis and acute liver failure. 
============================================================= 
Isr Med Assoc J 1999 Nov;1(3):221 


Comment on: 
Isr Med Assoc J. 1999 Oct;1(2):89-91 

Weiss P. 

Publication Types: 
Comment 
Letter 
============================================================= 

============================================================= 
17.) [Toxic hepatitis caused by nimesulide, presentation of a new case and review of the literature]. 
============================================================= 
Gastroenterol Hepatol 2000 Nov;23(9):428-30 

[Article in Spanish] 

Ferreiro C, Vivas S, Jorquera F, Dominguez AB, Espinel J, Munoz F, Herrera A, Fernandez MJ, 
Olcoz JL, Ortiz de Urbina J. 

Seccion de Aparato Digestivo y Servicio de Farmacia, Hospital de Leon, Leon. 

Nimesulide is a potent non-steroidal anti-inflammatory drug. It is a new, selective cyclooxygenase-2 
inhibitor with few adverse effects on the gastrointestinal system. We present a case of hepatotoxicity 
in which other possible causes of liver damage were excluded. A biochemical pattern of cholestasis 
was predominant. Evolution was favorable after the drug was stopped and enzymatic alterations 
progressively returned to normal. The cases reported to date are reviewed. The precise mechanism 
by which nimesulide produces liver damage is not known but it is probably caused by an 
idiosyncratic reaction. Because of the severity of the hepatitis described in some cases, treatment 
should be stopped when liver dysfunction is detected and the patients should be closely monitored. 

============================================================= 
18.) [Bleeding gastric ulcers and acute hepatitis: 2 simultaneous adverse reactions due to nimesulide 
in a case]. 
============================================================= 
Rev Med Chil 2000 Dec;128(12):1349-53 

[Article in Spanish] 

Tejos S, Torrejon N, Reyes H, Meneses M. 

Servicios de Medicina y de Anatomia Patologica, Hospital del Salvador, Departamento de Medicina 
(Campus Oriente), Facultad de Medicina, Universidad de Chile, Santiago, Chile. [email protected] 

A 66 year-old obese woman with arthrosis, self-medicated with oral nimesulide, 200 mg daily. After 
6 weeks she developed nausea, jaundice and dark urine. Two weeks later she had recurrent 
hematemesis and was hospitalized. Besides obesity and anemia her physical examination was 
unremarkable. An upper GI endoscopy revealed 3 acute gastric ulcers and a 4th one in the pyloric 
channel. Abdominal ultrasonogram showed a slightly enlarged liver with diffuse reduction in 
ecogenicity; the gallbladder and biliary tract were normal. Blood tests demonstrated a conjugated 
hyperbilirubinemia (maximal total value: 18.4 mg/dl), ALAT 960 U/l, ASAT 850 U/l, GGT 420 U/l, 
alkaline phosphatases mildly elevated, pro-time 49% and albumin 2.7 mg/dl. Serum markers for 
hepatitis A, B and C viruses were negative. ANA, AMA, anti-SmA, were negative. Ceruloplasmin 
was normal. A liver biopsy showed bridging necrosis and other signs of acute toxic liver damage. 
Gastric ulcers healed after conventional treatment and hepatitis subsided after 2 months leaving no 
signs of chronic liver damage. The diagnosis of toxic hepatitis due to nimesulide was supported by 
the time-course of drug usage, sex, age, absence of other causes of liver disease, a compatible liver 
biopsy and the improvement after drug withdrawal. Peptic ulcers or toxic hepatitis have been 
previously described as independent adverse reactions in patients taking nimesulide or other 
NSAIDs but their simultaneous occurrence in a single patient is a unique event that deserves to be 
reported. 

============================================================= 
19.) Nimesulide-induced acute hepatitis: evidence from six cases. 
============================================================= 
J Hepatol 1998 Jul;29(1):135-41 

Comment in: 
J Hepatol. 2000 Jan;32(1):174 

Van Steenbergen W, Peeters P, De Bondt J, Staessen D, Buscher H, Laporta T, Roskams T, 
Desmet V. 

Department of Internal Medicine, University Hospital Gasthuisberg-St Rafael, Catholic University of 
Leuven, Belgium. 

BACKGROUND/AIMS: A number of nonsteroidal anti-inflammatory drugs have been reported to 
provoke hepatic injury. Nimesulide is a new agent of the sulfonanilide class, and is a more selective 
inhibitor of cyclooxygenase type 2 than of type 1. Well-documented cases of acute hepatitis have 
not yet been reported with this drug. We report on six patients who developed acute liver damage 
after initiation of nimesulide. METHODS: Between April 1996 and January 1997, six patients with 
apparent nimesulide-induced liver injury were admitted. Clinical, laboratory, serologic, radiological, 
and histologic data of all six cases were extensively analyzed. The causal relationship between 
nimesulide and liver injury was assessed, using a scoring system elaborated by the French and 
International consensus meeting group. RESULTS: Four women developed a centrilobular (three) or 
panlobular (one) bridging necrosis, whereas two men showed a bland intrahepatic cholestasis. 
Jaundice was the presenting symptom in five of the six cases. One patient with hepatocellular 
necrosis and one with cholestasis had hallmarks of hypersensitivity with an increased blood and 
tissue eosinophilia. The causal relationship could be designated as "highly probable" in one, 
"probable" in four, and "possible" in one patient. One patient died from a pancreatic tumor 5 months 
after the diagnosis of toxic liver injury. In all other patients, liver tests returned to completely normal 
values within a late follow-up period of 6 to 17 months. CONCLUSIONS: Nimesulide-induced 
liver injury can present with hepatocellular necrosis or with pure cholestasis. >From clinical and 
histologic data, it appears that both immunologic and metabolic idiosyncratic reactions can be 
invoked as the pathogenic mechanisms of nimesulide-induced liver disease. 

============================================================= 
20.) Nimesulide-induced purpura. 
============================================================= 
Dermatology 2000;201(4):376 

Kanwar AJ, Kaur S, Thami GP. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
21.) Modification of antihistaminic activity of cetirizine by nimesulide. 
============================================================= 
J Assoc Physicians India 1999 Apr;47(4):389-92 

Rewari S, Gupta U. 

Dept of Pharmacology, Maulana Azad Medical College and Associated Hospitals, New Delhi. 

OBJECTIVE: To study the effect of nimesulide (4-nitro-2-phenoxymethane sulfonanilide) a 
non-steroidal anti-inflammatory drug, on antihistaminic activity of cetirizine. METHOD: A 
randomized, double blind, cross over study was conducted in ten healthy male volunteers. Wheal 
and flare responses to histamine were measured by performing intradermal injection of histamine (2 
micrograms base) diluted in 100 microliters volume of saline on the volar surface of forearm, on four 
occasions (0, 2, 4, and 6 hrs. post-dosing). Each volunteer was randomized to receive either 
treatment A (cetirizine 10 mg + placebo) or treatment B (cetirizine 100 mg + nimesulide 100 mg), 
with one week wash out period in between each administration. Wheal and flare responses were 
measured ten minutes after each histamine injection. RESULTS: Both cetirizine 10 mg alone and 
cetirizine 10 mg + nimesulide 100 mg, decreased wheal and flare responses significantly at 2 hrs. and 
this continued till 6 hrs. post-dosing. This decrease was highly significant when cetirizine was given 
along with nimesulide. CONCLUSION: The results suggest a synergistic effect exhibited by the 
combined use of cetirizine with nimesulide. 

============================================================= 
22.) Perinatal vasoconstrictive renal insufficiency associated with maternal nimesulide use. 
============================================================= 
Am J Perinatol 1999;16(9):441-4 

Landau D, Shelef I, Polacheck H, Marks K, Holcberg G. 

Department of Pediatrics, Soroka Medical Center and Ben Gurion University of the Negev, Beer 
Sheva, Israel. 

A full-term newborn developed oliguric renal failure at 24 hr of life, which persisted for several days. 
Her mother ingested therapeutic doses of nimesulide, a non-steroidal anti-inflammatory 
(cyclo-oxygenase-2 inhibitor) drug, during the last 2 weeks of pregnancy. She was found at delivery 
to have developed oligohydramnion, esophagitis, and a bleeding peptic ulcer. The infant's fractional 
excretion of sodium was very low (0.5%) pointing for a severe vasoconstrictive mechanism involved. 
Renal sonogram showed hyperechogenic medullary papillae, which resolved during convalescence. 
This case emphasizes the importance of renal prostagandins in the control of vascular tone and 
sodium homeostasis. This is the first report of an adverse effect of fetal renal circulation by maternal 
ingestion of nimesulide. 

============================================================= 
23.) Acute renal failure induced by nimesulide in a patient suffering from temporal arteritis. 
============================================================= 

Nephrol Dial Transplant 1997 Jul;12(7):1493-6 Related Articles, Books, LinkOut 

Apostolou T, Sotsiou F, Yfanti G, Andreadis E, Nikolopoulou N, Diamantopoulos E, Billis A. 

Department of Medicine, Evangelismos Hospital, Athens, Greece. 

============================================================= 
============================================================= 
24.) Drug-induced cholestasis. 
============================================================= 
Semin Gastrointest Dis 2001 Apr;12(2):113-24 

Chitturi S, Farrell GC. 

Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead Hospital, New 
South Wales, Australia. 

The spectrum of drug-induced cholestasis ranges from 'bland' reversible cholestasis to chronic forms 
due to the vanishing bile duct syndrome. Agents known for many years to cause cholestasis include 
estrogens and anabolic steroids, chlorpromazine, erythromycin, and the oxypenicillins; structurally 
similar congeners of these drugs (tamoxifen, newer macrolides) may also cause cholestasis. 
Contemporary drugs linked to cholestastic liver injury include ticlopidine, terfenadine, terbinafine, 
nimesulide, irbesartan, fluoroquinolones, cholesterol-lowering 'statins,' and some herbal remedies 
(greater celandine, glycyrrhizin, chaparral). Amoxillin-clavulanate, ibuprofen, and pediatric cases of 
the vanishing bile duct syndrome are recent additions to a long list of drugs associated with the 
vanishing bile duct syndrome. Particular human leukocyte antigen profiles have recently been 
identified among those who have developed cholestasis with specific drugs (tiopronin and 
amoxicillin-clavulanate), and the mechanistic relevance of these genetic associations is being 
explored. The treatment of drug-induced cholestasis is largely supportive. The offending drug should 
be withdrawn immediately. Cholestyramine or ursodeoxycholic acid are used to alleviate pruritus, 
with rifampicin and opioid antagonists being reserved for those who fail first line therapy. Nutritional 
support is essential for those with prolonged cholestasis, a subgroup who are at risk of developing 
biliary cirrhosis and liver failure. Timely referral for liver transplant assessment is crucial in these 
patients. 

============================================================= 
25.) Adverse drug reactions postal survey-bronchial asthma and angioedema with nimesulide. 
============================================================= 
J Assoc Physicians India 2000 May;48(5):548 

Mangalvedhekar SS, Gogtay NJ, Phadke AV, Gore S, Shah JM, Shah SM, Kshirsagar NA. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
26.) Hypothermia with nimesulide. 
============================================================= 
Indian Pediatr 2001 Jul;38(7):799-800 

Sharma S. 

Professor, Department of Pediatrics, Medical College, Amritsar, Punjab, India. 

============================================================= 
27.) [Nimesulide-induced acute hepatitis]. 
============================================================= 
Gastroenterol Hepatol 2001 Apr;24(4):219-20 

[Article in Spanish] 

Montesinos S, Hallal H, Rausell V, Conesa F, Lopez A. 

Servicio de Farmacia y aSeccion de Aparato Digestivo. Hospital Santa Maria del Rosell. Cartagena. 
Murcia. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
28.) [Nimesulide toxic hepatitis in pregnancy]. 
============================================================= 
Gastroenterol Hepatol 2000 Dec;23(10):498-9 

[Article in Spanish] 

Perez-Moreno J, Llerena Guerrero RM, Puertas Montenegro M, Jimenez Arjona MJ. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
29.) Positive lesional patch tests in fixed drug eruptions from nimesulide. 
============================================================= 
Contact Dermatitis 2000 Nov;43(5):307 

Cordeiro MR, Goncalo M, Fernandes B, Oliveira H, Figueiredo A. 

Clinica de Dermatologia, Hospitais da Universidade, Coimbra, Portugal. 

============================================================= 
30.) Nimesulide-induced acute hepatitis. 
============================================================= 
Ann Pharmacother 2001 Sep;35(9):1049-52 

Sbeit W, Krivoy N, Shiller M, Farah R, Cohen HI, Struminger L, Reshef R. 

Department of Gastroenterology, Nahariya Hospital, B. Rappaport Faculty of Medicine, Technion, 
Israel. [email protected] 

OBJECTIVE: To report the occurrence of nimesulide-induced acute hepatitis confirmed by biopsy 
and an in vitro lymphocyte toxicity assay. CASE SUMMARY: A 54-year-old Arabic woman 
treated with nimesulide for chronic low back pain was admitted to the hospital with acute hepatitis 
confirmed by biopsy. Her liver function test results returned to normal within one month after 
nimesulide discontinuation. An in vitro lymphocyte toxicity assay confirmed that the liver injury was 
due to nimesulide exposure. DISCUSSION: A case of acute hepatitis secondary to nimesulide, 
confirmed by biopsy and a laboratory in vitro assay, is described. Although the occurrence of 
clinically significant liver damage due to nonsteroidal antiinflammatory drugs (NSAIDs) is low, the 
enormous consumption of these drugs has made them an important cause of liver damage. 
Nimesulide, a relatively new NSAID commonly used in Europe, with a relative selectivity to 
cyclooxygenase type 2, can cause a wide range of liver injuries, from mild abnormal liver function to 
severe liver injuries. These effects are usually reversible on discontinuation of the drug, but 
occasionally can progress to fatal hepatic failure. CONCLUSIONS: Drug-induced acute hepatitis is 
a well-recognized adverse effect of many drugs, including nimesuilde. Identification of a drug as a 
cause for this life-threatening disease is important because the discontinuation of it may be life saving. 
This article confirms the occurrence of nimesulide-induced hepatitis. It also highlights the importance 
of monitoring liver function test results after initiating therapy with such a drug. 

============================================================= 
31.) [Severe acute hepatitis probably induced by nimesulide]. 
============================================================= 
Gastroenterol Clin Biol 2000 May;24(5):592-3 

[Article in French] 

Rodrigues de Oliveira J, Correia J, Silvestre F, Meirelles A, Bernardo A. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
32.) Bullous and erosive stomatitis induced by nimesulide. 
============================================================= 
Dermatology 1992;185(1):74-5 

Valsecchi R, Reseghetti A, Cainelli T. 

Publication Types: 
Letter 

============================================================= 
============================================================= 
33.) The uncoupling effect of the nonsteroidal anti-inflammatory drug nimesulide in liver mitochondria 
from adjuvant-induced arthritic rats. 
============================================================= 
Cell Biochem Funct 2001 Jun;19(2):117-24 Related Articles, Books, LinkOut 

Caparroz-Assef SM, Salgueiro-Pagadigorria CL, Bersani-Amado CA, Bracht A, Kelmer-Bracht 
AM, Ishii-Iwamoto EL. 

Laboratory of Biological Oxidations, Department of Biochemistry, University of Maringa, 87020900 
Maringa, Brazil. 

The aim of the present study was to evaluate the changes caused by adjuvant-induced arthritis in 
liver mitochondria and to investigate the effects of the nonsteroidal anti-inflammatory drug nimesulide. 
The main alterations observed in liver mitochondria from arthritic rats were: higher rates of state IV 
and state III respiration with beta-hydroxybutyrate as substrate; reduced respiratory control ratio 
and impaired capacity for swelling dependent on beta-hydroxybutyrate oxidation. No alterations 
were found in the activities of NADH oxidase and ATPase. Nimesulide produced: (1) stimulation of 
state IV respiration; (2) decrease in the ADP/O ratio and in the respiratory control ratio; (3) 
stimulation of ATPase activity of intact mitochondria; (4) inhibition of swelling driven by the oxidation 
of beta-hydroxybutyrate; (5) induction of passive swelling due to NH(3)/NH(4)+ redistribution. The 
activity of NADH oxidase was insensitive to nimesulide. Mitochondria from arthritic rats showed 
higher sensitivity to nimesulide regarding respiratory activity. The results of this work allow us to 
conclude that adjuvant-induced arthritis leads to quantitative changes in some mitochondrial functions 
and in the sensitivity to nimesulide. Direct evidence that nimesulide acts as an uncoupler was also 
presented. Since nimesulide was active in liver mitochondria at therapeutic levels, the impairment of 
energy metabolism could lead to disturbances in the liver responses to inflammation, a fact that 
should be considered in therapeutic intervention. Copyright 2001 John Wiley & Sons, Ltd. 

============================================================= 
34.) Can a cyclo-oxygenase type-2 selective tocolytic agent avoid the fetal side effects of 
indomethacin? 
============================================================= 
BJOG 2001 Mar;108(3):325-6 

Locatelli A, Vergani P, Bellini P, Strobelt N, Ghidini A. 

Department of Obstetrics and Gynaecology, San Gerardo's Institute of Biomedical Sciences, 
University of Milano-Bicocca, Monza, Italy. 

We evaluated the efficacy and safety of nimesulide (100 mg orally twice daily for > 48 hours) in a 
pilot series of five women (two with twin pregnancies) at 24(+6) weeks (range 21(+3) - 27(+2)) in 
preterm labour which was unresponsive to intravenous ritodrine. Nimesulide therapy was continued 
for eight days (5-16) and was associated with a prolongation of pregnancy of 27 days (6-69). 
Oligohydramnios occurred in all seven fetuses after three to nine days of therapy, and in the five 
pregnancies that continued after discontinuation of nimesulide, it resolved within four days (2-7). 
None of the babies manifested permanent renal damage. 

============================================================= 
ROFECOXIB (VIOXX) MERCK SHARP AND DOHME 
============================================================= 
1.) Tolerability to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions. 
============================================================= 
Ann Allergy Asthma Immunol 2001 Sep;87(3):201-4 

Sanchez Borges M, Capriles-Hulett A, Caballero-Fonseca F, Perez CR. 

Allergy-Immunology Service, Centro Medico-Docente La Trinidad, Caracas, Venezuela. 
[email protected] 

BACKGROUND: The safety of new anti-inflammatory drugs in patients intolerant to classic 
cyclooxygenase (COX) inhibitors with urticaria and angioedema has not been determined. 
OBJECTIVES: To investigate the clinical tolerance to COX-2 inhibitors in patients with cutaneous 
symptoms attributable to classic nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: 
Patients with urticaria or angioedema triggered by NSAIDs were challenged with COX-2 inhibitors 
by the single-blinded, placebo-controlled oral method. RESULTS: One hundred ten 
NSAID-sensitive patients were submitted to 184 oral challenges with COX-2 inhibitors. Eighty-two 
patients (74.5%) were cross-reactors and 28 patients (25.4%) were single reactors. Reaction rates 
for COX-2 inhibitors were 21.3% for nimesulide, 17.3% for meloxicam, 33.3% for celecoxib, and 
3.0% for rofecoxib. CONCLUSIONS: Some COX-2 inhibitors, such as rofecoxib, are relatively 
safe in NSAID-sensitive patients with urticaria or angioedema. However, the tolerance profile varies 
with the drug, which might be related to a differential selectivity of the drug for COX-1 and COX-2. 
COX-1 inhibition would represent a major mechanism for cutaneous adverse reactions to NSAIDs. 
Controlled oral provocation with new NSAIDs is useful for the proper management of patients 
sensitive to classic NSAIDs requiring analgesic and anti-inflammatory treatment. 

============================================================= 
2.) FDA warns Merck over its promotion of rofecoxib. 
============================================================= 
BMJ 2001 Oct 6;323(7316):767A 

Josefson D. 

San Francisco. 

============================================================= 
============================================================= 
3.) Nephrotoxicity of selective COX-2 inhibitors. 
============================================================= 
J Rheumatol 2001 Sep;28(9):2133-5 

Woywodt A, Schwarz A, Mengel M, Haller H, Zeidler H, Kohler L. 

Department of Medicine, University of Hannover School of Medicine, Germany. 
[email protected] 

We describe 2 male patients, a 49-year-old with psoriatic arthritis and impaired renal function and a 
43-year-old renal transplant recipient, who both sustained a marked decline in glomerular filtration 
rate in conjunction with a selective inhibitor of cyclooxygenase-2 (COX-2), rofecoxib. In the second 
patient, acute renal failure necessitated hemodialysis. Both patients made an uneventful recovery. 
Our report lends further support to the assumption that COX-2 inhibitors, as a class, can be as 
nephrotoxic as their nonselective predecessors. Therefore, COX-2 inhibitors should be used with 
caution in renal transplant recipients and in patients with salt depletion and renal insufficiency. 

============================================================= 
4.) [Upper gastrointestinal bleeding secundary to rofecoxib]. 
============================================================= 
Med Clin (Barc) 2001 Oct 13;117(11):438 

[Article in Spanish] 

C Duro J. 

CAP Carreras Candi. Institut Catala de la Salut. Barcelona. 

============================================================= 
5.) Celecoxib- and rofecoxib-induced delirium. 
============================================================= 
J Neuropsychiatry Clin Neurosci 2001 Spring;13(2):305-6 

Macknight C, Rojas-Fernandez CH. 

Publication Types: 
Letter 

============================================================= 
============================================================= 
6.) Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, 
rofecoxib. 
============================================================= 
Lancet 2001 Jun 16;357(9272):1946-7 

Rocha JL, Fernandez-Alonso J. 

The nephrotoxic effect of COX-2 selective inhibitors has not yet been established. We report a case 
of reversible acute renal failure due to acute tubulointerstitial nephritis, confirmed by histology of a 
renal biopsy sample, associated with taking rofecoxib, a selective cyclo-oxygenase-2 (COX-2) 
inhibitor. 

Publication Types: 
Letter 
============================================================= 
7.) Rofecoxib-induced renal dysfunction in a patient with compensated cirrhosis and heart failure. 
============================================================= 
Am J Gastroenterol 2001 Jun;96(6):1941 

Ofran Y, Bursztyn M, Ackerman Z. 

Publication Types: 
Letter 
============================================================= 
8.) Gastrointestinal damage induced by celecoxib and rofecoxib in rats. 
============================================================= 
Dig Dis Sci 2001 Apr;46(4):779-84 

Laudanno OM, Cesolari JA, Esnarriaga J, Rista L, Piombo G, Maglione C, Aramberry L, 
Sambrano J, Godoy A, Rocaspana A. 

Gastroenterologia Experimental Catedras de Patologia Medica III e Histologia y Embriologia, 
Facultad de Ciencias Medicas, Rosario, Argentina. 

Five experimental models were developed in different groups of Wistar rats (N = 15) to study 
selective COX-2-inhibitor NSAIDs such as celecoxib and rofecoxib, as follows: (1) 
dose-dependent oral Celecoxib and Rofecoxib for 5 days, and 24 hr after oral indomethacin; (2) 
Same as 1 but subcutaneously; (3) gastric ulcer induced by glacial acetic acid; (4) duodenal ulcer 
induced by cysteamine; and (5) stress by immobilization and immersion in water at 15 degrees C for 
6 hr. Celecoxib and Rofecoxib, either orally or subcutaneously, did not produce necrotic lesions in 
healthy gastrointestinal mucosa (0%), showing normal histology. In contrast, previously 
indomethacin-induced lesions were aggravated (90%, P < 0.001). Total necrosis in the small 
intestine as well as increased ulcers and perforation of gastric and duodenal ulcers induced by acetic 
acid and cysteamine were observed. There was also aggravation of the necrotic gastric area in stress 
(60-90%, P < 0.05). Celecoxib and rofecoxib showed neutrophilia (5000/mm3) similar to that with 
indomethacin. In contrast, there was no leukocyte infiltration in the gastric mucosa; thus, we can 
consider it a selective COX-2 NSAID. In conclusion, celecoxib and rofecoxib at doses causing 
COX-2 but not COX-1 inhibition did not produce toxic lesions in healthy gastrointestinal mucosa, 
yielding a broad therapeutic margin. In contrast, when administered in altered gastrointestinal 
mucosa, they aggravated and complicated gastric ulcers as well as necrosis in the small intestine, 
consequently restricting their clinical use. 

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9.) FDA refuses companies' request to drop ulcer warning 
============================================================= 
BMJ 2001;322:385 ( 17 February ) 
News 

Scott Gottlieb, New York 

Two competing manufacturers of the top selling prescription "superaspirins" in the United States, 
vying for a marketing edge, went before a panel of the US Food and Drug Administration (FDA) 
last week to ask the government to relax ulcer warnings on their labels but failed to win the 
expanded wording that they sought. 

Traditional non-steroidal anti-inflammatory drugs block both the related enzymes 
(cyclo-oxygenase-1 (COX 1) and cyclo-oxygenase-2 (COX 2)), which cause inflammation and 
pain. But COX 1 also protects the stomach lining. Researchers found that they could control pain by 
blocking the COX 2 pain enzyme while leaving the COX 1 enzyme alone. 

The manufacturers of the two competing drugs (celecoxib (Celebrex) and rofecoxib (Vioxx)), have 
long maintained that COX 2 inhibitors cause fewer stomach ailments, such as ulcers, normally 
associated with long term use of non-steroidal anti-inflammatory drugs. 

The manufacturers want the drugs to be considered in a class of their own, as they interfere only with 
the inflammation and pain enzyme, not the protective one. 

The FDA refused, however, to put celecoxib and rofecoxib in a class by themselves. Therefore the 
drugs will continue to carry the same ulcer warning found on other non-steroidal anti-inflammatory 
drugs. The companies tested celecoxib and rofecoxib separatelyeach in trials of 8000 patientsto 
determine the drugs' risk of causing stomach problems. 

In the study of celecoxib, the manufacturer, Pharmacia, compared the drug with the generic drugs 
ibuprofen and diclofenac. The FDA's panel said that the difference in the rate of ulcers was not 
significant enough to change the label. One important factor was that many patients in the study also 
took low doses of aspirin, a common prescription for prevention of heart attack, negating any benefit 
from celecoxib. 

In a study of rofecoxib, the manufacturer, Merck, compared patients taking that drug with a group 
taking naproxen. Although the study showed that rofecoxib did cause fewer ulcers, the FDA's panel 
said that the drug's label should still retain its broad warning that rofecoxib, like celecoxib, can still 
cause ulcers. 

Also, the panel said that patients and doctors must be warned that in the study patients taking 
rofecoxib had twice the risk of heart attacks or other cardiovascular side effects as naproxen users. 
It is believed that naproxen may work as an antiplatelet agent, much like aspirin, and thus using 
rofecoxib in the study instead deprived patients of the other drug's benefit. 

Some critics say, however, that rofecoxib and celecoxib may themselves increase the risk of blood 
clots. The FDA's panel concluded that more research was needed but that meanwhile rofecoxib's 
label should warn of the concern. 

============================================================= 
10.) Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on 
cyclooxygenase-2-selective inhibition. 
============================================================= 
Am J Med 1999 Dec 13;107(6A):65S-70S; discussion 70S-71S Related Articles, Books, 
LinkOut 

Brater DC. 

Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USA. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) can affect renal function in a variety of ways. The 
most important clinical effects are decreased sodium excretion, decreased potassium excretion, and 
declines in renal perfusion. Decreased sodium excretion can result in weight gain, peripheral edema, 
attenuation of the effects of antihypertensive agents, and rarely precipitation of chronic heart failure. 
Hyperkalemia can occur to a degree sufficient to cause cardiac arrhythmias. Renal function can 
decline sufficiently enough to cause acute renal failure. Risk factors for all of these effects have been 
identified, allowing prospective identification of patients at risk with institution of appropriate 
precautionary measure. All NSAIDs seem to share these adverse effects. Preliminary data from 
cyclooxygenase-2-selective inhibitors suggest that they also affect renal prostaglandins. Therefore, 
the same cautions should be exercised with their use as with traditional NSAIDs. 

============================================================= 
MELOXICAM (MOBIC) BOEHRINGER INGELHEIM PHARMACEUTICALS INC 
============================================================= 
Original Application #: 020938 
Approval Date: 13-APR-00 
Trade Name: MOBIC 
Chemical Type: 1 
Therapeutic Potential: S 
Dosage Form: TABLET 
Applicant: BOEHRINGER INGELHEIM PHARMACEUTICALS INC 
Active Ingredient(s): MELOXICAM 
OTC/RX Status: RX 
Indication(s): For relief of the signs and symptoms of osteoarthritis 

============================================================= 
1.) Meloxicam-induced liver toxicity. 
============================================================= 
Acta Gastroenterol Belg 1999 Apr-Jun;62(2):255-6 

Staerkel P, Horsmans Y. 

Department of Gastroenterology, Cliniques Universitaires Saint Luc, Catholic University of Louvain, 
Brussels, Belgium. 

We report the case of a female patient with rheumatoid arthritis who developed acute cytolytic 
hepatitis due to meloxicam. Recently introduced in Belgium, meloxicam is the first nonsteroidal 
antiinflammatory drug with selective action on the inducible form of cyclooxygenase 2. The acute 
cytolytic hepatitis occurred rapidly after meloxicam administration and was associated with the 
development of antinuclear antibodies suggesting a hypersensitivity mechanism. This first case of 
meloxicam related liver toxicity demonstrates the potential of this drug to induce hepatic damage. 

============================================================= 
2.) [Meloxican-induced cholestasis]. 
============================================================= 
Acta Gastroenterol Latinoam 2000;30(5):511-4 

[Article in Spanish] 

Gierer IM, Abdala O, Calderon C, Risoli E, Cravero A, Pinchuk L. 

The cholestasis by meloxicam has not been often described. However, we present here the clinic, 
laboratory, histologic and follow up of a patient with cholestatic hepatitis produced by this drug. 

============================================================= 
3.) Meloxicam-induced erythema multiforme. 
============================================================= 
Am J Med 1999 Nov;107(5):532-4 

Nikas SN, Kittas G, Karamaounas N, Drosos AA. 

Publication Types: 
Letter 
============================================================= 
4.) Meloxicam, 15 mg/day, spares platelet function in healthy volunteers. 
============================================================= 
Clin Pharmacol Ther 1999 Oct;66(4):425-30 

de Meijer A, Vollaard H, de Metz M, Verbruggen B, Thomas C, Novakova I. 

Department of Clinical Pharmacy and Clinical Chemistry, Canisius Wilhelmina Hospital, Nijmegen, 
The Netherlands. 

OBJECTIVE: To study the influence of meloxicam, a cyclooxygenase-2 (COX-2) preferential 
nonsteroidal anti-inflammatory drug, on serum thromboxane and platelet function in healthy 
volunteers with use of the maximum recommended daily dosage of 15 mg/day. METHODS: This 
study used an open, randomized crossover design. Indomethacin (INN, indometacin) was given as a 
positive control for nonsteroidal anti-inflammatory drug-induced inhibition of platelet function. The 
following variables were recorded: thromboxane B2 serum concentrations by radioimmunoassay, 
platelet aggregation by whole blood aggregometry in response to collagen 1.1 microg/L and to 
arachidonic acid 0.35 mmol/L, and closure time with use of the PFA-100. RESULTS: Serum 
thromboxane B2 at baseline was 535+/-233 nmol/L (mean +/- SD) and was reduced for 95% by 
indomethacin to 26+/-19 nmol/L (P < .001) and for 66% by meloxicam to 183+/-62 nmol/L (P < 
.001). Maximal platelet aggregation in response to collagen at baseline was 18.7+/-1.6 ohms 
(ohms). It was reduced by indomethacin to 7.3+/-4.5 ohms (P < .001), but not by meloxicam 
(19+/-2.5 ohms). Platelet aggregation in response to arachidonic acid at baseline was 12.2+/-2.0 
ohms. It was reduced by indomethacin in all subjects to 0 ohms, but not by meloxicam (11+/-2.4 
ohms). Closure time at baseline was 128+/-24 seconds and was prolonged by indomethacin to 
286+/-38 seconds (P < .001). Meloxicam caused a minor prolongation of the closure time 
(141+/-32 seconds; P < .05). CONCLUSION: Meloxicam, 15 mg/day caused a major reduction 
of maximum thromboxane production but no reduction in collagen- or arachidonic acid-induced 
platelet aggregation and only minor increase of the closure time. 

============================================================= 
5.) [Upper digestive hemorrhage caused by meloxicam.] 
============================================================= 
Rev Esp Enferm Dig 1998 Jun;90(6):461-2 

[Article in Spanish] 

del Val A, Llorente MJ, Tenias JM, Lluch A. 

============================================================= 
6.) Gastrointestinal complications and meloxicam. 
============================================================= 
Br J Rheumatol 1997 Nov;36(11):1234 

Fenn GC, Morant SV, Shield MJ. 

Publication Types: 
Letter 
============================================================= 
=============================================================7.) 
MELOXICAM ADVERSE EFFECTS 
============================================================= 
CONTRAINDICATIONS 

MOBIC is contraindicated in patients with known hypersensitivity to meloxicam. It should not be 
given to 
patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or 
other 
NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such 
patients 
(see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, Pre-existing Asthma). 

WARNINGS 

Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation: 

Serious gastrointestinal toxicity, such as inflammation, bleeding, ulceration, and perforation of the 
stomach, 
small intestine or large intestine, can occur at any time, with or without warning symptoms, in 
patients 
treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal 
problems, such 
as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, 
physicians 
and patients should remain alert for ulceration and bleeding, even in the absence of previous GI 
symptoms. 
Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to 
take if 

they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been 
adequately assessed. Only one in five patients who develop a serious upper GI adverse event on 
NSAID 
therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or 
perforation, 
caused by NSAIDs, appear to occur in approximately 1% of the patients treated for 3-6 months, 
and in about 
2-4% of patients treated for one year. These trends continue thus, increasing the likelihood of 
developing a 
serious GI event at some time during the course of therapy. However, even short-term therapy is 
not 
without risk. 

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or 
gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated 
patients 
and therefore special care should be taken in treating this population. To minimize the potential risk 
for an 
adverse GI event, the lowest effective dose should be used for the shortest possible duration. For 
high-risk 
patients, alternate therapies that do not involve NSAIDs should be considered. 

Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal 
bleeding and who use NSAIDs, have a greater than 10-fold risk for developing a GI bleed than 
patients with 
neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological 
studies 
have identified several other co-therapies or co-morbid conditions that may increase the risk for GI 
bleeding 
such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of 
NSAID 
therapy, smoking, alcoholism, older age, and poor general health status. 

Anaphylactoid Reactions 

As with other NSAIDs, anaphylactoid reactions have occurred in patients without known prior 
exposure to 
MOBIC. MOBIC should not be given to patients with the aspirin triad. This symptom complex 
typically 
occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit 
severe, 
potentially fatal bronchospasm after taking aspirin or other NSAIDs (see 
CONTRAINDICATIONS and 
PRECAUTIONS, Pre-existing Asthma). Emergency help should be sought in cases where an 
anaphylactoid 
reaction occurs. 

Advanced Renal Disease 

In cases with advanced kidney disease, treatment with MOBIC is not recommended. If NSAID 
therapy must 
be initiated, close monitoring of the patient's kidney function is advisable (see PRECAUTIONS, 
Renal 
Effects). 

Pregnancy 

In late pregnancy, as with other NSAIDs, MOBIC should be avoided because it may cause 
premature 
closure of the ductus arteriosus. 

PRECAUTIONS 

General 

MOBIC cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. 
Abrupt 
discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged 
corticosteroid 
therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. 

The pharmacological activity of MOBIC in reducing inflammation and possibly fever may diminish 
the utility 
of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. 

Hepatic Effects 

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, 
including 
MOBIC. These laboratory abnormalities may progress, may remain unchanged, or may be transient 
with 
continuing therapy. Notable elevations of ALT or AST (approximately three or more times the 
upper limit of 
normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In 
addition, rare 
cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and 
hepatic 
failure, some of them with fatal outcomes, have been reported with NSAIDs. 

Patients with signs and/or symptoms suggesting liver dysfunction, or in whom an abnormal liver test 
has 
occurred, should be evaluated for evidence of the development of a more severe hepatic reaction 
while on 
therapy with MOBIC. If clinical signs and symptoms consistent with liver disease develop, or if 
systemic 
manifestations occur (e.g., eosinophilia, rash, etc.), MOBIC should be discontinued. 

Renal Effects 

Caution should be used when initiating treatment with MOBIC in patients with considerable 
dehydration. It 
is advisable to rehydrate patients first and then start therapy with MOBIC. Caution is also 
recommended in 
patients with pre-existing kidney disease (see WARNINGS, Advanced Renal Disease). 

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal 
medullary 
changes. Renal toxicity has also been seen in patients in whom renal prostaglandins have a 
compensatory 
role in the maintenance of renal perfusion. In these patients, administration of NSAIDs may cause 
dose- 
dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may 
precipitate 
overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal 
function, 
heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. 
Discontinuation 
of NSAID therapy is usually followed by recovery to the pretreatment state. 

The extent to which metabolites may accumulate in patients with renal failure has not been studied 
with 
MOBIC. Because some MOBIC metabolites are excreted by the kidney, patients with significantly 
impaired 
renal function should be more closely monitored. 

Hematological Effects 

Anemia is sometimes seen in patients receiving NSAIDs, including MOBIC. This may be due to 
fluid 
retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on 
long-term 
treatment with NSAIDs, including MOBIC, should have their hemoglobin or hematocrit checked if 
they 
exhibit any signs or symptoms of anemia. 

Drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent with platelet 
function 
and vascular responses to bleeding. 

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. 
Unlike aspirin their effect on platelet function is quantitatively less, or of shorter duration, and 
reversible. 
MOBIC does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin 
time 
(PTT). Patients receiving MOBIC who may be adversely affected by alterations in platelet function, 
such as 
those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. 

Fluid Retention and Edema 

Fluid retention and edema have been observed in some patients taking NSAIDs, including MOBIC. 
Therefore, as with other NSAIDs, MOBIC should be used with caution in patients with fluid 
retention, 
hypertension, or heart failure. 

Pre-existing Asthma 

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin- 
sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross 
reactivity, 
including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been 
reported 
in such aspirin-sensitive patients, MOBIC should not be administered to patients with this form of 
aspirin 
sensitivity and should be used with caution in patients with pre-existing asthma. 

Information for Patients 

MOBIC, like other drugs of its class, can cause discomfort and, rarely, more serious side effects, 
such as 
gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although 
serious GI 
tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the 
signs 
and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any 
indicative signs or symptoms. Patients should be made aware of the importance of this follow-up 
(see 
WARNINGS, Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding and Perforation). 

Patients should report to their physicians signs or symptoms of gastrointestinal ulceration or bleeding, 
skin 
rash, weight gain, or edema. 

Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, 
fatigue, 
lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these 
occur, 
patients should be instructed to stop therapy and seek immediate medical therapy. 

Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid 
reaction (see WARNINGS, Anaphylactoid Reactions). 

In late pregnancy, as with other NSAIDs, MOBIC should be avoided because it may cause 
premature 
closure of the ductus arteriosus. 

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DATA-MEDICOS/DERMAGIC-EXPRESS No 3-(109)  27/10/2.001 DR. JOSE LAPENTA R. 
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