Reply to the Vioxx Debacle

Letters

93

legends we share. Some physician attitudes, on the other hand, may be more reflective of the days before medical consumerism, with an emphasis on paternalistically instructing patients rather than educating them. Consequently, there may be reluctance from various influences to prescribe erectile dysfunction medications. This opens the door for procurement from nontraditional sources. There are no stigmata like addiction, socioeconomic disadvantage, loss of esteem, or even criticism from partners associated with using PDE5 inhibitors. Maniacal sex, priapism, and antisocial behavior ensue from its use with even less frequency than transient visual disturbances. The increased incidence of sexually transmitted diseases (STDs) reported by Swearingen and Klausner2 occurred in a cohort of high-risk gay men being seen in several STD clinics who were abusing multiple psychoactive and behavior-altering drugs. That sane and safe sexual precautions were not used by individuals using methamphetamine, poppers, GHB, ketamine and Ecstasy along with their PDE5 drugs should hardly be surprising. In an STD clinic with men at high risk to start with, clearly, intensive counseling is appropriate. However, expecting that counseling to have serious impact when sexual choices and decisions are made in the heat of arousal and the cloud of mind-altering drugs seems unrealistic. Although Viagra may have been the enabler allowing for improved performance, the ensuing STDs were the result of poor decisions made in a drug-induced state. The proper role of the physician for those at high risk is to discourage the use of mind-altering drugs, not Viagra. For the non-drug-abusing public, the proper role is to ethically and responsibly improve the quality of life of patients with the resources that exist, including erectile dysfunction drugs. It also behooves the physician to assure that any drug he does prescribe is taken correctly and contains the active ingredient and is not a fake pill. There is no reason to spread alarms about a safe drug intended for appropriate recreational use. Sam J. Sugar, MD, FACP Evanston, Ill

doi:10.1016/j.amjmed.2005.07.040

References 1. Alpert JS. Viagra: the risks of recreational use. Am J Med. 2005;118: 569-570. 2. Swearingen SD, Klausner JD. Sildenafil use, sexual risk behavior, and risk for sexually transmitted diseases, including HIV infection. Am J Med. 2005;118:571-577.

Reply to the Vioxx Debacle To the Editor: We offer 2 clinically relevant observations in light of the safety issues associated with the widely prescribed cyclo-

oxygenase-2 (cox-2) inhibitors celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx).1 Preferential cox-2 inhibitors are not all created equal, even though they all pose serious cardiovascular risks, according to a Food and Drug Administration panel. We characterized the drugs’ dissimilarities in an article titled “Structure-Activity Relationship as Predictors of Adverse Drug Events,” in April 2003.2 We showed that an understanding of the structural features of molecules, the pharmacophore, is likely to facilitate the prediction of adverse drug events. We demonstrated a structure-adverse event relationship between such disparate groups of drugs as cox-2 inhibitors and the newly marketed antiepileptic drugs topiramate and zonisamide. Using various theoretical binding models, we rationalized that celecoxib and valdecoxib, which are both structurally characterized by the pharmacophore ⫺SO2NH2 (as were topiramate and zonisamide), were capable of inhibiting carbonic anhydrase in a fashion similar to the prototypical carbonic anhydrase inhibitor acetazolamide, which was originally used acutely as a mild diuretic. We posited that rofecoxib, which lacks the unsubstituted sulfonamide motif, the major determinant of substrate and inhibitor specificity, would not be a carbonic anhydrase inhibitor, and as such, would not manifest the structure-adverse event relationship that is characteristic of carbonic anhydrase inhibitors. We were the first to report that celecoxib did indeed exhibit the characteristic of a potent carbonic anhydrase inhibitor, showing in vitro human carbonic anhydrase II inhibitory activity in the nanomolar range.3 Valdecoxib was much less potent as a carbonic anhydrase inhibitor. Rofecoxib and diclofenac were without inhibitory activity. Our work was later corroborated by Weber et al.4 Why is our rather surprising observation clinically intriguing? Because, in part, we now know that mechanisms of action as well as adverse events associated with celecoxib, unlike rofecoxib, can be explained by its dual action as a preferential cox-2 inhibitor and as a potent carbonic anhydrase inhibitor. Carbonic anhydrases, of which more than a dozen enzymatically active isoforms exist, are expressed in various cell types, including those of the kidney. The isoforms modulate levels of H⫹ and HCO3⫺ and thereby are important in regulating intracellular/extracellular pH and volume homeostasis. Clinically, apart from the known mild diuretic effect of carbonic anhydrase inhibitors, some of the known structure-activity adverse events of carbonic anhydrase inhibitors are hyperchloremic, nonanion gap metabolic acidosis; bicarbonateuria; hypophosphatemia; and nephrolithiasis. The renal effects correlate well with the inhibitory activity of the enzyme and the degree of accumulation in proximal tubules. Importantly, about one-half of the enzyme activity must be abolished before any biologic response is evident, hence pointing to differences in the manifestation of carbonic anhydrase inhibition in acute versus long-term exposure to carbonic anhydrase inhibitors. Clinically, metabolic acidosis may be

94 asymptomatic or associated with adverse hemodynamic and metabolic consequences. Specifically, elderly patients, often those taking cox-2 inhibitors, have renal insufficiency and can develop a serious metabolic acidosis. The negative cardiac inotropic actions of acidosis are well characterized. It seems intuitive that the manufacturers of these 3 cox-2 preferential inhibitors would have examined the molecular structures of these drugs long before marketing them and would have characterized the predictable side effects of celecoxib and valdecoxib knowing the relevant pharmacophore, the unsubstituted sulfonamide. A second observation that intrigued us occurred during our review of the Product Information sections in the 2000 to 2005 editions of the Physicians’ Desk Reference (PDR; Montvale, NJ: Medical Economics Company).5 We viewed these data to determine whether or not adverse events known to be associated with carbonic anhydrase inhibitors were listed for the cox-2 inhibitors. We also examined rofecoxib, even though it is not a carbonic anhydrase inhibitor. The addition of an adverse event to the Product Information section of the PDR represents the conclusion of a process of signal detection and evaluation. We report that the Laboratory Tests subsection listed under Precautions in the 2000 edition of the PDR states that, during controlled clinical trials, there was an increased incidence of hyperchloremia in patients receiving celecoxib compared with patients receiving placebo. Exposure time to the drug was probably less than 6 months. Other laboratory abnormalities that occurred more frequently in patients exposed to celecoxib included hypophosphatemia and elevated blood urea nitrogen. There was no mention of serum bicarbonate values; nevertheless, a serum bicarbonate value may be approximated. If the anion gap (when potassium is not included) is 6 to 13 mM (average 8 mM) and the serum sodium value is 140 mmol/L, then an abnormally elevated serum chloride value of 114 mmol/L would correspond to a bicarbonate value of 18 mmol/L (the common reference value for venous plasma or serum is 22-30 mmol/L). Some patients treated with celecoxib (duration unknown) were reported to have peak serum chloride values at last visit of 115 mmol/L and higher. There was a trend toward patients having abnormalities in both serum chloride and phosphate levels. Therefore, we deduced that hyperchloremic, nonanion gap metabolic acidosis may in some patients be associated with exposure to celecoxib. In fact, it is known that certain patients given cox-2 inhibitors over prolonged periods develop a form of low renin-angiotensin activity characterized by a modest hyperkalemia and a mild metabolic acidosis. The laboratory findings of hyperchloremia and hypophosphatemia were not listed in the PDR in the years following 2002. Renal calculus, another side effect associated with carbonic anhydrase inhibition, was mentioned for celecoxib in the Adverse Reactions section of the PDRs in all years. The Product Information sections for valdecoxib (PDR 2002-2005 editions) and rofecoxib (PDR 2000-2005

The American Journal of Medicine, Vol 119, No 1, January 2006 editions) do not mention dysfunction of renal acidification such as metabolic acidosis, hyperchloremia, hypophosphatemia, and defective bicarbonate reclamation. Renal calculus and urolithiasis were, however, reported in the Adverse Reactions sections of PDRs for valdecoxib and rofecoxib, respectively. Our results have implications in several areas of interest, not the least of which are the apparent multifaceted mechanisms of action of celecoxib. Based on our findings, the cox-2 inhibitor celecoxib, unlike rofecoxib, has another mechanism of action, that of inhibiting carbonic anhydrase II. Acute exposure to celecoxib initially may, in a fashion analogous to that of acetazolamide, induce a mild diuresis, unlike rofecoxib, which only inhibits prostaglandin synthesis. However, this sparing effect of the diuresis is selflimited. The continued exposure to celecoxib not only exposes a patient to the structure-adverse events of cox-2 inhibition, that of blocking endothelial prostacyclin production and the theoretical arterial thrombosis, but also to the structure-adverse events associated with the pharmacophore ⫺SO2NH2 and carbonic anhydrase inhibition. James F. Knudsen, MS, PhD, MD New Hope Cancer Center Hudson, Fla

Gerald H. Sokol, MS, MD H. Lee Moffitt Cancer Center at the University of South Florida College of Medicine Tampa, Fla

doi:10.1016/j.amjmed.2005.06.069

References 1. Alpert JS. The Vioxx debacle. Am J Med. 2005;118:203. 2. Knudsen J, Sokol GH, Cantilena LR. Structure-activity relationship as predictors of adverse drug events (ADEs). Clin Pharmacol Ther. 2003; 73:39-40. 3. Knudsen JF, Carlsson U, Hammarström P, Sokol GH, Cantilena LR. Cox-2 inhibitors and carbonic anhydrase activity [abstract]. Clin Pharmacol Ther. 2004;75:44. 4. Weber A, Casini A, Heine A, et al. Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition. J Med Chem. 2004;47:550-557. 5. Physician’s Desk Reference. Montvale, NJ: Thomson PDR.

Mechanical Ventilation Learns New Tricks To the Editor: The rapidly evolving field of noninvasive positive pressure ventilation (NPPV) makes necessary the inclusion of two additional studies in the excellent review by Calfee and Matthay on advances of mechanical ventilation.1 First, Diaz et al performed a prospective, open, noncontrolled study to assess the outcomes of NPPV therapy in patients with a Glasgow Coma Scale score of ⬍8 due to acute respiratory failure and found that a response rate of 80% (76/95) to NPPV therapy compared with a response