Supplement Editor:
Marc C. Hochberg, MD, MPH

Contents

Preface and Foreword
Marc C. Hochberg, MD, MPH

Development and clinical application of COX-2–selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis
Clifton G. Bingham III, MD

Cyclooxygenase-2–selective inhibitors: Translating pharmacology into clinical utility
Bruce N. Cronstein, MD

COX-2–selective inhibitors in the treatment of arthritis
Thomas J. Schnitzer, MD, PhD, and Marc C. Hochberg, MD, MPH

Gastrointestinal safety and tolerability of non-selective nonsteroidal anti-inflammatory agents and cyclooxygenase-2–selective inhibitors
David A. Peura, MD

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors
James M. Scheiman, MD

Current perspective on the cardiovascular effects of coxibs
Marvin A. Konstam, MD, and Matthew R. Weir, MD

Renal effects of nonselective NSAIDs and coxibs
Matthew R. Weir, MD

Developing an economic rationale for the use of selective COX-2 inhibitors for patients at risk for NSAID gastropathy
A. Mark Fendrick, MD

Cyclooxygenase-2–selective inhibitors in the management of acute and perioperative pain
Warren A. Katz, MD

Emerging options with coxib therapy
Mark J. Lema, MD, PhD

Supplement Editor:
Marc C. Hochberg, MD, MPH

Contents

Preface and Foreword
Marc C. Hochberg, MD, MPH

Development and clinical application of COX-2–selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis
Clifton G. Bingham III, MD

Cyclooxygenase-2–selective inhibitors: Translating pharmacology into clinical utility
Bruce N. Cronstein, MD

COX-2–selective inhibitors in the treatment of arthritis
Thomas J. Schnitzer, MD, PhD, and Marc C. Hochberg, MD, MPH

Gastrointestinal safety and tolerability of non-selective nonsteroidal anti-inflammatory agents and cyclooxygenase-2–selective inhibitors
David A. Peura, MD

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors
James M. Scheiman, MD

Current perspective on the cardiovascular effects of coxibs
Marvin A. Konstam, MD, and Matthew R. Weir, MD

Renal effects of nonselective NSAIDs and coxibs
Matthew R. Weir, MD

Developing an economic rationale for the use of selective COX-2 inhibitors for patients at risk for NSAID gastropathy
A. Mark Fendrick, MD

Cyclooxygenase-2–selective inhibitors in the management of acute and perioperative pain
Warren A. Katz, MD

Emerging options with coxib therapy
Mark J. Lema, MD, PhD

Supplement Editor:
Marc C. Hochberg, MD, MPH

Contents

Preface and Foreword
Marc C. Hochberg, MD, MPH

Development and clinical application of COX-2–selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis
Clifton G. Bingham III, MD

Cyclooxygenase-2–selective inhibitors: Translating pharmacology into clinical utility
Bruce N. Cronstein, MD

COX-2–selective inhibitors in the treatment of arthritis
Thomas J. Schnitzer, MD, PhD, and Marc C. Hochberg, MD, MPH

Gastrointestinal safety and tolerability of non-selective nonsteroidal anti-inflammatory agents and cyclooxygenase-2–selective inhibitors
David A. Peura, MD

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors
James M. Scheiman, MD

Current perspective on the cardiovascular effects of coxibs
Marvin A. Konstam, MD, and Matthew R. Weir, MD

Renal effects of nonselective NSAIDs and coxibs
Matthew R. Weir, MD

Developing an economic rationale for the use of selective COX-2 inhibitors for patients at risk for NSAID gastropathy
A. Mark Fendrick, MD

Cyclooxygenase-2–selective inhibitors in the management of acute and perioperative pain
Warren A. Katz, MD

Emerging options with coxib therapy
Mark J. Lema, MD, PhD

ABSTRACT

BACKGROUND: About 10% of people in the United States develop at least 1 symptomatic kidney stone during their lives. The recurrence rate after 10 years is at least 50%. Many physicians recommend a low-calcium diet in patients with calcium oxalate stones to prevent recurrence. Recent studies suggest that a low-calcium diet may not be effective and that intake of animal protein and salt may influence renal calcium excretion. This study compares the traditional low-calcium diet with a diet that is low in animal protein and salt.

POPULATION STUDIED: This study enrolled 120 men with idiopathic hypercalciuria (urinary calcium excretion of more than 300 mg per day on an unrestricted diet) who had been referred to a nephrology clinic in Parma, Italy, and who had had at least 2 episodes of symptomatic renal stones. Reasons for exclusion included previous visits to any “stone disease center” and conditions associated with calcium stones, such as hyperparathyroidism or inflammatory bowel disease.

STUDY DESIGN AND VALIDITY: The investigators randomly assigned subjects, using concealed allocation, to 1 of 2 diets in this randomized controlled study. The low-calcium diet limited calcium intake to about 400 mg per day. The other diet, which included about 1200 mg per day of calcium, limited sodium chloride to about 3000 mg and animal protein to 93 g (15% of total calories). Both groups were advised to limit intake of high-oxalate foods and encouraged to drink 2 liters of water per day in cold weather and 3 liters in warm weather. Subjects were allowed moderate consumption of beer, wine, coffee, and sodas. (Detailed dietary instructions are available to New England Journal of Medicine subscribers in the supplement to the publication at www.nejm.org.) The study followed the patients for 5 years or until they developed clinical or radiologic evidence of a renal stone. Annual x-ray and ultrasound studies identified asymptomatic stone recurrences.

OUTCOMES MEASURED: The primary outcome was the time to development of the first recurrence of a renal stone, whether or not it was clinically evident. Other outcomes included changes in calcium and oxalate excretion and calcium oxalate saturation in the urine.

RESULTS: After 5 years, the low-protein, low-sodium diet led to fewer recurrences (20% compared with 38% in the low-calcium group, relative risk 0.49, number needed to treat with diet for 5 years = 5.5). The risk of recurrence in the low-calcium group was similar to the 35% to 40% expected in the absence of any intervention. The disease-oriented changes in urine characteristics were predictable: urinary calcium decreased in both groups, but oxalate secretion increased in the low-calcium group, causing greater calcium oxalate saturation.

ABSTRACT

BACKGROUND: About 10% of people in the United States develop at least 1 symptomatic kidney stone during their lives. The recurrence rate after 10 years is at least 50%. Many physicians recommend a low-calcium diet in patients with calcium oxalate stones to prevent recurrence. Recent studies suggest that a low-calcium diet may not be effective and that intake of animal protein and salt may influence renal calcium excretion. This study compares the traditional low-calcium diet with a diet that is low in animal protein and salt.

POPULATION STUDIED: This study enrolled 120 men with idiopathic hypercalciuria (urinary calcium excretion of more than 300 mg per day on an unrestricted diet) who had been referred to a nephrology clinic in Parma, Italy, and who had had at least 2 episodes of symptomatic renal stones. Reasons for exclusion included previous visits to any “stone disease center” and conditions associated with calcium stones, such as hyperparathyroidism or inflammatory bowel disease.

STUDY DESIGN AND VALIDITY: The investigators randomly assigned subjects, using concealed allocation, to 1 of 2 diets in this randomized controlled study. The low-calcium diet limited calcium intake to about 400 mg per day. The other diet, which included about 1200 mg per day of calcium, limited sodium chloride to about 3000 mg and animal protein to 93 g (15% of total calories). Both groups were advised to limit intake of high-oxalate foods and encouraged to drink 2 liters of water per day in cold weather and 3 liters in warm weather. Subjects were allowed moderate consumption of beer, wine, coffee, and sodas. (Detailed dietary instructions are available to New England Journal of Medicine subscribers in the supplement to the publication at www.nejm.org.) The study followed the patients for 5 years or until they developed clinical or radiologic evidence of a renal stone. Annual x-ray and ultrasound studies identified asymptomatic stone recurrences.

OUTCOMES MEASURED: The primary outcome was the time to development of the first recurrence of a renal stone, whether or not it was clinically evident. Other outcomes included changes in calcium and oxalate excretion and calcium oxalate saturation in the urine.

RESULTS: After 5 years, the low-protein, low-sodium diet led to fewer recurrences (20% compared with 38% in the low-calcium group, relative risk 0.49, number needed to treat with diet for 5 years = 5.5). The risk of recurrence in the low-calcium group was similar to the 35% to 40% expected in the absence of any intervention. The disease-oriented changes in urine characteristics were predictable: urinary calcium decreased in both groups, but oxalate secretion increased in the low-calcium group, causing greater calcium oxalate saturation.

ABSTRACT

BACKGROUND: About 10% of people in the United States develop at least 1 symptomatic kidney stone during their lives. The recurrence rate after 10 years is at least 50%. Many physicians recommend a low-calcium diet in patients with calcium oxalate stones to prevent recurrence. Recent studies suggest that a low-calcium diet may not be effective and that intake of animal protein and salt may influence renal calcium excretion. This study compares the traditional low-calcium diet with a diet that is low in animal protein and salt.

POPULATION STUDIED: This study enrolled 120 men with idiopathic hypercalciuria (urinary calcium excretion of more than 300 mg per day on an unrestricted diet) who had been referred to a nephrology clinic in Parma, Italy, and who had had at least 2 episodes of symptomatic renal stones. Reasons for exclusion included previous visits to any “stone disease center” and conditions associated with calcium stones, such as hyperparathyroidism or inflammatory bowel disease.

STUDY DESIGN AND VALIDITY: The investigators randomly assigned subjects, using concealed allocation, to 1 of 2 diets in this randomized controlled study. The low-calcium diet limited calcium intake to about 400 mg per day. The other diet, which included about 1200 mg per day of calcium, limited sodium chloride to about 3000 mg and animal protein to 93 g (15% of total calories). Both groups were advised to limit intake of high-oxalate foods and encouraged to drink 2 liters of water per day in cold weather and 3 liters in warm weather. Subjects were allowed moderate consumption of beer, wine, coffee, and sodas. (Detailed dietary instructions are available to New England Journal of Medicine subscribers in the supplement to the publication at www.nejm.org.) The study followed the patients for 5 years or until they developed clinical or radiologic evidence of a renal stone. Annual x-ray and ultrasound studies identified asymptomatic stone recurrences.

OUTCOMES MEASURED: The primary outcome was the time to development of the first recurrence of a renal stone, whether or not it was clinically evident. Other outcomes included changes in calcium and oxalate excretion and calcium oxalate saturation in the urine.

RESULTS: After 5 years, the low-protein, low-sodium diet led to fewer recurrences (20% compared with 38% in the low-calcium group, relative risk 0.49, number needed to treat with diet for 5 years = 5.5). The risk of recurrence in the low-calcium group was similar to the 35% to 40% expected in the absence of any intervention. The disease-oriented changes in urine characteristics were predictable: urinary calcium decreased in both groups, but oxalate secretion increased in the low-calcium group, causing greater calcium oxalate saturation.

Making a quick diagnosis in a hyperactive, inattentive child is often difficult. The National Institutes of Health concluded in a consensus statement that no independent diagnostic test for attention-deficit/hyperactivity disorder (ADHD) exists.¹ Furthermore, the American Academy of Child & Adolescent Psychiatry (AACAP) issued a treatment guideline classifying ADHD as a clinical diagnosis.

With the time constraints imposed by managed care organizations, questioning and history gathering must be precisely aimed to elicit specific information. Over the years, I have identified the following 5 red flags that help distinguish ADHD from mood problems,² anxiety, psychosis, obsessions, and other psychiatric disorders.

1. Moodiness is not part of ADHD. The DSM-IV criteria for ADHD do not include elevated mood. “Mood swings,” persistent clowning, or angry affect should prompt further questioning about similar features in relatives. Frequently we hear that “his father was never diagnosed with anything, but he was the class clown.”
2. ADHD is not an intermittent condition. By asking if the child has “good days and bad days,” we can obtain valuable information. ADHD has a biological basis and is present every day, like Parkinson’s disease or diabetes. Obviously, some days can be more challenging than others, but if a parent says, “Some days she is a perfect child,” the possibility of ADHD is small.
3. Symptoms are not present in kindergarten. The child with ADHD begins to show signs of this condition very early in life; parents are frequently informed of problems by preschool and kindergarten teachers. The usual complaints are inability to stay with a task and disrupting the class. Start of these symptoms as late as first or second grade is a red flag to question the ADHD diagnosis.
4. More than one diagnosis probably means “none of the above.” When a child has been diagnosed with conduct disorder (CD) and/or oppositional-defiant disorder (ODD) along with ADHD, chances are that we are missing the real diagnosis. I have seen cases of social anxiety disorder that had been diagnosed as ADHD/ODD because the child was inattentive secondary to nervousness. Incidentally, DSM-IV does not allow the diagnosis of ODD in the presence of CD.
5. Worsening of symptoms is not an expected outcome of stimulant medications for ADHD. Lack of response to psychostimulants or only mild improvement may occur in ADHD. Frequently, however, we see children with histories of getting worse after starting medication for presumed ADHD.

Making a quick diagnosis in a hyperactive, inattentive child is often difficult. The National Institutes of Health concluded in a consensus statement that no independent diagnostic test for attention-deficit/hyperactivity disorder (ADHD) exists.¹ Furthermore, the American Academy of Child & Adolescent Psychiatry (AACAP) issued a treatment guideline classifying ADHD as a clinical diagnosis.

With the time constraints imposed by managed care organizations, questioning and history gathering must be precisely aimed to elicit specific information. Over the years, I have identified the following 5 red flags that help distinguish ADHD from mood problems,² anxiety, psychosis, obsessions, and other psychiatric disorders.

1. Moodiness is not part of ADHD. The DSM-IV criteria for ADHD do not include elevated mood. “Mood swings,” persistent clowning, or angry affect should prompt further questioning about similar features in relatives. Frequently we hear that “his father was never diagnosed with anything, but he was the class clown.”
2. ADHD is not an intermittent condition. By asking if the child has “good days and bad days,” we can obtain valuable information. ADHD has a biological basis and is present every day, like Parkinson’s disease or diabetes. Obviously, some days can be more challenging than others, but if a parent says, “Some days she is a perfect child,” the possibility of ADHD is small.
3. Symptoms are not present in kindergarten. The child with ADHD begins to show signs of this condition very early in life; parents are frequently informed of problems by preschool and kindergarten teachers. The usual complaints are inability to stay with a task and disrupting the class. Start of these symptoms as late as first or second grade is a red flag to question the ADHD diagnosis.
4. More than one diagnosis probably means “none of the above.” When a child has been diagnosed with conduct disorder (CD) and/or oppositional-defiant disorder (ODD) along with ADHD, chances are that we are missing the real diagnosis. I have seen cases of social anxiety disorder that had been diagnosed as ADHD/ODD because the child was inattentive secondary to nervousness. Incidentally, DSM-IV does not allow the diagnosis of ODD in the presence of CD.
5. Worsening of symptoms is not an expected outcome of stimulant medications for ADHD. Lack of response to psychostimulants or only mild improvement may occur in ADHD. Frequently, however, we see children with histories of getting worse after starting medication for presumed ADHD.

Making a quick diagnosis in a hyperactive, inattentive child is often difficult. The National Institutes of Health concluded in a consensus statement that no independent diagnostic test for attention-deficit/hyperactivity disorder (ADHD) exists.¹ Furthermore, the American Academy of Child & Adolescent Psychiatry (AACAP) issued a treatment guideline classifying ADHD as a clinical diagnosis.

With the time constraints imposed by managed care organizations, questioning and history gathering must be precisely aimed to elicit specific information. Over the years, I have identified the following 5 red flags that help distinguish ADHD from mood problems,² anxiety, psychosis, obsessions, and other psychiatric disorders.

1. Moodiness is not part of ADHD. The DSM-IV criteria for ADHD do not include elevated mood. “Mood swings,” persistent clowning, or angry affect should prompt further questioning about similar features in relatives. Frequently we hear that “his father was never diagnosed with anything, but he was the class clown.”
2. ADHD is not an intermittent condition. By asking if the child has “good days and bad days,” we can obtain valuable information. ADHD has a biological basis and is present every day, like Parkinson’s disease or diabetes. Obviously, some days can be more challenging than others, but if a parent says, “Some days she is a perfect child,” the possibility of ADHD is small.
3. Symptoms are not present in kindergarten. The child with ADHD begins to show signs of this condition very early in life; parents are frequently informed of problems by preschool and kindergarten teachers. The usual complaints are inability to stay with a task and disrupting the class. Start of these symptoms as late as first or second grade is a red flag to question the ADHD diagnosis.
4. More than one diagnosis probably means “none of the above.” When a child has been diagnosed with conduct disorder (CD) and/or oppositional-defiant disorder (ODD) along with ADHD, chances are that we are missing the real diagnosis. I have seen cases of social anxiety disorder that had been diagnosed as ADHD/ODD because the child was inattentive secondary to nervousness. Incidentally, DSM-IV does not allow the diagnosis of ODD in the presence of CD.
5. Worsening of symptoms is not an expected outcome of stimulant medications for ADHD. Lack of response to psychostimulants or only mild improvement may occur in ADHD. Frequently, however, we see children with histories of getting worse after starting medication for presumed ADHD.