Corticosteroids or NSAIDs in Managing Acute Respiratory Infections: Valuable Differences

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O(2)(·-)) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled ((99m)Tc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy.

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

Tube digestif et traitements anti-inflammatoires (AINS, corticoïdes)

The term acute kidney injury has replaced acute renal failure and represents a spectrum of clinically meaningful kidney damage.After completing this article, readers should be able to:Acute kidney injury (AKI), formerly called acute renal failure, is characterized by multiple abnormalities, including increases in serum creatinine and blood urea nitrogen, electrolyte abnormalities, acidosis, and difficulties with fluid management. We have come to realize that what was previously thought to be relatively minor damage to the kidney can have significant short-term effects on morbidity and mortality and potential long-term implications for the development of chronic kidney disease. Thus, the term acute kidney injury has replaced acute renal failure, suggesting the spectrum of kidney damage that can occur.AKI is classically defined as an acute decrease in glomerular filtration rate, which results in an increase in serum creatinine. It is important to recognize the limitations of creatinine as a marker of AKI because an increase in creatinine can be delayed by as much as 48 hours after damage to the kidney has occurred. Despite this limitation, change in creatinine remains the gold standard for the diagnosis of AKI. An evolution in the definition of AKI to better understand, characterize, and study the disease spectrum, has occurred, which has sought to capture the clinical importance of even small variations in kidney function. In addition, previous definitions used in the literature were widely disparate; this lack of standardization made the understanding of AKI challenging. These circumstances have led to the development of 2 systems to define pediatric AKI that rely on changes in creatinine, estimated creatinine clearance, or urine output. The first of these definitions is the pediatric Risk, Injury, Failure, Loss, and End-stage (RIFLE) criteria, (1) which are modified from similar adult criteria. (2) The second is the Acute Kidney Injury Network (AKIN) definition, which relies on an increase in creatinine from a previous trough level. (3) The Kidney Disease: Improving Global Outcomes (KDIGO) consortium has put forth modifications to reconcile subtle differences in the adult AKIN and RIFLE criteria. (4) KDIGO is an international initiative composed of experts who, based on systematic review of evidence, develop and standardize clinical practice guidelines for children and adults with a variety of kidney diseases (including AKI). At this time, in practice and research, the pediatric RIFLE and modified AKIN criteria are most frequently used to define AKI in children (Table 1).A basic knowledge of renal development and normal renal physiology is necessary to better understand the pathophysiologic mechanisms of AKI. The kidney is immature at birth and continues to develop early in life. Term neonates are born with a full complement of nephrons but have only approximately 25% of their adult glomerular filtration rates. The renal function of a healthy child progressively increases, reaching a mature glomerular filtration rate by age 2 years. Neonates have immature compensatory mechanisms to handle changes in renal blood flow and are not able to fully concentrate their urine.Renal blood flow helps to drive a number of physiologic processes, including glomerular filtration, oxygen delivery to the kidneys, and solute or water reabsorption. Renal blood flow is under intricate control by a combination of hormones and reflex mechanisms. The afferent and efferent arterioles control renal blood flow to and from the glomerulus, respectively. The stretch of these arterioles (myogenic feedback) and delivery of sodium chloride sensed by the juxtaglomerular apparatus (tubuloglomerular feedback) drive a number of local and systemic hormone responses to low renal blood flow. In decreased renal perfusion, afferent arteriolar vasodilation occurs in response to prostaglandins (progtaglandins E and I), nitric oxide, and bradykinins to maintain glomerular filtration and renal blood flow. At the same time, the efferent arteriole is reflexively constricted by sympathetic nerve activation, endothelin, and activation of the renin-angiotensin system, leading to the production of angiotensin II. These mechanisms work in concert to maintain glomerular filtration and renal blood flow. Disease states and certain medical interventions may interfere with these mechanisms, leading to negative effects on glomerular filtration. Further, some of these compensatory mechanisms, when stressed beyond normal parameters, may themselves lead to diminished urinary output and clinical findings one would associate with AKI.With decreased renal perfusion, a number of these compensatory mechanisms also drive sodium and water reabsorption to increase extracellular volume. Increased activity of the renin-angiotensin system and production of angiotensin II (active in the proximal tubule) leads to increased secretion of aldosterone (active in the distal tubule), resulting in increased sodium reabsorption. Increased sympathetic nerve activity also drives sodium reabsorption. The reabsorption of urea and water is driven by antidiuretic hormone. The activity of these reflex mechanisms explains a number of the changes in urine electrolyte concentrations and clinical findings that help to differentiate the causes of AKI. The immaturity of these mechanisms in the neonate also explains why the diagnosis and evaluation of the cause of AKI in the neonate differs from that in older children.The epidemiology of AKI has evolved over the years and reflects the patient population under study. In developing countries the most common causes of AKI continue to be volume depletion, infection, and primary renal diseases (hemolytic uremic syndrome, glomerulonephritis). In developed countries, volume depletion and primary renal disease remain common causes of AKI in previously healthy children. In hospitalized children in developed countries, particularly in tertiary care centers, there has been a shift in the etiology of AKI from primary renal disease to secondary causes of AKI that are often multifactorial in nature and often complicate another diagnosis or its treatment (eg, heart disease, sepsis, and nephrotoxic drug exposure). (5) Despite this shift in epidemiology, an ordered approach to the diagnosis of AKI divides the potential origins into prerenal, intrinsic, and postrenal causes.Prerenal AKI results from a decrease in renal blood flow, leading to hypoperfusion (Table 2). The underlying pathophysiologic states may be due to a decrease in effective circulating volume, loss of vascular tone, or decreased cardiac output or blood delivery to the kidneys. Renal losses, gastrointestinal tract losses, or hemorrhage can lead to direct reduction in volume and decreased renal perfusion. Alternatively, a redistribution of fluid may occur from either reduced oncotic pressure within the blood (low albumin from liver disease, nephrotic syndrome, or protein losing enteropathy) or increased leak from vessels (systemic inflammatory response syndrome or sepsis), leading to suboptimal renal perfusion. Systemic vasodilation or poor vascular tone complicates a number of illnesses in critically ill children and may result in hypoperfusion of the kidneys. Finally, there may be a decrease in the delivery of blood to the kidneys because of an overall decrease in cardiac output (underlying heart disease or myocarditis) or increased resistance to flow (abdominal compartment syndrome or renal artery stenosis). In practice, previously healthy children frequently present with a decreased effective circulating volume from a single cause, whereas chronically ill or hospitalized children may have multifactorial processes.As noted above, low renal blood flow stimulates compensatory mechanisms, including increased sympathetic tone, activation of the renin-angiotensin system, release of antidiuretic hormone, and local paracrine activities (prostaglandin release). In the prerenal state, the afferent arterioles vasodilate in response to the local effects of prostaglandins in an effort to maintain renal blood flow and glomerular filtration. Consequently, nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, in volume-depleted children may worsen AKI by preventing this compensatory afferent arteriolar vasodilation. At the same time, angiotensin II causes efferent arteriolar constriction. Interruption of this compensatory mechanism by angiotensin-converting enzyme (ACE) inhibitors predisposes patients to prerenal AKI. The effects of renin-angiotensin system activation and antidiuretic hormone release result in increased sodium and urea reabsorption, respectively. The reabsorption of sodium, urea, and water leads to oliguria and the characteristic urine findings in prerenal AKI (Table 3).Neonates are a special group when considering prerenal AKI. Neonates have increased insensible losses because of a high body surface area to mass ratio, which can be exacerbated by the use of radiant warmers for critically ill newborns. Neonates are further at risk for prerenal AKI due to immature compensatory mechanisms, including poor urine concentrating abilities. This inability to concentrate urine explains why AKI in neonates is often nonoliguric, making its recognition more difficult.Patients with sickle cell disease are predisposed to prerenal AKI because of a number of pathophysiologic mechanisms inherent to the disease that may affect the kidney. The renal medulla represents an area of the kidney at risk in sickle cell disease because of a low oxygen concentration and high tonicity; this predisposes patients to sickling. Repeated episodes of sickling in the renal medulla result in vascular congestion and the loss of vasa recta of the juxtaglomerular nephrons, which can lead to chronic interstitial fibrosis and urine concentrating defects. In early childhood, the urinary concentrating defects frequently are reversible with treatment of the sickle cell disease but can progress to chronic concentrating defects over time.Intrinsic AKI refers to direct renal parenchymal damage or dysfunction. Categories include AKI associated with tubular, interstitial, glomerular, or vascular damage and nephrotoxin exposure (Table 4).The most common cause of intrinsic AKI in tertiary care centers is transformation of prerenal AKI to acute tubular necrosis (ATN) after prolonged hypoperfusion. The areas of the kidney that are most susceptible to damage with prolonged renal hypoperfusion include the third segment of the proximal tubule (high energy requirement) and the region of the thick ascending limb of the loop of Henle located within the medulla (low oxygen tension in the medulla). The damage seen from prolonged hypoperfusion can range from mild tubular injury to cell death. As cellular necrosis occurs, debris may build up in the tubules and further block tubular flow. Tubular dysfunction, a frequent hallmark of ATN, will not be evident during periods of oliguria but may become apparent during the recovery phase.In previously healthy children, glomerular and vascular causes of intrinsic AKI are more common. Where there is concern for glomerulonephritis, the clinical presentation and timing often suggest the origin, including isolated glomerulonephritides (eg, postinfectious glomerulonephritis) and multisystem immune complex–mediated processes that involve the kidney (eg, systemic lupus erythematosus). Vascular causes of intrinsic AKI include microangiopathic processes (hemolytic uremic syndrome and thrombotic thrombocytopenic purpura) and systemic vasculitides that involve larger vessels.Acute interstitial nephritis occurs after exposure to an offending agent, such as certain medications, including antibiotics, proton pump inhibitors, NSAIDs, and diuretics. Signs and symptoms may develop 3 to 5 days after a second exposure to as long as weeks to months after an initial exposure. Drugs can cause AKI in ways other than acute interstitial nephritis. Nephrotoxin exposure is an increasingly common cause of intrinsic AKI, particularly in hospitalized patients. As previously mentioned, drugs such as NSAIDs and ACE inhibitors can contribute to AKI by inhibiting renal vascular autoregulation. Other common drugs implicated in AKI include aminoglycosides, amphotericin, chemotherapeutic agents (cisplatin, ifosfamide, and methotrexate), and calcineurin inhibitors (cyclosporine and tacrolimus). Radiocontrast agents are a significant cause of nephrotoxin-related AKI; newer iso-osmolar agents are somewhat less nephrotoxic, but the risk remains. In instances of massive hemolysis or rhabdomyolysis, endogenous elements, such as myoglobin and hemoglobin, can obstruct tubules and/or cause direct toxic effects to the kidney.Postrenal AKI results from obstructive processes that block urine flow. Acquired causes of urinary tract obstruction include those that result from local mass effect (bilateral ureteral obstruction by a tumor), renal calculi, or clots within the bladder.An important developing paradigm in the study and treatment of AKI is the idea of renal angina, a term used to describe a high-risk state that occurs before AKI. (6) Earlier recognition of a prerenal state defines a period before significant parenchymal damage (eg, the development of ATN) where AKI can be reversed. Furthermore, patients who are identified as being at risk may have nephrotoxic medications held or dosages adjusted to potentially prevent the development of intrinsic AKI. Research using renal angina scoring systems is an active area that aims to identify patients at risk for AKI. Concurrently, investigation is under way to study novel biomarkers (urine neutrophil gelatinase–associated lipocalin and urine kidney injury molecule 1) that will allow for the earlier identification of kidney injury in critically ill children (often up to 48 hours before an increase in creatinine) to allow prevention and potentially earlier intervention.A detailed history and physical examination are invaluable for children who develop AKI. Quantifying the urine output during the previous several days may provide insight to the cause and severity of the episode of AKI and serves to categorize the event as oliguric (defined as urine output <1 mL/kg/h) or nonoliguric. Systematic evaluation of potential prerenal, intrinsic, and postrenal causes is key to diagnosing the origin of AKI. Frequently, the history will provide insight into causes or risk factors for prerenal AKI, including decreased circulatory volume (gastroenteritis and hemorrhage), redistribution of circulatory volume (edematous states, nephrotic syndrome, and sepsis), decreased cardiac output (heart disease), or increased resistance to blood flow (abdominal compartment syndrome and renal artery stenosis). In previously healthy children, the history and physical examination may offer clues (Table 4) to the underlying intrinsic renal origin, including volume depletion, recent viral illness or sore throat (possibly consistent with acute glomerulonephritis), rashes, swollen joints (suggesting systemic disorders such as lupus), hematuria, or medication exposures. In newborns with a suspected obstruction, a good prenatal history is important. For example, abnormalities on fetal ultrasonogram, including enlarged bladder, hydronephrosis, or decreased amniotic fluid, may suggest posterior urethral valves in a male infant. When evaluating AKI, it is important to remember that an increase in creatinine typically occurs up to 48 hours after renal injury and may reflect events that occurred 2 to 3 days earlier. Therefore, it is important to review episodes of hypotension, hypoxia, sepsis, surgery, contrast exposures, and drug exposures that occur 48 to 72 hours before the episode of AKI becomes apparent.As part of the initial evaluation for AKI, patients should have the following tests performed: basic electrolyte panel, serum creatinine measurement, urinalysis, urine sodium measurement, urine urea measurement, urine creatine measurement, urinalysis, and a renal ultrasound study. Frequently, urine studies will allow differentiation between prerenal AKI and intrinsic AKI (eg, ATN). Typical laboratory findings for prerenal AKI include a normal urinalysis result, concentrated urine (osmolality >500 mOsm/kg [>500 mmol/kg]), fractional excretion of sodium (FENa) less than 1% (<2% in neonates), fractional excretion of urea (FEurea) less than 35%, urine sodium less than 20 mEq/L (<20 mmol/L), and urea nitrogen to creatinine ratio greater than 20 (Table 3). A loss of urine concentrating ability is classically seen in ATN and results in the characteristic urine studies that differentiate it from prerenal AKI (Table 3). Urinalysis with accompanying urine microscopy can be illuminating and point toward particular diagnostic categories. Muddy granular casts on microscopy suggest ATN; red blood cell casts suggest glomerulonephritis. A urinalysis positive for blood on dipstick evaluation without evidence of red blood cells on microscopy should raise concerns for hemoglobinuria (hemolysis) or myoglobinuria (rhabdomyolysis).The presence of hematuria, proteinuria, and/or red blood cell casts in the right clinical scenario should raise concern for possible glomerulonephritis. In the context of a recent upper respiratory tract infection, one should consider the diagnosis of postinfectious glomerulonephritis (classically with pharyngitis 2-3 weeks earlier or skin infections 4-6 weeks earlier) and should evaluate serum complements (low C3 and normal C4). In patients with a more recent upper respiratory tract infection (2-3 days) with gross hematuria on urinalysis, one must consider IgA nephropathy (normal complement levels). A urinalysis consistent with glomerulonephritis in the context of the appropriate systemic symptoms (eg, rash and arthritis) may point toward systemic lupus erythematosus (low C3 and low C4) and may warrant further antibody testing (antinuclear and anti–double-stranded DNA antibodies). If there is involvement of the pulmonary system (cough, infiltrate on radiographs, and hemoptysis) and evidence of active glomerulonephritis, the pulmonary renal syndromes should be considered. These syndromes include granulomatosis with polyangiitis (formerly Wegener granulomatosis and cytoplasmic antineutrophil cytoplasmic antibody [ANCA]), microscopic polyangiitis (perinuclear ANCA), eosinophilic granulomatosis (formerly and ANCA), and syndrome A more detailed of glomerulonephritides is beyond the of this In the of a clinical and laboratory presentation of postinfectious glomerulonephritis, a renal is not but to the diagnosis and treatment of the a is of the glomerulonephritides is of glomerulonephritis, which is defined by blood urea nitrogen and creatine In this a renal and treatment are because renal injury may develop without for interstitial nephritis of and is not often seen in the and is in less than of patients. This is due to a change over in the most common offending In patients with suspected interstitial there is frequently urine that not have red blood cell casts but may have blood cell casts The is urine this is not can be of interstitial nephritis is of nephrotic range A renal is necessary to the a patient has a recent history of low and with AKI, one should consider uremic In the appropriate a blood with is In recent years there has been an increase in the recognition of uremic syndrome by infections (eg, or or abnormalities in complement (eg, or a high of is and is a small in the diagnosis of intrinsic renal disease. Kidney by renal can provide the of the disease. kidneys point toward an acute that active that are particularly small for age may suggest a more chronic the kidneys will increased in the of AKI, which is a A evaluation of the renal is an important initial there are concerns of renal artery but the result of the evaluation is negative and concern of renal artery further studies should be in with a pediatric by renal to is the most important initial in the diagnosis of an obstructive and may provide clues to the of the For example, a more distal If an obstructive is one should the obstruction most important for children with AKI is In the and the this can be by children who are at risk for developing AKI. In it is important to and be of medications children may in the term or long term and ACE that increase the risk of AKI. In hospitalized it is also important to be of volume nephrotoxic medications, or nephrotoxic exposures. For patients at risk for developing AKI, it is important that the potentially nephrotoxic medications, and of medications such as and initial in the treatment of children who present with hypotension, or is to volume. An initial of should be necessary in the of that may be used for short-term volume include normal and red blood The of fluid on the clinical but normal is most This treatment should be to the In children with underlying or suspected cardiac disease, initial fluid may be as for this will appropriate the risk of volume which be in the of heart disease. the fluid is necessary for children to for of fluid or and response and urine fluid early of may be may be for a child who with fluid in adults evaluating low renal have at these low not increase or urine output or the of AKI. should be to renal with the of based on the clinical the patient has been fluid one may consider a of the patient remains The literature results for in patients with The literature the use of is and this medication may be associated with effects serum pulmonary and AKI). The use of to urine output is not children who remain oliguric after volume fluid may be In these children, one may fluid to insensible fluid losses with AKI are to a number of electrolyte including acidosis, and Typical sodium in healthy children are 2 to 3 but should be in children with AKI, with made based on frequent sodium should be to prevent and other of sodium and should be from in these patients to the of and will to be replaced as necessary because low of and can have implications in critically ill children. to maintain or fluid in AKI patients represents an for renal remains one of the most of AKI. The symptoms of are frequently including and even For this and of laboratory results in children with AKI are important. The most of is cardiac abnormalities and changes may be noted when are to mEq/L mmol/L), but there can be significant on the clinical In pathophysiologic states of increased release from cells syndrome and changes may occur at The that result in changes with the underlying pathophysiologic mechanisms, and associated electrolyte abnormalities The changes are first by Other changes may include and prolonged may lead to patients with greater than mEq/L mmol/L), one should an If are to mEq/L and the patient has an appropriate urine output without abnormalities on one may consider treatment with a that in the or a with to and the to a more normal If there are changes on a greater than mEq/L mmol/L), or a in a child with high cell states (eg, and should be as and treatment include which to the cardiac potential and the risk of but not This may be by the of sodium and/or with of which cause of and reduction of blood but these not from the may be there is an associated with the evaluating sodium in adults with have not but this has not been in children. sodium may be as part of treatment for it should not be the by as it is for such as can be This has been to by mEq/L and is but may to be in children with cardiac because is a common effect of with drives into cells by sodium and In with these should be made to from the including loop with fluid and sodium should be in neonates or children with underlying disease. If these renal should be seen in AKI is characterized by an which reflects an inability of the kidneys to or the of the treatment of use of should be for and with of with can lead to a of as are on for which can result in of a suboptimal glomerular filtration rate in the of AKI, can particularly with increased cell syndrome and In most can be by In patients with it is important to and because may occur as a result of to children with AKI drug may be evaluation of patient medication is to drug the kidney function to of most drugs will in episodes of AKI, of kidney function can lead to of the glomerular filtration clinical is should evaluate the of nephrotoxic medications on a consider and drug as able when nephrotoxic medications are When children renal medication must be adjusted further episodes of AKI, it is important to medication in a approach that pediatric and AKI is by a state, particularly in critically ill children. The protein in these children may be as high as 3 of with an accompanying of to that of healthy children and should not protein delivery as a to control blood urea nitrogen to protein one may a blood urea nitrogen of to If and be this may be an for renal is when to AKI have or are to be for renal include volume fluid acidosis, blood urea nitrogen or or an inability to provide in patients with renal dysfunction. In recent years the importance of volume in critically ill children has become and the of fluid at the of renal has been to be associated with increased of renal include and renal The of is a of patient and clinical is in critically ill children and relatively to but not provide the same rate of or ability to volume as other during 3 to hours better but is not as in critically ill children or children with fluid during a can be in these patients. has been a shift toward renal as the of in critically ill children. This for volume and control during include increased of fluid and ability to provide and remain for those patients who renal but are not critically literature has that critically ill children who are after an episode of AKI are at increased risk of chronic kidney disease in life. of these patients is important. The for these children is not In more of AKI that renal should be with In one may consider blood pressure and

Acute Kidney Injury

Reducing the Gastrointestinal Risks of Low-Dose Aspirin

Ankylosing spondylitis (AS) and related spondyloarthropathies (SpA) are relatively common (1) chronic inflammatory rheumatic diseases of uncertain etiopathogenesis (2), frequently involving the axial skeleton, including sacroiliac joints (3). The therapeutic options for the treatment of these diseases mostly involve physiotherapy and nonsteroidal, anti-inflammatory drugs (NSAIDs) as stated in recent overviews on the subject (4–9). The newer cyclooxygenase (COX)-2 selective inhibitors celecoxib and rofecoxib provide significant symptomatic benefit, and cause less gastric ulcers, but are no more effective than established NSAIDs (10). Up to 20% of AS patients are intolerant or show lack of adequate response to NSAIDs (11). Corticosteroids are effective when injected locally or intra-articularly (12), but oral dose, unlike in rheumatoid arthritis (RA), rarely provides systemic relief in AS, an interesting difference for which the underlying pathophysiologic basis is unclear.

When cyclooxygenase (COX)-2–selective inhibitors (coxibs) first entered the market about 5 years ago, the major concern with regard to cardiovascular side effects related to their potential to increase blood pressure and cause salt and water retention, in a manner similar to conventional (nonselective) nonsteroidal antiinflammatory drugs (NSAIDs). In the short time since, wariness about these side effects has grown into widespread alarm about putative prothrombotic actions and generation of excess major cardiovascular events with these agents. See p 1024 In September 2004, safety findings of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study indicated an increase in risk for myocardial infarction and stroke among subjects randomized to rofecoxib compared with those randomized to placebo. This study had been designed to examine recurrent colonic polyps rather than cardiovascular disease end points and therefore could only be considered hypothesis generating. Subsequent data from a number of observational studies further implicated the drug’s association with arterial thromboembolic disease. As with APPROVe, no single study generated sufficiently robust attestation by itself, but they provided concordant signals, and the accumulating evidence eventually reached a critical mass. As the data on rofecoxib emerged, concerns about other COX-2–selective agents on the market also grew. This was based on the assumption of a “class effect” for an increase in risk of cardiovascular disease related to preferential inhibition of prostacyclin over thromboxane and thus a tendency toward prothrombosis. The results presented by McAdam and colleagues in this issue of Circulation 1 challenge our view with regard to this prostanoid hypothesis and raise new questions about the mechanisms underlying the potential cardiovascular side effects of coxibs and traditional NSAIDs. The authors hypothesized that the enhanced systemic biosynthesis of prostacyclin in smokers was dependent on COX-2 activity. They also sought to determine the functional importance of COX2–derived prostacyclin (PGI2) in limiting platelet activation in smokers in vivo. Contrary to the conventional wisdom of an expected increase in the biosynthesis of TxA2 (related to increased platelet activation via COX-1), the authors demonstrated the opposite finding—ie, that COX-2 contributed to, and a COX-2 inhibitor reduced, TxA2 biosynthesis in smokers.

Objective To study the diagnostic value of capsule endoscopy for asymptomatic non–steroid antiinflammatory drugs(NSAID)–induced enteropathy. Methods A total of 110 health exam cases(38 cases taking NSAID orally)were recruited to the study and underwent capsule endoscopy. The incidence of small intestine lesion of NSAID takers and non–NSAID takers, that of those whose medication time longer than 3 months and less than 3 months, and who took low dose asprin and who took non–asprin NSAID were compared. The location of mucosal lesions and recovery status were followed up. Results The incidence of small intestine lesions was significantly different between NSAID group(55.3%, 21/38) and non–NSAID group(5.6%, 4/72)(P<0.01). The incidence of small intestine lesion was significantly higher in the over–three–month–medication group than in the less–than–three–month group(7/24 VS 4/14, P=0.01). The incidence of small intestine lesions was also significantly higher in the non–asprin group than asprin group(11/14 VS 10/24, P<0.05). The ulcerative lesions were predominantly located in the ileum(10/11), while the erosive lesions were predominantly found in the jejunum(8/10). Eight ulceration cases recovered after stopping taking NSAID or the use of rebamipide. Four erosion cases recovered after the use of rebamipide. Conclusion Capsule endoscopy is of favourable diagnostic and therapeutic value for asymptomatic NSAID–induced enteropathy. Key words: Small intestine; Non–steroid antiinflammatory drugs; Aspirin; Capsule endoscopy; Endoscopy

Background Information on the extent of high-risk prescribing for nonsteroidal anti-inflammatory drugs (NSAIDs) across developing countries is scarce. Objectives This study examines the prescribing pattern for NSAIDs in primary care, assesses the extent of high-risk NSAIDs prescribing and identifies associated factors. Setting 129 public and 416 private primary care clinics in Malaysia. Methods Data were derived from the National Medical Care Survey 2014, a cross-sectional survey on primary care morbidity patterns and clinical activities in Malaysia. Types of NSAIDs, indications for NSAIDs use and proportion of high-risk NSAIDs prescribing were assessed. Factors associated with high-risk NSAIDs prescribing were identified with a multivariable logistic regression. Weighted results, adjusted for sampling design and non-response were presented. Main outcome measures Prescribing pattern of NSAIDs, proportion of high-risk NSAIDs prescribing and its associated factors. Results Among the 55,489 patients who received NSAIDs, diclofenac was the most frequently prescribed NSAID (40.5%, 95% CI 40.1-40.9%), followed by mefenamic acid (29.2%, 95% CI 28.8-29.6%). The commonest indications for NSAIDs use were musculoskeletal condition and respiratory tract infection, both at 17.8% (95% CI 17.4-18.1%). A total of 22.9% (95% CI 22.6-23.3%) patients received high-risk NSAID prescriptions. Of these, 47.8% (95% CI 46.9-48.7%) did not receive adequate gastroprotection despite being at risk, 24.8% (95% CI 24.0-25.5%) were prescribed NSAIDs despite having cardiovascular comorbidities and 22.4% (95% CI 21.7-23.2%) were prescribed high-dose NSAIDs. The odds of receiving high-risk NSAID prescriptions increased with the number of drugs prescribed (OR 1.23, 95% CI 1.06-1.43) and the number of diagnoses in one visit (OR 2.21, 95% CI 1.71-2.86). The odds of being prescribed high-risk NSAID prescriptions were lower in patients with secondary (OR 0.52, 95% CI 0.35-0.77) and tertiary education (OR 0.39, 95% CI 0.22-0.68) compared to patients without formal education. Patients' citizenship, indication for NSAID prescriptions and whether a medical certificate was issued were also significantly associated with the likelihood of receiving high-risk NSAID prescriptions. Conclusions A quarter of NSAIDs prescribed in Malaysian primary care setting is categorised as high-risk prescribing. Targeted strategies are necessary to improve patient safety.

Commentary Heterotopic ossification (HO) is a process in which unwanted and potentially disabling bone tissue forms in abnormal locations such as muscles, musculotendinous junctions, and joint capsules. It may occur after trauma and after surgery. It is well known around the elbow and hip following fracture surgery and total hip replacement. The number of hip arthroscopies performed has increased exponentially over the last decade1, and HO has become well recognized following this mini-invasive procedure2. Although not as commonly experienced as a clinical problem, it is frequently demonstrated on postoperative radiographs. It is therefore of interest to investigate whether this abnormal bone formation can be reduced in a controlled study. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to prevent HO for years in other settings and are also commonly used following hip arthroscopy3. However, NSAIDs may also cause serious complications, and knowledge about the effect and risk in each specific indication is important. The article by Beckmann et al. addressed this problem in a well-conducted double-blind randomized controlled trial (RCT) in which three weeks of treatment with 500 mg of naproxen twice daily was compared with a placebo. They found a remarkable difference between the NSAID group and the placebo group with regard to radiographic findings of HO (documented in 4% and 46% of the patients, respectively). Medication compliance was 69% overall, and minor adverse events were reported in 42% in the treatment group and 35% in the control group. Only one patient developed symptomatic HO that required revision surgery. Unfortunately, few RCTs have been performed in orthopaedics, including the quickly evolving field of hip arthroscopy. New techniques have been developed and implemented without full knowledge of the benefit for the patients and how to select the right treatment for the right patient. In a PubMed search for “hip arthroscopy,” 801 studies were found, but when the search was limited to RCTs there were eight (and all were not actually RCTs). However, there is promising research under way: RCTs on the general efficacy of hip arthroscopy are ongoing4. The study by Beckmann et al. is an important and welcomed contribution to this so far limited number of Level-I hip arthroscopy studies. NSAIDs may affect tissue healing. Healing of soft tissue (such as a tendon) to bone has been shown to be impaired by NSAIDs in experimental studies5. A negative effect of NSAIDs on the healing of the sutured labrum or capsule in hip arthroscopy may therefore be an issue. NSAIDs have potential serious side effects, and although Beckmann et al. did not report serious or fatal complications in their study of 108 patients, they may occur sooner or later in a larger patient population. Clinically relevant HO is uncommon, and this has to be weighed against the risk of serious side effects caused by NSAIDs. Another question is whether the HO is a temporary phenomenon. A follow-up study of this patient cohort would be of great interest to see to what extent the HO develops further, is reduced, or disappears. This well-performed double-blind RCT documents that NSAIDs can reduce the frequency of radiographic evidence of HO following hip arthroscopy to a minimum. However, the clinical benefit and potential harm of routine NSAID prophylaxis are still unknown. As the authors point out, the lowest dose and shortest duration of NSAID prophylaxis that still prevent HO remain to be determined. This important study raises new questions, and there are many possible directions for further research in this field.

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NSAIDs, Risks, and Gastroprotective Strategies: Current Status and Future

Until recently, nonsteroidal anti-inflammatory drugs (NSAIDs) were regarded as weak analgesic agents with a potent antiplatelet effect that severely limited their perioperative usefulness. However, the recent development of injectable NSAIDs has stimulated a re-evaluation of the potential role of this class of drugs in postoperative pain management. In general surgery, NSAIDs have been shown to be effective analgesics when administered after surgery, as judged by either a reduction in pain scores and/or by an opioid sparing effect. Parenteral NSAIDs alone, notably ketorolac and diclofenac, may be adequate or even preferred analgesic agents after minor surgery. In dental surgery, NSAIDs produce greater initial analgesia than steroids, although the latter produce greater suppression of swelling and less functional loss. NSAID pretreatment results in only modest suppression of swelling compared with placebo. These data suggest that the acute analgesic effects of NSAIDs in oral surgery and probably other models result from suppression of a nociceptive process, rather than a generalised anti-inflammatory effect. This view challenges the traditional association between inhibition of prostaglandin synthesis and the therapeutic effects of these drugs. The variety of NSAIDs leads to a range in half-lives from short, e.g. diclofenac (1 h), intermediate, e.g. ketorolac (5h), to long, e.g. tenoxicam (60h), which has implications for both convenience of the dosage regimen and drug accumulation. For some racemic NSAIDs (e.g. ibuprofen), metabolic 'activation' of the inactive R-enantiomer to the active S-enantiomer occurs. Renal dysfunction may increase both the plasma concentration and body residence time of NSAIDs, thereby increasing the risk of adverse effects. The concomitant effects of anaesthesia have not yet been studied. The principal concern regarding the use of perioperative NSAIDs is the risk of decreased haemostasis and wound healing. Although it has been found that NSAIDs prolong bleeding times in patients, values generally remain below the upper limits of those in generally healthy patients. Healing of gastrointestinal anastomoses may be compromised by NSAID administration but corneal healing and bone remodelling are not. There is a need for further research into the potential for renal side effects with NSAIDs in the perioperative setting, where the effects of anaesthesia and surgery may increase the risk of side effects, particularly in elderly patients. The main benefits of NSAIDs derive from opioid sparing (e.g. reduction in perioperative nausea and vomiting and improvement in ventilation), although some studies allude to an enhanced quality of analgesia from the combination compared with either NSAID or opioid alone. The question of pre- vs postinjury treatment with NSAIDs remains unresolved.

Role of redox status on the activation of mitogen-activated protein kinase cascades by NSAIDs