Nonsteroidal anti-inflammatory drugs and the gut

Aberrant crypt foci (ACF) are putative precursor lesions of colon cancer, recently identified on the methylene blue-stained mucosal surface of human colon. No mutations in K-ras or p53 genes were found by non-radioactive single-strand conformation polymorphism analysis in 14 ACF collected from five patients. Using the more sensitive method of allele-specific polymerase chain reaction (PCR) for K-ras, 8 of 14 ACF were found to contain K-ras mutations, suggesting that mutated cells are present in minute clones in ACF. No dysplasia was observed in any of the ACF containing a mutated clone. The presence of K-ras mutations in ACF suggests that these lesions occur at a very early stage in human colorectal carcinogenesis.     

Nonsteroidal anti-inflammatory drugs and severe psychiatric side effects

In the systemic mucopolysaccharidoses (MPS) in animals, corneal clouding resulted from storage of glycosaminoglycans (GAG) in stromal keratocytes. The corneal epithelium was normal (MPS VI and VII) or minimally affected (MPS I), and stromal edema was not a feature even though the corneal endothelium demonstrated variable pathology. The MPS I (cat) cornea showed endothelial cells with large numbers of secondary lysosomal inclusions that were vacuolated or had a granular matrix. The endothelium was uniformly affected, but was not markedly hypertrophied. In contrast, the MPS VI (cat) cornea showed no endothelial cell disease. The MPS VII (dog) cornea had the most significant and dramatic endothelial pathology. The cells were massively hypertrophied and contained large numbers of vacuolated lysosomal inclusions. Regardless of the severity of the morphologic disease, the endothelial cells in these animal models functioned normally in maintaining the relative dehydration of the cornea. The corneal clouding was the result of storage in stromal keratocytes rather than corneal edema from endothelial dysfunction.     

Nonsteroidal anti-inflammatory drugs and bone mineral density in older women: the Rancho Bernardo study

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to inhibit synthesis of prostaglandins and may help prevent bone loss, but no study has shown the differential association of type or dose of NSAID compound with bone mineral density (BMD). The purpose of this study was to determine the relation of NSAIDs by type and dose to BMD. Participants were 932 Caucasian, community-dwelling women aged 44-98 years from southern California. Data were collected from 1988 to 1991 through the use of standardized medical questionnaires. Medication use was validated by a nurse. BMD at the ultradistal and midshaft radii were measured using single-photon absorptiometry, and at the hip and lumbar spine using dual-energy X-ray absorptiometry. Women (mean age, 72 years) were classified into 818 nonusers and 114 regular daily users of NSAIDs, of which 84 used propionic acid NSAIDs and the remainder used acetic acid NSAIDs. Occasional NSAID users were excluded. Women who used propionic acid NSAIDs, but not acetic acid NSAIDs, had higher BMD at all five sites and significantly higher BMD at the midshaft radius and lumbar spine. These differences remained after controlling for known covariates of osteoporosis. When women with self-reported osteoarthritis were excluded from the model, significantly higher BMD in propionic acid NSAID users was also observed at the femoral neck and total hip. Those who concurrently used estrogen and propionic acid NSAIDs had the highest BMD at all sites, suggesting an additive effect. We conclude that regular daily use of propionic acid NSAIDs, with or without simultaneous use of estrogen, may be helpful in preventing bone loss in older women. However, further research is needed to confirm these results before any clinical practice guidelines can be recommended due to the increased risk of serious complications associated with NSAID use.     

Nonsteroidal anti-inflammatory drugs and cognitive function: do they have a beneficial or deleterious effect?

AIMS/BACKGROUND: A recent advancement in Doppler ultrasonography (US) is power Doppler for detecting low-velocity blood flow at the microvascular level with angle independence. The present study was performed to characterize the factors contributing to the power Doppler signals of hepatocellular carcinoma (HCC). METHOD: Correlation of Doppler signals of HCC in 114 patients with 178 HCC nodules was analyzed in relation to the findings of CT and angiography, tumor characteristics (size, echo pattern, and histological differentiation of tumor), viral markers and severity of liver disease. RESULTS: The sensitivity of power Doppler US was superior to that of CT and angiography (each p<0.05; McNemar's test). The detection rate of power Doppler signal was significantly higher in tumors with diameter > or =2 cm (vs <2 cm in diameter), and with low/mixed echo pattern (vs high echo appearance), and with moderately/poorly differentiated HCC (vs well-differentiated HCC). Univariate analysis revealed that echo pattern, tumor size and histological differentiation of HCC in addition to CT and angiographic findings were significant. Multivariate analysis showed that tumor size and differentiation were significant. CONCLUSION: These results indicate that tumor characteristics play an important role in power Doppler signals and that these could be assessed by the presence or absence of power Doppler signals.     

Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging

Infant rats were passively immunized to determine the protective capacity of pneumococcal anticapsular antibodies. Animal-passaged strains of Streptococcus pneumoniae serotypes 1, 4, 5, 6b, 7f, 9v, 14, 18c, 19f, and 23f were used as challenge inocula (1-1500 cfu) in a model of pulmonary infection that resulted in bacteremia, meningitis, and death. From untreated control animals, histologic sections of lung demonstrated infiltrative pneumonia and lung homogenate cultures grew S. pneumoniae at concentrations of 10(3)-10(8) cfu per gram of lung tissue. A type-specific anti-capsular antibody serum concentration of 0.1-1.15 microg/mL resulted in a statistically significant reduction in mortality compared with the reduction in untreated controls, except for serotype 14, which required 2.32 microg/mL for a significant reduction in mortality. The serum antibody level that provided 50% reduction in mortality ranged from 0.1-3.5 microg/mL for all serotypes.     

Nonsteroidal anti-inflammatory drug-induced enteropathy: case discussion and review of the literature

A computer simulation of a catheter manometer system was used to quantify measurement errors in neonatal blood pressure parameters. Accurate intra-arterial pressure recordings of 21 critically ill newborns were fed into this simulated system. The dynamic characteristics, natural frequency and damping coefficient, were varied from 2.5 to 60 Hz and from 0.1 to 1.4, respectively. As a result, errors in systolic, diastolic and pulse arterial pressure were obtained as a function of natural frequency and damping coefficient. Iso-error curves for 2%, 5% and 10% were constructed. Using these curves, the maximum inaccuracy of any neonatal catheter manometer system can be determined and used in the clinical setting.     

Nonsteroidal anti-inflammatory drugs increase tumor necrosis factor production in the periphery but not in the central nervous system in mice and rats

Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin (PG) synthesis, augment production of tumor necrosis factor (TNF) in most experimental models. We investigated the effect of two NSAIDs, indomethacin and ibuprofen, on the production of TNF in the CNS induced by intracerebroventricular injection of lipopolysaccharide (LPS). Indomethacin and ibuprofen, administered intraperitoneally, augmented (three- to ninefold) the levels of TNF in serum and peripheral organs of mice injected intraperitoneally with LPS and in rats with adjuvant arthritis (up to a sevenfold increase). However, NSAIDs (intraperitoneally or intracerebroventricularly) did not increase brain TNF production induced by intravenous LPS. In fact, indomethacin decreased (1.4-1.8-fold) TNF levels in the spinal cord of rats with experimental autoimmune encephalomyelitis and in the cortex of rats with focal cerebral ischemia. Systemic administration of iloprost inhibited serum TNF levels after intraperitoneal LPS, whereas intracerebroventricular injection of iloprost or PGE2 did not inhibit brain TNF induced by intracerebroventricular LPS. Both peripheral and central TNF productions were inhibited by cyclic AMP level-elevating agents or dexamethasone. Thus, a PG-driven negative feedback controls TNF production in the periphery but not in the CNS.     

Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation

OBJECTIVE: There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) damage; it has been suggested that mucosal damage may be initiated by a "topical" action of NSAIDs involving mitochondrial injury. We evaluated the effect of a range of NSAIDs and related compounds on mitochondrial function and assessed the differences between them in relation to their physicochemical properties. METHODS: Stimulation of respiration, as an indicator of mitochondrial uncoupling, was measured in isolated coupled rat liver mitochondrial preparations, using an oxygen electrode. RESULTS: Conventional NSAIDs and acidic prodrugs all had stimulatory effects on mitochondrial respiration at micromolar concentrations (0.02-2.7 microM); higher concentrations were inhibitory. The uncoupling potency was inversely correlated with drug pKa (r = -0.87, P < 0.001; n = 12). Drugs known to have good GI tolerability, including modified flurbiprofen (dimero-flurbiprofen and nitrobutyl-flurbiprofen), nabumetone (a non-acidic prodrug), and non-acidic highly selective COX-2 inhibitors, did not cause uncoupling. CONCLUSION: The ability to uncouple mitochondrial oxidative phosphorylation is a common characteristic of antiinflammatory agents with an ionizable group. Modification or absence of an ionizable moiety reduces the effect on mitochondria and could lead to improved NSAID GI safety.     

Nonsteroidal anti-inflammatory agents: potential modifiers of periodontal disease progression

The most recent studies of NSAIDs as potential modifiers of periodontal disease progression are reviewed. These studies indicate that NSAIDs have the ability to alter or control the progression of periodontal disease. Reductions in gingival inflammation and in bone loss have been observed following the administration of various NSAIDs. In some cases, bone gain has been achieved. More research is required to determine the possible long-term side effects associated with the chronic usage of NSAIDs, as well as to achieve consensus on the most effective drug for the control of periodontal disease. Until this occurs, and this application of NSAIDs receives government approval, the use of these drugs to control periodontal disease is not recommended.     

Prescription of non-steroidal anti-inflammatory drugs

BACKGROUND AND PURPOSE: Tacrolimus, an immunosuppressant agent, has been shown to reduce tissue injury and leukocyte accumulation after transient ischemia. This study was designed to evaluate quantitatively the inhibitory effects of tacrolimus on leukocyte rolling and on subsequent leukocyte accumulation in vivo after transient retinal ischemia and the protective effects of tacrolimus on ischemia-induced neural damage. METHODS: Retinal ischemia was induced for 60 minutes in anesthetized pigmented rats by temporary ligation of the optic sheath. Tacrolimus was administered at 10 minutes after ischemic induction. At 4, 12, 24, and 48 hours after reperfusion, leukocyte behavior in the retinal microcirculation was evaluated in vivo with acridine orange digital fluorography. After 7 days of reperfusion, ischemia-induced retinal damage was evaluated histologically. RESULTS: Treatment with tacrolimus suppressed leukocyte rolling; the maximum number of rolling leukocytes was reduced by 60.1% at 12 hours after reperfusion (P<0.05). In tacrolimus-treated rats, the velocity of rolling leukocytes was significantly faster than in vehicle-treated rats (P<0.01). The subsequent leukocyte accumulation was reduced by 61.6% at 24 hours after reperfusion (P<0.01). Histological examination demonstrated the protective effect of tacrolimus on ischemia-induced retinal damage, which was more substantial in the inner retina (P<0.01). CONCLUSIONS: The present study demonstrated the inhibitory effect of tacrolimus on leukocyte rolling and on subsequent leukocyte accumulation and the therapeutic potency to neural injury after transient retinal ischemia.     

Nephrotoxicities of nonsteroidal anti-inflammatory drugs

While the relative incidence of serious nephrotoxicities in the population consuming nonsteroidal anti-inflammatory drugs (NSAIDs) is very low, the frequency of adverse events in patients at risk has considerably increased due to the rising popularity of the use of the drugs in recent years. Under normal conditions, NSAIDs have relatively little effect on the kidney because of low renal production of prostaglandins. However, in the presence of renal hypoperfusion in which local synthesis of vasodilator prostaglandins is increased to protect the glomerular hemodynamics and to maintain appropriate renal tubular transport of fluid and electrolytes, inhibition of prostaglandin synthesis by NSAIDs can lead to vasoconstrictive acute renal failure as well as fluid and electrolyte disorders such as sodium retention and resistance to diuretics, hyponatremia and hyperkalemia. Conditions that increase the risk for NSAID-induced nephrotoxicities include volume depletion from diuretics and other causes, edematous states such as congestive heart failure and cirrhosis of the liver, old age and underlying renal disease, especially in the presence of renal functional impairment. In addition, renal parenchymal diseases may develop in susceptible patients taking NSAIDs. These include acute tubulointerstitial nephritis, frequently associated with nephrotic syndrome, and chronic progressive renal disease, with or without renal papillary necrosis. Rare cases of vasculitis and glomerulonephritis have also been reported. Finally, NSAIDs may aggravate hypertension by interacting with antihypertensive drugs, especially with diuretics and beta-blockers. Withdrawal of NSAIDs in patients at risk can frequently reverse or improve the nephrotoxicities. It is recommended that physicians be aware of the clinical settings that increase the risk for NSAID-induced nephrotoxicities and take preventive or therapeutic measures accordingly.     

Biologic effects of nonsteroidal anti-inflammatory drugs

Experimental glaucoma was induced in 1 eye of 6 cynomolgus monkeys by laser treatment of the trabecular meshwork. In 5 of the 6 monkeys the increased intraocular pressure (IOP) caused marked glaucomatous damage in the experimental eye. Ocular blood flow was determined with labeled microspheres 4 years after the laser treatment. IOP was regulated with an external reservoir. With the same perfusion pressure in both eyes no statistically significant difference was observed between the 2 eyes for total ocular blood flow or for blood flow through any of the ocular tissues. Total ocular blood flow was 343.5 +/- 61.4 mg/min (mean +/- SEM) in the control eye and 385.3 +/- 107.7 mg/min in the experimental eye.     

Toxicity of antirheumatic and anti-inflammatory drugs in children

In multiple sulfatase deficiency, a rare human lysosomal storage disorder, all known sulfatases are synthesized as catalytically poorly active polypeptides. Analysis of the latter has shown that they lack a protein modification that was detected in all members of the sulfatase family. This novel protein modification generates a 2-amino-3-oxopropanoic acid (C alpha-formylglycine) residue by oxidation of the thiol group of a cysteine that is conserved among all eukaryotic sulfatases. The oxidation occurs in the endoplasmic reticulum at a stage when the nascent polypeptide is not yet folded. The aldehyde is part of the catalytic site and is likely to act as an aldehyde hydrate. One of the geminal hydroxyl groups accepts the sulfate during sulfate ester cleavage leading to the formation of a covalently sulfated enzyme intermediate. The other hydroxyl is required for the subsequent elimination of the sulfate and regeneration of the aldehyde group. In some prokaryotic members of the sulfatase gene family, the DNA sequence predicts a serine residue, and not a cysteine. Analysis of one of these prokaryotic sulfatases, however, revealed the presence of the C alpha-formylglycine indicating that the aldehyde group is essential for all members of the sulfatase family and that it can be generated from either cysteine or serine.     

Surgical management of osteoarthritis

The surgical management of osteoarthritis has progressed greatly in the past 30 years and often is indicated when noninvasive measures can no longer provide sufficient pain relief and maintenance of function. Physicians can choose from a variety of surgical procedures, depending on patient age, the joint involved, functional expectations, patient activity demands, and degree of cartilaginous loss. Surgical procedures for arthritic joints can be classified in two broad categories: those that are cartilage-sparing, such as osteotomy, and those that are cartilage-sacrificing, such as arthroplasty. This article discusses those procedures most commonly used for the major weightbearing joints of the lower extremities (hip, knee, ankle) as well as the large joints of the upper extremity (shoulder, elbow).     

Nonsteroidal antiinflammatory drugs are associated with both upper and lower gastrointestinal bleeding

We retrospectively evaluated antiinfective therapy for methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) endocarditis in 54 patients who had 57 treatment courses for the disease. Three treatments were assessed: 27 nafcillin-treated courses of MSSA endocarditis, 18 vancomycin-treated courses of MSSA endocarditis, and 11 vancomycin-treated courses of MRSA endocarditis. At baseline, patients with MSSA treated with vancomycin had more chronic conditions (p<0.01), a lower frequency of intravenous drug use (p<0.01), a lower hematocrit concentration (p<0.05), and a higher serum creatinine concentration (p<0.05) than the nafcillin group. Vancomycin-treated patients had a higher complication rate during therapy (p<0.05) and a longer duration in an intensive care unit (p<0.01) than the nafcillin group. The trend was for a higher complete response rate in the nafcillin group (74% vs 50%, p=0.12), but no difference in mortality (22% vs 28%, p=0.73). Patients with MRSA infection treated with vancomycin had higher mortality than those with MSSA who received that drug (55% vs 28%, p=0.24). Patients with vancomycin-treated MSSA endocarditis may have a poorer outcome than those who receive nafcillin, but this may be influenced by different or more severe clinical features.     

A clinical evaluation of non-steroidal anti-inflammatory drugs (NSAIDS) as adjuncts in the management of periodontal disease

Several effectors and mediators of inflammation have been identified as principle factors in periodontal disease progression. It has been reported that topical and systemic application of flurbiprofen (non-steroidal anti-inflammatory drug) reduced the rate of alveolar bone loss as well as signs of gingival inflammation. Twenty rapidly progressive as well as juvenile periodontitis patients were included in the present study. Results of the present study showed a significant reduction in pocket depth & gingival index in the experimental group over the control group. Radiographs revealed more bone fill in the experimental group over the control group.     

Prospective study of nonsteroidal anti-inflammatory drugs and breast cancer

We have studied the feasibility of detecting tumor-associated aberrant p16 methylation in the circulation of patients with hepatocellular carcinoma (HCC). We extracted DNA from the tumor tissues and peripheral blood plasma or serum of 22 HCC patients. p16 methylation was found in 73% (16 of 22) of HCC tissues using methylation-specific PCR. Among the 16 cases with aberrant methylation in the tumor tissues, similar changes were also detected in the plasma/serum samples of 81% (13 of 16) of the cases. No methylated p16 sequences were detected in the peripheral plasma/serum of the six HCC cases without these changes in the tumor, in 38 patients with chronic hepatitis/cirrhosis, or in 10 healthy control subjects. These results suggest that circulating liver tumor DNA may be detected using tumor-associated DNA methylation changes. Because methylation abnormalities have been found in many other genes and tumor types, this approach may have implications for the noninvasive detection of a wide variety of cancers.