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.     

The effects of nonsteroidal anti-inflammatory drugs on human hypertensive vascular disease

The co-administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive agents often, but not always, results in blunting of the effect of antihypertensive therapy. Although NSAIDs have no detectable pressor effects in normal subjects or untreated hypertensive people, they seem to antagonize the action of the majority of antihypertensive agents, making it necessary to increase their dosage, and often preventing proper control of blood pressure, particularly in black and elderly patients. The mechanism of this pharmacodynamic interaction is not completely understood, but may involve inhibition of vascular and renal prostaglandin (PG) synthesis, with resulting vasoconstriction and impaired renal excretion of Na+ and water. Also, suppression of a possible intermediary action of PG in the antihypertensive action of agents such as angiotensin converting enzyme inhibitors has been proposed. Certain antihypertensive drugs, such as Ca(2+)-channel blockers, centrally acting alpha agonists, and diuretics seem less sensitive to antagonism by NSAIDs. Aspirin and sulindac seem to be devoid of pressor effects, and thus provide a safe alternative in patients at risk for this interaction. These compounds may, in selected circumstances, even potentiate the effects of antihypertensive medications. Studies are underway to evaluate the hemodynamic effects of more selective blockers of arachidonate metabolism, such as thromboxane synthase inhibitors and selective inhibitors of PGH synthase-2.     

A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have well-known gastrointestinal and renal toxic reactions. Effects of NSAIDs on blood pressure are less appreciated. A meta-analysis was performed to determine the hypertensive effects of NSAIDs and rank them by magnitude of change in mean arterial pressure (MAP). METHODS: A literature search of published English-language studies of NSAIDs and their effects on blood pressure was done. Studies were included if they met the following criteria: (1) the studies were intervention studies; (2) NSAIDs at any dose or aspirin at doses of 1.5 g/d or greater were included; (3) documentation of blood pressure was provided; and (4) the studies were 24 hours in duration. Studies were excluded if 20% or more of their participants dropped out or if the dose of antihypertensive drugs was adjusted while the subjects were taking NSAIDs. The major outcome was change in MAP while patients were receiving NSAIDs. Each NSAID arm was extracted from its trial. Information on possible confounders, including subject age, trial quality, amount of dietary salt intake, and whether study subjects were hypertensive or normotensive, was recorded. We calculated the average change in MAP on each NSAID, adjusting for confounders. RESULTS: Fifty-four studies with 123 NSAID treatment arms met inclusion criteria. The mean age of subjects was 46 years. Of the 1324 participants, 1213 subjects (92%) were hypertensive. The effects of NSAIDs on blood pressure were found solely in hypertensive subjects. Among these, the increase in MAP after adjusting for amount of dietary salt intake was 3.59 mm Hg for indomethacin (57 treatment arms), 374 mm Hg for naproxen (four arms), and 0.49 mm Hg for piroxicam (four arms). The MAP decreased by 2.59 mm Hg for placebo (10 arms), 0.83 mm Hg for ibuprofen (six arms), 1.76 mm Hg for aspirin (four arms), and 0.16 mm Hg for sulindac (23 arms). The effects on MAP by using placebo, sulindac, and aspirin were statistically significantly different from indomethacin. CONCLUSIONS: In short-term use, NSAIDs vary considerably in their effect on blood pressure. Of the drugs studied, indomethacin and naproxen were associated with the largest increases in blood pressure. The average effects of piroxicam, aspirin, ibuprofen, and sulindac were negligible.     

Laxative-like effects of nonsteroidal anti-inflammatory drugs on intestinal fluid movement and membrane integrity

Certain nonsteroidal anti-inflammatory drugs (NSAID) of the fenamate chemical class are known to cause diarrhea in clinical use. Paradoxically, this action is shared by prostaglandins, against whose syntheses are inhibited by NSAID. This study was done to investigate the laxative potential of 5 NSAID (meclofenamate, flufenamate, mefenamate, indomethacin and aspirin). The ability to produce a laxative response was assessed by determining effects on fluid absorption in vitro in hamster everted sacs and by the enteropooling assay in hamster small intestine. In addition, the lytic action of these drugs on the erythrocyte membrane was determined to arrive at a possible mechanism of action. All of the NSAID, except aspirin, produced dose-related inhibition of fluid transport, similar to prostaglandin E1 and E2. The order of inhibition was flufenamate greater than meclofenamate greater than mefenamate greater than indomethacin. Like results were obtained when enteropooling was measured in vivo. Flufenamate and meclofenamate produced lumenal fluid accumulation comparable to two laxatives, dioctyl sodium sulfosuccinate and ricinoleic acid. Finally, the effects of these NSAID on fluid movement paralleled their lytic action on the erythrocyte membrane model, suggesting that NSAID may produce diarrhea in a manner similar to certain laxatives, by increasing mucosal permeability through membrane damage.     

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.     

An international evaluation of the cancer-preventive potential of nonsteroidal anti-inflammatory drugs

The most common complication in children with varicella is cutaneous superimposed infection with pyogenic bacteria. Group A beta-hemolytic streptococci, which are known to cause life-threatening infections in both previously healthy children and those with underlying diseases, are the most frequently associated pathogens. A newly recognized disease, called streptococcal toxic shock syndrome, is associated with severe morbidity and mortality. We report a 3-year-old boy with a diagnosis of this syndrome who presented with increasing fever, vomiting, and lethargy 7 days after the development of a classic varicella skin lesion. In spite of aggressive fluid supply, administration of inotropic agents, and cardiopulmonary resuscitation, a rapidly deteriorating clinical course led to death 4 hours after hospitalization. This is the first report of this association in Taiwan. Pediatricians evaluating children with varicella must be mindful of the potential for Group A beta-hemolytic streptococcal infection.     

Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application

Nonsteroidal anti-inflammatory drugs (NSAIDs) are being administered increasingly by transdermal drug delivery for the treatment of local muscle inflammation. The human epidermal permeabilities of different NSAIDs (salicylic acid, diethylamine salicylate, indomethacin, naproxen, diclofenac and piroxicam) from aqueous solutions is dependent on the drug's lipophilicity. A parabolic relationship was observed when the logarithms of NSAID permeability coefficients were plotted against the logarithms of NSAID octanol-water partition coefficients (log P), the optimum log P being around 3. The local tissue concentrations of these drugs after dermal application in aqueous solutions were then determined in a rat model. The extent of local, as distinct from systemic delivery, for each NSAID was assessed by comparing the tissue concentrations obtained below a treated site to those in contralateral tissues. Local direct penetration was evident for all NSAIDs up to a depth of about 3 to 4 mm below the applied site, with distribution to deeper tissues being mainly through the systemic blood supply. A comparison of the predicted tissue concentrations of each NSAID after its application to human epidermis was then made by a convolution of the epidermal and underlying tissue concentration-time profiles. The estimated tissue concentrations after epidermal application of NSAIDs could be related to their maximal fluxes across epidermis from an applied vehicle.     

Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion transporter, OAT-K1

We recently cloned and characterized the rat kidney-specific organic anion transporter, OAT-K1, which was suggested to mediate renal tubular transport of methotrexate. In this study, we investigated the interactions of nonsteroidal anti-inflammatory drugs (NSAIDs) with OAT-K1 by evaluating the effects of these drugs on renal distribution of methotrexate in vivo, and on methotrexate accumulation in the stably transfected LLC-PK1 cells expressing OAT-K1 (LLC-OAT-K1). NSAIDs such as indomethacin and ketoprofen had significant inhibitory effects on renal accumulation of methotrexate in rats after coadministration. Indomethacin and ketoprofen inhibited methotrexate accumulation by LLC-OAT-K1 cells in a competitive manner with the apparent inhibition constant values of 1. 0 mM and 1.9 mM, respectively. Other NSAIDs including ibuprofen, flufenamate and phenylbutazone also showed potent inhibitory effects on methotrexate accumulation. However, indomethacin was not transported via OAT-K1. These results indicate that NSAIDs have potent inhibitory effects against the OAT-K1-mediated methotrexate transport, which suggests that the OAT-K1 may be one of interaction sites for methotrexate and NSAIDs in the kidney.     

Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs

Factors that modify onset of Alzheimer's disease (AD) may be revealed by comparing environmental exposures in affected and unaffected members of discordant twin pairs or sibships. Among siblings at high risk of AD, sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with delayed onset and reduced risk of AD. After adjustment for use of NSAIDs, there was minimal effect on onset with reported history of any of three common illnesses (arthritis, diabetes, or acid-peptic disease). However, independent of exposure to NSAIDs, onset was unexpectedly delayed in those reporting extended use of histamine H2 blocking drugs. Randomized clinical trials will be needed to affirm the utility of these drugs for prevention, but the present findings may have implications for pathogenesis: because NSAIDs block the calcium-dependent postsynaptic cascade that induces excitotoxic cell death in NMDA-reactive neurons, and because histamine potentiates such events, excitotoxicity may deserve additional investigation in AD.     

The epidemiology of the gastroduodenal damage induced by aspirin and other nonsteroidal anti-inflammatory drugs

A substantial body of studies (controlled, cohort and case-control studies) now confirm the long established impression that there is an increased prevalence of gastric and duodenal ulcer and of associated complications in subjects treated with aspirin (ASA) or with non-steroidal anti-inflammatory drugs (NSAIDs). The overall percentage of ulcers/erosions in patients treated with ASA ranges from 10 to 50% with a relative risk of bleeding ranging from 1.8 to 15%. The overall relative risk of ulcers/erosions in NSAIDs-treated subjects is around 3%, with complications detectable in 2.4% of cases. The risk of lesions and complications associated with ASA/NSAIDs is more marked in patients aged over 65, in those with a previous history of ulcer (both symptomatic and silent), in those treated with substantial doses or with combinations of NSAIDs and in those concomitantly using anticoagulants and/or steroids. The epidemiological data highlight the importance of implementing ASA/NSAIDs therapy only when strictly necessary as well as the advisability of adopting as broad a range of measures as possible to reduce the tissue-damaging effects of these pharmacological agents.     

Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs

PURPOSE: The authors determined the effect of photocoagulation of drusen on visual acuity and progression to subretinal neovascular membranes (SRNV). METHODS: One of paired eyes was randomized to photocoagulation with other eye to control in 27 patients having symmetrical maculopathy and visual acuities, aged 46 to 81 years (mean, 69.7 years); follow-up 1 to 6 years (mean, 3.2 years). RESULTS: Final visual acuity was improved in treated eye or decreased in control eye in 12 patients, equal in 13 patients, and decreased in treated eye in 2 patients (P < 0.006). Progression to SRNV was less with treatment. CONCLUSION: Laser photocoagulation of confluent soft macular drusen may improve long-term visual prognosis.     

Gastropathy caused by nonsteroidal anti-inflammatory agents

Nonsteroidal anti-inflammatory drugs (NSAID) are widely used in current clinical practice. Several gastric lesions occur as a side effect. This review paper describes the spectrum of gastric lesions, its pathogenesis, prevalence and incidence as well as clinical data, common risk factors, treatment and the prophylaxis of NSAID gastric toxicity.     

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.     

Effect of nonsteroidal anti-inflammatory drugs on the action of misoprostol in a regimen for early abortion

BACKGROUND AND OBJECTIVES: Because warts are often found in the male urethra, human papillomavirus (HPV) may well be present in urine of patients with urethral condylomata. GOAL: To detect HPV DNA in urine specimens of men with condylomata acuminata using polymerase chain reaction. STUDY DESIGN: Forty-seven urine specimens and 25 paraffin-embedded tissues of condylomata acuminata were obtained from men. Of the 47 urine specimens, 29 were from patients with urethral condylomata, 3 from patients with penile condylomata only, and 15 from control subjects without condylomata. Both L1 consensus primers and type-specific primers for-HPV 6, 11, 16, 18, and 33 were used. RESULTS: HPV DNA was detected in 22 of the 29 (76%) urine specimens from patients with urethral condylomata, in none of the 3 urine specimens from patients with penile condylomata, and in none of the 15 controls. Paraffin-embedded tissues of all 25 condylomas were positive for HPV DNA. The HPV types detected in urine were identical to those detected in urethral condylomas. CONCLUSIONS: HPV DNA is present in urine of patients with urethral condylomata. Urine may be used for noninvasive screening of asymptomatic HPV infections of the male genital tract. Detection of HPV DNA in urine may be useful for monitoring the response to treatment of urethral condylomata.