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1986 14: 83Toxicol PatholHugh E. Black

Renal Toxicity of Non-Steroidal Anti-Inflammatory Drugs  

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SYMPOSIUM Renal Pathology and Toxicity

TOXICOLOGIC PATHOLOGY ISSNZO 192-6233 Volume 14, Number 1, 1986

Copyright Q 1986 by the Society of Toxicologic Pathologists

Renal Toxicity of Non-Steroidal Anti-Inflamma < ory Drugs*

HUGH E. BU'CK

Schering Corporation, P.O. Box 32. Lafayette, New Jrrsey 07848

ABSTRAC~

Non-steroidal anti-inflammatory drugs represent the most heavily prescribed and used class of drugs in human medicine. Most are derivatives of either salicylates, propionic acid, indoleacetic acid, anthranilic acid, pyrazolonc, or oxicams. They depress the synthesis ofprostaglandins from arachidonic acid by reversible inhibition of the enzyme cyclooxygcnase. In the kidney, prostaglandins PGE, and PGI, modulate the va- soconstrictor effects ofangiotensin 11, norepinephrine, and vasopressin. In the presence ofvolume contraction, anesthesia, or disease states associated with high levels of these hormones, prostaglandins regulate glomerular filtration, vascular resistance, and renin secretion. They additionally influence urine volume and sodium content. In man, a syndrome of analgesic abuse that has been identified worldwide occurs more frequently in females than males and can result in severe renal damage, most notably renal papillary necrosis. Most common laboratory animals are relatively resistant to developing the renal lesion associated with NSAIDs unless high doses are given over long periods of time and some withholding of water is introduced into the protocol. Diuresis with 5% dextrose and water is protective. Studies of paracematol and salicylate have demonstrated that these compounds concentrate in the papillary tip of the kidney at concentrations of 4 to 13 times the plasma levels in dogs and rabbits, respectively. Renal papillary necrosis has been described in horses on maintenance doses of phenylbutazone where dehydration or reduced water consumption has occurred. The lesion can be reproduced experimentally if water is withheld during a portion of the dosing interval. An increased incidence of uroepithelial tumors have been reported in patients with a history of analgesic abuse. Mixtures containing phenacetin appear to have been at fault. However, carcinogenicity studies with phenacetin have yielded inconsistent results in laboratory animals.

INTRODUCTION The purpose of this paper is to review the renal

toxicity associated with the administration of non- steroidal anti-inflammatory drugs (NSAIDs). Sev- eral excellent reviews of prostaglandins, non-ste- roidal anti-inflammatory agents, and the renal tox- icity of these agents in clinical practice have already been published (15, 19, 23, 27, 47, 48, 74).

The NSAIDs are widely used drugs in human medicine and to a lesser extent in veterinary prac- tice. In human medicine they are now the most widely prescribed of all drugs when grouped by ge- neric categories, not including aspirin (16). Ap- proximately 6.5 million Americans have rheuma- toid arthritis and an additional 30 million have other chronic rheumatologic disorders for which NSAIDs are prescribed. About one in every seventh Amer- ican is likely to be treated with one of these drugs (6).

Presented at the Founh International Symposium of the So- ciety of Toxicologic Pathologists, June 5-7, 1985 in Washington, D.C.

SITE OF AC~ION OF NSAIDs

Most NSAIDs are organic acids and have in com- mon antipyretic, analgesic, and anti-inflammatory activity, They constitute several different chemical categories that include the salicylates and dcriva- tives of propionic acid, indoleacetic acid, anthranilic acid, pyrazolone, and oxicams (1 5).

NSAIDs exert their pharmacologic action by act- ing as reversibie inhibitors of prostaglandin synthe- sis. The prostaglandins are unsaturated fatty acid compounds derived principally from arachidonic acid that has been freed from cellular membrane lipids (45). Phospholipase enzyme or enzymes (phospholipase A2, phospholipase C, and diglycer- ide lipase) may be pathways by which arachidonic acid is freed from membrane lipids. This step can be inhibited by anti-inflammatory glucocorticoid hormones (32). Once free within the cell, arachi- donic acid may be converted to prostaglandins via the cyclooxygenase pathway or to leukotrienes via the lipoxygenase pathway. Cyclooxygenase incor- porates oxygen into arachidonic acid to form PGG2

83

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84 BLACK TOXICOLOGIC PATHOLOGY

(45). It is this step that is sensitive to inhibition by NSAIDs. Acetylsalicylic acid inactivates this step by acetylation (76). Most non-steroidal anti-inflam- matory agents act as reversible inhibitors of this enzyme.

PHYSIOLOGICAL EFFECTS OF RENAL PROSTAGLANDINS

The prostaglandins are ubiquitous in their distri- bution and function, for the most part, as local hor- mones (autacoids). They are found in virtually all organs and are products of virtually all cells. There are a variety of possible roles and mechanisms of action of these agents. There appears to be a balance between thromboxane A, production by the platelet (which tends to promote platelet aggregation, clot formation, and vascular contraction) and PGI,, pro- duced by the endothelium (which tends to inhibit platelet aggregation and relax blood vessels) (57). This counterbalancing ofactions is believed to occur in all blood vessels in the body, including the kidney.

At the level of the kidney, prostaglandins have effects on renal blood flow and glomerular filtration rate and upon sodium and water excretion. Infusing increasing doses of several prostaglandins (PGE,, PGD, or PGI,) into the renal artery of the dog pro- duces a dose-related increase in renal blood flow. However, doses needed to produce this effect are significantly higher than normal circulating levels (47). PGF2, has no such effects. Results of prosta- glandin infusion studies have also suggested that these agents have a local effect on regional blood flow distribution with relatively more blood being distributed to the inner cortical zone (29). When glomerular filtration rate has been measured, the prostaglandins have been noted to produce similar directional changes to those observed for renal blood flow (47). Prostaglandins also appear to have some role in regulating glomerular filtration rate during reduction of systemic pressure (80). However, in the conscious unstressed state, in both animals and man, the resting 'renal blood flow seems to be only min- imally dependent on renal prostaglandin synthesis

Studies with inhibitors of prostaglandin synthesis have suggested that prostaglandins, rather than playing a major role in regulating total blood flow, may instead modulate the vasoconstricting effects of other hormones such as angiotensin 11, norepi- nephrine, and vasopressin (15, 19, 43, 93). Their action, at the level of the kidney, appears to be large- ly vasodilatory. PGEz and PGI, appear to be the most likely candidates since thromboxane A, and PGF, either have little or no effect or constrict the renal vasculature (37, 45).

Inhibition of prostaglandin synthesis by NSAIDs

(19).

approximately doubles the vasoconstricting effects of intrarenal infusion of angiotensin (2, 69). PGE, and PGI, reduce the vasoconstrictor actions of an- giotensin I1 in the kidney since they directly antag- onize the action of angiotensin on vascular smooth muscle. This role of the prostaglandins to reduce angiotensin-mediated vasoconstriction has been demonstrated in the dog, cat, rabbit and rat (7, 13, 25, 49).

Renal PGE, and PGI, also antagonize a-adrener- gic-mediated renal vasoconstriction. PGE, and PGII, are known to reduce both pre- and post-synaptic adrenergic neural transmission (88). Inhibition of prostaglandin synthesis has been shown to augment renal vasoconstriction induced by renal nerve trans- mission stimulation (53, 64).

Further study of the interaction of prostaglandins and vasoconstrictor agents has shown that angio- tensin, vasopressin, and norepinephrine elicit the compensatory release of PGE, and PGI, and that these vasodilatory prostaglandins modulate the ex- tent of renal vasoconstriction (19). The synthesis of PGE,, so formed, appears to be proportional to the increments in renal vascular resistance (1 9). The sites of synthesis are the arterioles and glomeruli in the cortex (70, 78) and the collecting tubule and interstitial cell in the medulla (20).

Prostaglandins play a role in regulating the main- tenance of water balance in animals and man. This function is performed under both anti-diuretic and water-diuretic conditions (9 1). Prostaglandins an- tagonize the hydrostatic activity of antidiuretic hor- mone (3, 68), inhibit active chloride transport by the medullary thick ascending limb (86, 87) and regulate medullary blood flow (43, 47).

Prostaglandin infusion into animals or man caus- es a marked increase in sodium excretion with PGE, producing a greater increase than does PGI, or PGD, (81, 90, 92). The mechanisms for this effect or its site of action still remain to be clarified. Increased natriuresis may be secondary to augmented renal blood flow (38, 54) and/or to direct effects upon tubular sodium and chloride transport (38). In the isolated rabbit nephron, prostaglandin E, inhibits the active transport of chloride in the medullary portion of the thick ascending limb of Henle (87) and sodium transport in the cortical collecting tu- bule (86).

E m c r s OF NSAIDs ON THE KIDNEY In normal animals or man, inhibition of renal

prostaglandins does not depress renal blood flow or glomerular filtration rate. Renal blood flow is not impaired in normal dogs or baboons treated with indomethacin (89). However, inhibition of prosta- glandin synthesis has a profound effect upon renal

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Vol. 14, No. 1, 1986 RENAL TOXICITY OF NSAIDs 85

blood flow and glomerular filtration rate when it is superimposed on a preceding hemodynamic insult. This effect has been demonstrated in dogs subjected to hypotensive hemorrhage (3 l), salt depletion (9, 65), or general anesthesia (43) and in experimental models of biliary cirrhosis (93), or heart failure (66), in which glomerular filtration rate and renal blood flow are no longer autoreguIated after treatment with inhibitors of prostaglandin synthesis.

NSAIDs have a significant effect upon urine con- centration. When renal prostaglandin synthesis is suppressed by NSAIDs, concentration of urine oc- curs in the proximal tubules and excretion of free water is limited (7 1, 81). When the ability of dogs, rats or man to increase urine osmolality was studied following administration of a fixed dose of vaso- pressin, with or without indomethacin, meclofena- mate or aspirin, the same dose of vasopressin led to a greater increase in urine osmolality following the inhibitors of prostaglandin synthesis (8, 50, 75). One possible mechanism by which prostaglandin inhibition increases urine osmolality is that anti- diuretic hormone seems to have a greater effect on the collecting system in the presence ofreduced levels of prostaglandin. A second mechanism may be a direct effect of NSAIDs which increases papillary interstitial osmolality and thus creates a greater gra- dient for water to move from the collecting system into the interstitium of the kidney and out of the urine (84). Thus, under conditions where urine is relatively diluted, the administration of NSAIDs is

'associated with an increase in urine osmolality.

RENAL TOXICITY OF NSAIDs Analgesic Nephropathy froiti Analgesic Abiise.

The potential for NSAIDs to produce renal disease in man is a well established fact. An association between renal disease and abuse of analgesic mix- tures, usually containing phenacetin, was first rec- ognized and reported by Spuhler and Zollinger in Europe in 1953 (83). However, the potential for analgesic abuse to occur on a wide scale was initially alluded to in 1907 when it was noted that ". . . what the drink habit is among men in Australia, the head- ache powder is among women [The Lotie Haiid, 19071 . . ." (62). In the years following the reports of Spuhler and Zollinger, analgesic nephropathy has been reported from most parts of the world includ- ing the Middle East and Japan (62, 73). The disease is most common, however, in Austrrilia, the United Kingdom, the United States, Canada, and South Africa.

The extent of analgesic abuse as a major com- munity problem has been carefully researched and reported in Australia. Between approximately 5 and 45% of subpopulations in the community consume

analgesics daily, often for inapproprite reasons. In 1979 terminal renal failure from analgesic nephrop- athy was responsible for 20% of the national dialysis and transplantation program in Australia. This fig- ure is approximately 4 and 6% in Europe and Can- ada, respectively (62).

A clinical syndrome of analgesic abuse is now recognized and characterized (23, 62). It has -been shown that a relationship exists between the dura- tion, intensity, and total amount of analgesic mix- ture consumed, and the degree of renal impairment: Analgesic nephropathy should be expected after ap- proximately 2 to 3 kg of the index agent has been consumed over a 2 to 5 year period and is likely to be clinically apparent after the consumption of 7 or more kg.

The disease has a female to male ratio of 6: 1 with the typical patient being over 30 and usually over 50 years of age. One third of the patients have a personality disorder and a history of dependency on other agents (alcohol, psychotropics) in common. Analgesic intake usually has been for headache or musculoskeletal pain although mood elevation and sleep are also reasons for abuse. Sometimes there is an underlying condition such as arthritis.

The renal lesions associated with analgesic ne- phropathy have been well characterized (23). Pap- illary necrosis is the predominant and primary le- sion while the cortical lesions appear later and may well be secondary to papillary necrosis. The initial lesions are patchy and consist of necrosis of inter- stitial cells, thin loops of Henle and capillaries. The collecting ducts are spared. The tubular and capil- lary basement membrane and interstitial ground substance are increased. With persistent insult, the changes extend to the outer medulla where the le- sions are patchy involving the interstitial cells, loops of Henle, and the vasa recta. At this stage, the in- termedullary lesions are more severe with sclerosis and obliteration of the capillaries, atrophy and de- generation of the thin limbs of the loops of Henle and collecting ducts, and calcification ofthe necrotic papillae. In more advanced stages, the papillae be- come entirely necrotic with sequestration and de- marcation of the necrotic tissue which ultimately slough into the pelvis and may be recovered in the urine. In most instances, however, the papillae do not slough but remain in sill[, where they become calcified and atrophied. Cortical scarring, charac- terized by interstitial fibrosis, tubular atrophy, and periglomerular fibrosis, develops over the necrotic medullary segments, which become demarcated by mononuclear cell infiltration.

The fact that the lesions start in the papillary tip may be to a great extent a result of the local con- centration of the drugs and their metabolites in the

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86 BLACK TOXICOLOGIC PATHOLOGY

inner medulla and of structural factors unique to the vasculature of the region. The blood supply of the papilla is derised from two sources: the vasa recta and the branches of the arteries in the adven- titia of the minor calyces. As the vascular bundles formed in the outer medulla descend toward the papillary tip, they decrease in size and at the tip only single vessels remain. The net effect is that the pap- illary blood supply is poor compared to the rest of the medulla.

Clinical Aspects. Renal papillary necrosis has been frequently observed at autopsy or following renal biopsy of arthritic patients. This population may be at greater risk because of quantities of NSAIDs con- sumed (74). The incidence of papillary necrosis and chronic interstitial nephritis has becn claimed to be 2 1-28% (74). Definitive renal papillary necrosis has been reported following the use of alclofenac, ami- nophenazone, phenazone, acetylsalicylic acid, feno- profen, ibuprofen, indomethacin, paracetamol, and phenylbutazone (74).

It has been proposed that certain types of patients, those dependent upon renal prostaglandin produc- tion to maintain renal blood flow under conditions of reduced effective intravascular volume, are es- pecially vulnerable to NSAID-related renal impair- ment (1 8). Renal prostaglandin synthesis. is in- creased in a number ofdiseases that affect the kidney including Bartter’s syndrome, renal ischemia, uni- lateral ureteral obstruction, cirrhosis of the liver with ascites, glomerulonephritis (particularly that asso- ciated with systemic lupus erythematosus), hyper- tension, and acute renal failure (15).

NSAIDs have little effect upon the glomerular filtration rate in normal human beings. However, the combination of an inhibition of prostaglandin synthesis and salt depletion leads to impaired renal function (1 5). It is postulated that volume contrac- tion caused by sodium depletion leads to activation of pressor mechanisms (adrcnergic and renin angio- tensin). Normally, the renal vasoconstrictive influ- ences of norepinephrine and angiotensin I1 are mitigated by their simultaneous stimulation of va- sodilatory renal prostaglandins. Renal blood flow and glomerular filtration rate are maintained and prerenal azotemia or ischemic damage to renal parenchyma is avoided. When this prostaglandin- mediated counterrcgulatory mechanism is sup- pressed by drugs that inhibit cyclooxygenase, im- pairment of renal hemodynamics results (1 5).

Any clinical situation in which elevated levels of angiotensin I1 and catecholamines exists must be considered a high risk setting for the development of NSAID-induced renal failure. Since an activated renin-angiotensin system characterizes the anesthe- tized state (71), it is not surprising that the effects

ofcyclooxygenase inhibitors on glomerular filtration rate and renal blood flow are more pronounced in the anesthetized than in the conscious animal (43). This may also apply to patients undergoing general anesthesia and perhaps to patients with sepsis, cn- dotoxemia, or serious infections (67).

It has been observed that NSAID therapy has been associated with acute renal failure when su- perimposed on chronic renal disorders (40). Such disorders are associated with increased prostaglan- din excretion suggesting that prostaglandins may pl$ a contributing role in the maintenance of renal hemodynamics under these adverse conditions. In- hibition ofprostaglandin synthesis by NSAIDs leads to acute deterioration of renal function.

NSAID-induced nephrotic syndrome and inter- stitial nephritis represent acute renal failure with proteinuria in the nephrotic range that occurs from 2 weeks to 18 months after initiation of therapy. Histological examination of the kidney demon- strates the presence of focal to diffuse interstitial infiltrates consisting predominantly of lympho- cytes, with vacuolar degeneration of proximal and distal tubules. The glomeruli are minimally altered. The syndrome has been reported in persons taking fenoprofen, indomethacin, naproxen, and tolmetin (1 5). The lesion is similar to that described by am- picillin. It is produced by two distinct classes of NSAIDS, the phenylpropionic acid and indoleacetic acid derivatives. It has been proposed that T-lym- phocyte activation may be the immunologic process that mediates this syndrome.

Acute interstitial nephritis with proteinuria that is not in the nephrotic range has also been described in patients given phenylbutazone, tolmetin, zome- pirac, naproxen, and mefenamic acid (1 5).

RENAL TOXICITY OF NSA1D.S IN ANIhfALS Laboratory Species. In animals, several NSAIDs

cause papillary necrosis after prolonged administra- tion. Compounds include meclofenamate, fenopro- fen, and phenylbutazonc (24, 39,42). However, the usual animal models (dogs, rats and rabbits) are quite resistant to larger quantities of salicylates and phenacetin (14,2 1,82). Rats fed large doses ofphen- acetin for short periods of time fail to develop renal lesions (1 1, 59, 6 1). Doses from 300 to 600 mg/kg/ day for short periods of time induce primary tubular epithelial degenerative changes with only a modest increase in interstitial tissue (1,5). Doses with 1,OOCk 3,000 mg/kg/day givcn for 2 to 15 months lead to more severe tubulointerstitial nephritis with papil- lary necrosis in approximately one third of the an- imals, particularly if the rats are dehydrated for 16 hours per day (1, 26, 56, 61): The lesions can be completely prevented if the animals are undergoing

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Vol. 14, No. 1, 1986 RENAL TOXICITY OF NSAIDs 87

a water diuresis induced by providing 5% glucose in water ad libifunt (56,6 1). Rats receiving the larger doses of phenacetin develop abnormalities in uri- nary concentration, acidification and sodium con- centration that are reversible when phenacetin administration is discontinued (26, 61, 65, 85).

Chronic studies of paracetamol (acetaminophen) at small doses in the cat and rat do not produce renal lesions (5 , 10, 21). Doses of 100-300 mg/kg/ day produce minor tubular and interstitial changes in one third of the rats (22), while doses of 900 to 3,000 mg/kg/day for longer periods produce papil- lary necrosis in 40-60% of rats (4, 56, 61). Studies in dogs have shown that paracetamol concentrates in the papillary tip to levels fourfold higher than in the cortex or plasma (17). However, hydration to- tally obliterates this gradient for both free and con- jugated forms of the compound (10, 17). The high papillary concentration of paracetamol may be re- sponsible for renal papillary necrosis. In rats, the incidence of renal papillary necrosis can be com- pletely prevented by providing a 5% dextrose so- lution ad libift(m (56, 61).

In acute studies, aspirin, at doses of 50 to 500 mg/kg/day in the rat (4, 72) and cat (2 1) and 1,000 mg/kg/day in the pig (55 ) , did not produce renal lesions. Larger doses for longer periods produced papillary necrosis, interstitial fibrosis, and miner- alization in 30 to 70% of animals (14, 44, 59). A renal medullary gradient for salicylate has been shown in the rabbit renal medulla with cortical and papillary concentrations of 1.5 and 13 times the plasma level, respectively (1 2, 17). Renal papillary necrosis is reduced from 55% in dehydrated rats fed 200 mg/kg/day of aspirin to 0% in rats undergoing water diuresis induced by free access to glucose- containing water (6 1).

Mixtures of salicylate and phenacetin or paracet- amol result in higher incidences of renal papillary necrosis than when each component is administered alone (1, 56, 59). These studies have shown that individually, the above compounds were only mod- erately nephrotoxic, that mixtures when combined with dehydration were more potent in inducing the lesion, that the toxicity was dose-dependent, and that diuresis was protective. It has been postulated that decreased papillary blood flow, leading to isch- emia, subsequently resulted in cellular necrosis (56). Others have demonstrated that in rats given 500 mg/kg of salicylates, medullary blood volume, as demonstrated by the fluorescent-tagged red cell techniq ue, was decreased (5 9). Sal icyla tes, however, also decrease the affinity of hemoglobin for oxygen by decreasing red blood cell 2,3-diphosphoglycer- idc, and could, by this mechanism, also contribute to anoxia in the renal papilla. Salicylates have also

been shown to inhibit the hexosemonophosphate shunt in the renal medulla and can diminish the ability of cells to generate sufficient reducing agents to protect themselves against oxidative damage (28, 61). The concentration of salicylate in the rabbit kidney cortex and papilla at levels 6 and 13 times plasma concentration is sufficient to result in un- coupling of oxidative phosphorylation (1 7). Mefab- olism in the deeper parts of the nephron is predom- inently anaerobic (28). Metabolism of paracetamol to an activated compound has been proposed as a.! mechanism that produces a nephrotoxic radical in the papilla (94).

Horses. Renal papillary necrosis occurs in the horsc and has been associated with therapy em- ploying antiprostaglandin drugs, mostly phenylbu- tazone, along with clinical evidence of dehydration or impaired water intake (30). Horses receiving maintenance doses of phenylbutazone have devel- oped this lesion (77). In the horse, elevations of blood urea nitrogen and serum creatinine concen- trations above 35 mg/dl and 2 mg/dl, respectively, have been noted within 24 hours of death. The mi- croscopic renal lesion consists of sharply demarcat- ed focal coagulative necrosis involving all aspects of the tubular and interstitial structures compatible with an ischemic origin. Vascular and cellular in- flammatory responses follow the occurrence of ne- crosis along a line of demarcation between viable and nonviable tissue. ’

Further study of acute renal papillary necrosis in horses has demonstrated that the lesion can be re- produced experimentally in healthy horses given a maintenance dose of phenylbutazone if water is withheld for 36 to 48 hours prior to necropsy. Horses given the same dose of phenylbutazone but provid- ed adequate water do not develop the lesion. Lim- ited water deprivation also is known to enhance the development of renal papillary necrosis in rats and man undergoing analgesic therapy with aspirin and phenacetin (41, 60). The intravenous administra- tion of phenylbutazone to horses at 8, 15 or 30 mg/ kg/day for up to 2 weeks can be lethal within 4 to 7 days at 15 or 30 mg/kg and all doses produce renal papillary necrosis (5 1).

NSAIDS AND RENAL TUhiORS

In 1965 Hultengren et al, and later Johansson et al, reported on the development of tumors in the lower urinary tract of man after long-term use of phenacetin (33,35,36). In long-term feeding studies of phenacetin in rodents or dogs, conflicting results were achieved. Negative results were obtained when phenacetin was fed alone or in combination with aspirin and/or caffeine by several groups (52, 63, 79). However, phenacetin was shown to cause

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88 BLACK

marked chromosomal aberrations in an in viro assay system using cultured Chinese hamster fibroblasts (34). Studies by other investigators in which phen- acetin was incorporated into the diet and pelleted resulted in the deveIopment oftumors in thc kidney, lower urinary tract, and nasal cavity of rats (36,37). A dose-related induction of renal cell tumors was also demonstrated in male mice (58). An earlier experiment had demonstrated that phenacetin in- duced hyperplastic lesions in the mucosa of the rat urinary bladder and acted as a promoter after initiation with N-butyl-N(4-hydroxybutyl) nitrosa- mine (58).

The presumptive carcinogenic or mutagenic ac- tivity of phenacetin and the nitroso-metabolites of aminopyrine and aminophenazone are apparently due to the actions of these substances on deoxyri- bonucleic acid (74).

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