Drug-Related Carcinogenesis: Risk Factors and Approaches for Its Prevention.

The review summarizes the data on the role of metabolic and repair systems in the mechanisms of therapy-related carcinogenesis and the effect of their polymorphism on the cancer development risk. The carcinogenic activity of different types of drugs, from the anticancer agents to analgesics, antipyretics, immunomodulators, hormones, natural remedies, and non-cancer drugs, is described. Possible approaches for the prevention of drug-related cancer induction at the initiation and promotion stages are discussed.

Status of non-steroidal anti-inflammatory drugs use and its association with chronic kidney disease: a cross-sectional survey in China.

AIM: Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to be associated with adverse effects including kidney injury, while relevant studies from developing countries are limited. We aimed to explore the status of NSAIDs use in China, as well as cross-sectional association between NSAIDs intake and presence of chronic kidney disease (CKD). METHODS: A national representative sample of 47,204 adults in China was used. Prevalence of regular NSAIDs use was reported. Age- and sex- matched controls of NSAIDs users were then selected. The association between NSAIDs use and kidney injury were analyzed using logistic regression. RESULTS: Altogether 1129 participants reported regular use of NSAIDs, with the adjusted prevalence of 3.6% (95% CI, 3.2%-3.9%). And 76.9% of them (n = 868) had taken phenacetin-containing analgesics, with an adjusted prevalence of 3.2% (95% CI, 2.9%-3.5%). After adjusting for potential confounders, long-term NSAIDs intake (≥ 48 months) was associated with eGFR < 60 mL/min per 1.73 m2, with an OR of 2.36 (95% CI, 1.28-4.37). CONCLUSION: Regular use of NSAIDs, especially phenacetin-containing drugs, is prevalent in China. And long-term NSAIDs intake (≥ 48 months) was independently associated with reduced renal function.

Non-phenacetin analgesics and analgesic nephropathy: clinical assessment of high users from a case-control study.

BACKGROUND: A recent large-scale case-control study on analgesic nephropathy (SAN) [1] found no increased risk of end-stage renal disease (ESRD) in users of combined or single formulations of phenacetin-free analgesics. In a subgroup of 22 high users, however, a dose-dependent increased risk was found, which raised the question if these patients presented or not with analgesic nephropathy (AN). METHODS: The individual questionnaires of this subgroup of high users were reviewed, and the total lifetime intake of different types of analgesics was calculated. For evidence of AN, the following data were considered: (1) the amount and type of analgesics consumed, (2) the cause of ESRD, as diagnosed by the nephrologist in charge of the patient and (3) renal imaging and other relevant laboratory data. RESULTS: This group of ESRD patients consumed on average 7.8 kg of antipyretic analgesics (range 30.8-2.7 kg) over an average of 21.5 years (range 35-6 years). Single analgesics were exclusively used by 12 patients (54.5%) and combined analgesics by 5 patients (22.7%), while 5 patients used both. None of the patients was diagnosed as having AN, and a review of the questionnaires did not disclose evidence suggestive of AN. The possibility that, irrespective of AN, the analgesic (ab)use contributed to the progression of existing renal diseases cannot be answered in the absence of well-defined criteria. The data supporting the existence of such an analgesic-associated nephropathy (AAN) are, however, not consistent and most likely due to confounding by indication. CONCLUSION: In a group of ESRD patients with high use of non-phenacetin analgesics, no evidence of AN was found. There is no evidence that (ab)use of analgesics or NSAIDs other than phenacetin leads to a pathologically or clinically defined renal disease that could be named AN or AAN.

A toxicogenomic approach revealed hepatic gene expression changes mechanistically linked to drug-induced hemolytic anemia.

A variety of pharmaceutical compounds causes hemolytic anemia as a significant adverse effect and this toxicity restricts the clinical utility of these drugs. In this study, we applied microarray technology to investigate hepatic gene expression changes associated with drug-induced hemolytic anemia and to identify potential biomarker genes for this hematotoxicity. We treated female Sprague-Dawley rats with two hemolytic anemia-inducing compounds: phenylhydrazine and phenacetin. Hepatic gene expression profiles were obtained using a whole-genome oligonucleotide microarray with pooled RNA samples from individual rats within each dose group and analyzed in comparison with hepatic histopathology, hematology, and blood chemistry data. We identified a small subset of genes that were commonly deregulated in all the severe hemolytic conditions, some of which were considered to be involved in hepatic events characteristic of hemolytic anemia, such as hemoglobin biosynthesis, heme metabolism, and phagocytosis. Among them, we selected six upregulated genes as putative biomarkers, and their expression changes from microarray measurements were confirmed by quantitative real-time PCR using RNAs from individual animals. They were Alas2, beta-glo, Eraf, Hmox1, Lgals3, and Rhced. Expression patterns of all these genes showed high negative and positive correlation against erythrocyte counts and total bilirubin levels in circulation, respectively, suggesting that these genes may be the potential biomarkers for hemolytic anemia. These findings indicate that drug-induced hemolytic anemia may be detected based on hepatic changes in the expression of a subset of genes that are mechanistically linked to the hematotoxicity.

Serum sickness-like reaction to Pamabrom.

Pamabron is a common over-the-counter diuretic used for relief of menstrual-associated symptoms. An urticarial eruption, with systemic complaints consistent with a serum sickness-like reaction, attributed to Pamabron is described. A review of the literature concerning Pamabron and dermatology is discussed.

A population--based case--control study of renal cell carcinoma.

A population-based case-control study of renal cell carcinoma (495 cases and 697 controls) in the Minneapolis-St. Paul seven-county metropolitan area implicated cigarette smoking as a risk factor with an odds ratio (OR) among men of 1.6 (95% confidence intervals: 1.1-2.4) and among women of 1.9 (1.3-3.0). A statistically significant dose response was observed in both sexes for pack-years of cigarette use. On the basis of calculations of attributable risk, it was estimated that 30% of renal cell cancers among men and 24% among women were due to smoking. High relative adult weight as measured by the body mass index (BMI) was found to be a major risk factor among women but not among men, with those in the highest 5% of the BMI having an OR of 5.9 (1.8-20.4) in comparison to the lowest quartile. This association with excess weight was not seen at age 20, but it became more pronounced with increasing age, suggesting that the primary influence of weight gain is during the late stages of renal carcinogenesis. Excess risks were also related to ethnic background (particularly, German), which may account in part for the elevated incidence of renal cancer in the North Central area of the United States. In addition, positive associations were observed for long-term use of phenacetin-containing analgesics, heavy meat consumption, and heavy tea drinking (females only). An occupational clue was provided by an increased risk for exposure to petroleum, tar, and pitch products. Excesses of certain urologic and cardiovascular diseases were also observed among the cases compared to controls.

Chronic renal failure and end-stage renal disease in northwest North Carolina. Importance of analgesic-associated nephropathy.

A retrospective study was undertaken to determine the extent to which analgesic-associated nephropathy (AAN) causes chronic renal failure (CRF) and end-stage renal disease (ESRD). Of 363 cases of CRF diagnosed between 1974 and 1976, 48 were caused by AAN; 14 of 140 cases of ESRD were caused by AAN. Of the 14 patients with ESRD from AAN, 12 initially had ESRD and two progressed to ESRD while continuing consumption of analgesics. The remaining 34 patients who had AAN with CRF discontinued using analgesics and have not progressed to ESRD. Thus, 34 of 36 patients with AAN-CRF who initially did not have ESRD discontinued use of analgesics and have not progressed to ESRD. We conclude that AAN causes a large percentage of CRF and ESRD in our patient population. Early recognition of this entity can prevent progression to ESRD if analgesic consumption is discontinued.

Do caffeine-containing analgesics promote dependence? A review and evaluation.

OBJECTIVE: Debates about the suspected association between kidney disease and use of analgesics have led to concern about whether caffeine could stimulate an undesirable overuse of phenacetin-free combined analgesics. A committee was asked to critically review the pertinent literature and to suggest guides for clinical practice and for consideration of international regulatory authorities. PARTICIPANTS: A group of international scientists, jointly selected by the regulatory authorities of Germany, Switzerland, and Austria and the pharmaceutical industry. EVIDENCE: All invited experts evaluated relevant literature and reports and added further information and comments. CONCLUSIONS: Caffeine has a synergistic effectiveness with analgesics. Although caffeine has a dependence potential, the potential is low. Experimental data regarding dependence potential for caffeine alone may not correspond to the conditions in patients with pain. Withdrawal is not likely to cause stimulation or sustainment of analgesic intake. For drug-induced headache, no single or combined analgesic was consistently identified as causative, and no evidence exists for a special role of caffeine. Strong dependence behavior was observed only in patients using phenacetin-containing preparations, coformulated with antipyretics/analgesics and caffeine. This finding may have led to the impression that caffeine stimulates overuse of analgesics. SUMMARY: Although more experimental and long-term data would be desirable to show possible mechanisms of dependence and to offer unequivocal proof of safety, the committee concluded that the available evidence does not support the claim that analgesics coformulated with caffeine, in the absence of phenacetin, stimulate or sustain overuse.

Renal disease from habitual antipyretic analgesic consumption: an assessment of the epidemiologic evidence.

The quantitative evidence relating habitual antipyretic analgesic consumption to the development of renal disease is reviewed. For purposes of analysis, "abuse" of analgesics is defined as regular, usually daily consumption. The prevalence of habitual consumption demonstrates marked geographic variation for poorly defined reasons. Prevalence tended to be highest in those populations in which phenacetin was available and popular. The prevalence of nephropathy among habitual consumers also shows marked interpopulation variability. A highly significant linear relationship exists between the prevalence of habitual analgesic consumption in a given population and the prevalence of nephropathy in the subset of that population that habitually consumes analgesics. This relationship may represent a dose-response curve relating amount of analgesic intake to prevalence of nephropathy. Four cross-sectional studies, 1 longitudinal, and 1 case-control study have shown significant differences in prevalence of nephropathy between habitual users of phenacetin-containing analgesics and control populations. Conversely, 2 cross-sectional studies and 1 case control study showed no difference between habitual users of analgesics and control populations. However, those studies showing no difference were performed in populations with low prevalence of habitual consumption of compound analgesics and a lower prevalence of nephropathy than was found in those populations where differences were observed. The relative risk for developing various manifestations of analgesic nephropathy has been estimated in 4 studies and varies depending on which abnormality is considered. Data are available only for subjects consuming phenacetin-containing compound analgesics. The relative risk for elevated serum creatinine is in the range of 8 to 11, about twice that for an abnormal renal concentrating test (approximately 4). The relative risk for clinical papillary necrosis is approximately 18, and for cause-specific death (and by inference for end-stage renal disease) about 4. The difference in risk between most clinical manifestations of analgesic nephropathy and death (or end-stage renal disease) may be due to the fact that most patients with nephropathy do not progress to terminal renal failure. Rheumatology clinic studies indicate that the prevalence of nephropathy in habitual consumers of phenacetin-containing compounds is higher than that for habitual consumers of aspirin alone. Removal of phenacetin from compound analgesics in Scandinavian countries appears to have reduced the prevalence of papillary necrosis and death from interstitial nephritis.(ABSTRACT TRUNCATED AT 400 WORDS)

Analgesic dilemma in chronic hemodialysis patients.

Analgesic drug abuse led to end-stage renal disease in 31% of 122 patients in a cross-sectional investigation at our center. Addiction to analgesics and tranquilizers remained a serious problem in these patients even after they were placed on chronic hemodialysis. There is strong evidence that drug addiction leading to end-stage renal disease and chronic hemodialysis correlates with a special type of personality typified by the 60-year-old depressive woman suffering from chronic headache.

Effects of nonsteroidal anti-inflammatory drugs on prostaglandins and renal function.

In the past 15 years, there has been an explosion in the number of nonsteroidal anti-inflammatory drugs on the market. Along with this explosion have come increasing reports of the physiologic and pathologic changes seen in the kidneys. This report reviews the effects of prostaglandins on the kidney and the physiologic changes that result when prostaglandin synthesis is blocked. The world literature on renal complications of nonsteroidal anti-inflammatory drugs is reviewed and 274 cases of acute renal disease associated with their use are reported. The following cases are described: nephrotic syndrome (34); acute interstitial nephritis (51); acute tubular necrosis (29); papillary necrosis (53); poor perfusion with renal failure (40); acute glomerulitis or vasculitis (13); and unspecified renal failure (102). Fenoprofen appeared to be more nephrotoxic than other nonsteroidal anti-inflammatory drugs and resulted in multiple renal lesions in the same patient.

Analgesic nephropathy.

Many questions about analgesic nephropathy (AN) lack clear-cut answers. We present available evidence for and against proposed answers to many of these questions. These include: (1) Is acetaminophen (AC) nephrotoxic when taken as the sole analgesic? (2) Is the combination of acetylsalicylic acid (ASA) and AC more nephrotoxic than AC taken alone, and if so, why? (3) What are the minimum doses and durations of ingestion required to produce analgesic nephrotoxicity? (4) Is the combination of ASA and AC (a major metabolite of phenacetin) less nephrotoxic than that of phenacetin and ASA combined? (5) Does caffeine in combination with analgesics contribute to nephrotoxicity? (6) What is the incidence of end-stage renal disease (ESRD) due to AN? (7) What uniform diagnostic criteria should be established for AN? (8) What are the earliest anatomic and biochemical abnormalities? (9) What are the mechanisms of renal injury? (10) Does AC cause uroepithelial neoplasia? (11) What research might be most beneficial? Based mainly on associations, some strong, we suggest that AN still exists as a cause of ESRD in the United States, where AC/ASA combinations are available over the counter, and in Canada, where they are not. We also suggest that the evidence needed to recommend that the AC/ASA combination be excluded from over-the-counter analgesic preparations still has limitations. A prospective multicenter study comparing incidence related to AC/ASA in the United States and to AC in Canada and the United States may be needed to answer this question. For such a study to be worthwhile, an adequate incidence in both countries is required.

Phenacetin-induced haemolytic anaemia.

Haemolytic anaemia, rarely severe, is a common yet often unrecognized complication of the prolonged use or abuse of phenacetin-containing analgesics. Irregularly contracted (pyknocytes) or fragmented erythrocytes (schistocytes) are commonly present in the peripheral blood in this form of anaemia. It is emphasized that their recognition during screening of blood films may reveal patients previously unsuspected of analgesic abuse and at a stage before the development of the more serious complication of nephropathy. Fourteen such patients, detected during the last 18 months, are briefly described and the pathogenesis and laboratory features of the anaemia reviewed.

Bladder tumor associated with phenacetin abuse.

The association between phenacetin abuse and renal papillary necrosis is widely known. Recently, reports in the European literature indicated a possible correlation between phenacetin abuse and the development of transitional cell carcinoma of the renal pelvis and bladder. A case of transitional cell carcinoma associated with phenacetin abuse is presented. The pharmacology of phenacetin metabolites is discussed, and the world literature is reviewed. The data available warrant careful reappraisal of the ready availability of phenacetin.

Phenacetin nephritis.

Prolonged ingestion of mixed analgesics containing phenacetin has been associated significantly with the development of a chronic interstitial nephritis frequently associated with papillary necrosis. This disease is frequently underdiagnosed. If an adequate history of headache and/or backache (of which most of these patients complain) is not taken, the central causative effect of phenacetin ingestion may never be appreciated. Laboratory tests show the usual abnormalities seen in any form of chronic interstitial nephritis such as poor urinary concentration, renal failure with large urine output, and no hypertension. Papillary necrosis is helpful but not pathognomonic. The type of medications ingested appears to be changing to prescription compounds. The with significant improvement in renal function.

Phenacetin-induced renal papillary necrosis: pyonephros, anuria, and bilateral ureteral obstruction.

A fifty-five-year-old man was seen with anuria. Retrograde pyelograms demonstrated bilateral ureteral obstruction subsequently shown to have resulted from sloughed renal papillae. A twenty-year history of phenacetin was obtained. Treatment included bilateral ureteral intubation, then ureterotomy on one side.

Analgesic abuse syndrome: a frequently overlooked cause of reversible renal failure.

The incidence of analgesic nephropathy in the United States is greater than previously reported. Because of the characteristic radiographic features of papillary necrosis, this diagnosis may be made while it is still clinically unsuspected. Early diagnosis is extremely important because cessation of analgesic abuse may avert progressive renal damage. Uncovering the diagnosis calls for special care in obtaining the telltale history. This must be sought in patients with radiographic evidence of papillary necrosis when a history of diabetes mellitus, obstructive uropathy, or sicle cell anemia is absent, or in patients with unexplained nephrocalcinosis or nephrolithiasis.