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.

Consumidores de cocaína y manifestaciones cutáneo-mucosas / Cocaine users and cutaneous and mucosal manifestations

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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.

The ban on phenacetin is associated with changes in the incidence trends of upper-urinary tract cancers in Australia.

BACKGROUND: Phenacetin is an analgesic that causes renal diseases and cancers of the upper-urinary tract (UUT). It was banned in most countries from the late 1960s. This study aimed to evaluate, for the first time, the long-term population impact of the phenacetin ban on UUT cancer rates. METHODS: We used cancer registry data from Australia, where phenacetin was widely used, to study age- and sex-specific incidence trends of cancers of the renal pelvis and the ureter after the phenacetin ban (1979). Incidence rate ratios and average annual percentage change (AAPC) were calculated to quantify changes in rates over time. RESULTS: Incidence rates of renal pelvis cancer decreased by 52% in women and 39% in men between 1983-1987 and 2003-2007. The decline in women was stronger in states where the use of phenacetin was the most widespread, e.g. New South Wales (AAPC: -4.1%; 95% CI -5.3, -2.9) and Queensland (AAPC: -3.3%; 95% CI -4.9, -1.8), and after the mid-1990s. Incidence rates of ureteral cancer remained stable for both sexes throughout the study period. CONCLUSIONS: Our findings strongly suggest a beneficial impact of the ban on phenacetin on the incidence of renal pelvis cancer in Australia, particularly among women.

A population-based study of tumours of the renal pelvis and ureter: incidence, aetiology and histopathological findings.

OBJECTIVE: Carcinoma of the renal pelvis and ureter are unusual tumours and our limited knowledge comes mainly from case reports and small series from large academic hospitals, as a rule without histopathological review. This study reports aetiological and demographical factors as well as clinicopathological findings of all patients in a large geographical region. MATERIAL AND METHODS: All patients in western Sweden with a renal pelvic or ureteral tumour diagnosed between 1971 and 1998 (n = 930) were included. Untreated cases were not excluded. Demographic data and results of preoperative examinations were retrieved from the original clinical records. The histopathological slides were reviewed and tumour stage, grade, configuration, presence of carcinoma in situ and angiolymphatic invasion were determined. RESULTS: The majority of patients (80%) had invasive or high-grade tumours. Carcinoma in situ was present among 30% of patients with non-invasive high-grade tumours. Angiolymphatic invasion (62%) and solid (non-papillary) growth pattern (84%) were very common among patients with stage T2-T4 tumours. Twenty-three women out of 138 (16.7%) with ureteral carcinoma had a history of abdominal radiotherapy for gynaecological cancer 22 years (median) earlier. Forty-one patients out of 930 (4.4%) had a history of abuse of phenacetin-containing analgesics. CONCLUSIONS: This study demonstrates a very high incidence of high-grade upper tract tumours with carcinoma in situ, angiolymphatic invasion and solid (non-papillary) growth pattern, which underscores the malignant character of the disease. The possible association between pelvic radiotherapy and ureteral carcinoma warrants further study.

Metabolic activation by human arylacetamide deacetylase, CYP2E1, and CYP1A2 causes phenacetin-induced methemoglobinemia.

Phenacetin has been used as an analgesic antipyretic but has now been withdrawn from the market due to adverse effects such as methemoglobinemia and renal failure. It has been suggested that metabolic activation causes these adverse effects; yet, the precise mechanisms remain unknown. We previously demonstrated that human arylacetamide deacetylase (AADAC) was the principal enzyme catalyzing the hydrolysis of phenacetin. In this study, we assessed whether AADAC was involved in phenacetin-induced methemoglobinemia. A high methemoglobin (Met-Hb) level in the blood was detected 1 h after administration of phenacetin (250 mg/kg, p.o.) to male C57BL/6 mice. Pre-administration of tri-o-tolylphosphate, a general esterase inhibitor, was found to decrease the levels of Met-Hb and the plasma concentration of p-phenetidine, a hydrolyzed metabolite of phenacetin. An in vitro study using red blood cells revealed that incubation of phenacetin or p-phenetidine with human liver microsomes (HLM) increased the formation of Met-Hb. To identify the enzymes involved in the formation of Met-Hb, we used recombinant enzymes and HLM treated with inhibitors in the measurement of the formation of Met-Hb. High levels of Met-Hb were observed following incubation of human AADAC with either cytochrome P450 (CYP) 1A2 or CYP2E1. Furthermore, the increased Met-Hb formation by the incubation of HLM with phenacetin was significantly inhibited to 25.1 ± 0.7% of control by eserine, a potent AADAC inhibitor. In conclusion, we found that the hydrolysis by AADAC and subsequent metabolism by CYP1A2 and CYP2E1 play predominant roles in phenacetin-induced methemoglobinemia.

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.

Bladder tumor associated with phenacetin abuse: a case report and a review of the literature.

We herein report the case of a bladder tumor in an 85-year-old man who had been engaged in phenacetin abuse. He had been taking phenacetin owing to migraine headaches since he was 45 year of age. His total intake of phenacetin was approximately 7.3 to 11.5 kg over a period of years. He visited the Department of Urology in our hospital due to gross hematuria and pain on urination. IVP and a pelvic CT scan revealed a tumor mass on the right lateral wall of the urinary bladder. TUR-BT was performed. A histopathological examination of the resected specimen was diagnosed as urotherial carcinoma, grade 2∼3, pT2N0M0. To our acknowledge, only 24 cases of urotherial tumors owing to phenacetin abuse have been previously reported in the Japanese literature, making this the 25 th such case to be reported in Japan.

Obituary to analgesic nephropathy--an autopsy study.

BACKGROUND: To determine whether classic analgesic nephropathy with renal papillary and urothelial capillary sclerosis could still be detected at autopsy in the beginning of the 21st century, the present study which is similar to a previous one performed in 1980 was undertaken as suggested by the Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy. METHODS: Consecutive autopsies of 616 adults performed at the Basle Institute of Pathology between November 2000 and February 2002 were analysed. Tissue samples of renal cortex and papilla of 1220 kidneys and of each ureter and main renal artery available were subjected to a very careful and meticulous study using classical histopathological methodology. RESULTS: A number of lesions was found macroscopically but not a single case of papillary necrosis or analgesic nephropathy could be detected preceding histological analysis. Histologically, the most frequent lesions were vascular in 57.8% of kidneys followed by glomerular lesions in 13.1% (mostly diabetic glomerulosclerosis). Tubulo-interstitial lesions, mostly pyelonephritis were detected in 9.3% with only a single case of classic analgesic nephropathy with bilateral complete papillary necrosis and ureteral capillary sclerosis in a female who had received a renal transplant 14 years before her demise at the age of 67. In another five cases, complete papillary necrosis was detected associated with pyelonephritis, hydronephrosis or in completely shrunken kidneys. However, in the absence of capillary sclerosis, a histopathological diagnosis of classic analgesic nephropathy could not be made in any of these five cases. CONCLUSIONS: The Basle autopsy prevalence of analgesic nephropathy decreased continuously from some 3% in 1980 to 0.2% in 2000 as shown by the present study. Similarly, capillary sclerosis of the urinary tract, the initiating event in the pathophysiology of papillary necrosis and analgesic nephropathy and the histological hallmark of the effect of toxic metabolites of phenacetin in analgesic abusers decreased from 4% of autopsy cases between 1978 and 1980 to the single case of the present study observed at the end of 2000. Thus, the classic analgesic nephropathy has disappeared some 20 years after the removal of phenacetin from the analgesic market despite the fact that mixed analgesics containing paracetamol, the main metabolite of phenacetin, have continued to be popular and widely used drugs.

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.

Analgesic nephropathy in Hungary: the HANS study.

BACKGROUND: The diagnosis of analgesic nephropathy has improved significantly with modern imaging techniques. We reviewed a large portion of the Hungarian dialysis population to obtain additional insight into the problem. METHODS: Twenty-two participating dialysis units enrolled 1400 patients on renal replacement therapy between 1 January 1995 and 1 January 1998. Patients with no known aetiology (n = 284) were interviewed and studied with renal imaging. We assessed the presence of decreased renal mass combined with either bumpy contours, papillary calcification, or both. The subjects studied were interrogated extensively. RESULTS: Our survey suggested analgesic nephropathy in 47 of 1400 patients (3.3%), 3-fold higher than the EDTA database estimate for Hungary. The analgesics most commonly abused were phenacetin-containing mixtures. The driving symptoms were mainly headache and joint pain. Cardiovascular complications were more common than in the rest of the dialysis population, independent of smoking and lipid values (P<0.01). CONCLUSIONS: Phenacetin should be banned. Our study results support the need for longitudinal cohort and case-control studies in Hungary.

Caffeine as a promoter of analgesic-associated nephropathy--where is the evidence?

Individual groups of nephrologists - in their responsibility for their patients - initiated a most controversial discussion whether or not caffeine - coformulated to analgesics - might initiate or sustain analgesic overdosing. The original sources (data) of such suspicion have got lost during the debate of the last two decades. Therefore, it seemed to be appropriate to investigate the original data background and the reasons why nephrologists started to suspect caffeine as a stimulant of analgesic overdosing by employing a systematic and exhaustive review of primary nephrological publications. Their selection followed a precise selection plan, including all epidemiological studies on analgesic-associated nephropathy, the original papers of all groups having been involved in those studies, further originals from the mainly involved countries (academically, politically), and any literature thereof cited as a proof. The following results emerged from the investigation: (i) The epidemiological studies warranted no conclusion about a role of caffeine in prompting excessive analgesic use. (ii) The identified groups of nephrologists provided not substantial data to advocate the said suspicion, except for the observation of a preferential choice of phenacetin-containing combinations, especially powder preparations. (iii) Only two cited original data sources revealed drug-seeking behaviour with phenacetin-containing preparations which subsided, after phenacetin was banned from the respective markets. Conclusively, it appears that there is no substantial data to support a pivotal role of caffeine in initiating or sustaining analgesic overdosing. However, there is strong data that phenacetin, by its psychotropic properties, may have caused drug-seeking behaviour and thus led to analgesic overdosing. This conclusion is convincingly supported by thorough pharmacokinetic investigations. Note: All caffeine-related statements within the reviewed literature have been collected in tables (referred to as Table SX) which are provided in full text for check on the following website: http://www.blackwellpublishing.com/products/journals/suppmat/FCP/FCP174/FCP174sm.htm

Use of analgesics in self-medication.

Self-medication with analgesics is common and accepted and even recommended by health systems in order to avoid reimbursement. Self-medication, nevertheless, is not an easy task, since making choices is difficult for patients on the basis of the available standard information. Guiding information for patients has to be improved, but also physicians need to be trained how to handle self-medication of their patients. Special attention should be paid to the approval of combination analgesics for the treatment of headache and migraine. There were two major points of discussion during the last decades: possible risks of nephropathy and possible drug-induced overuse. According to a very recent evaluation, analgesic-associated nephropathy appears to have been primarily caused by phenacetin rather than any other single or combination analgesics. Analgesic-induced overuse is also caused by the psychotropic actions of phenacetin in presentations providing rapid absorption, such as powders, rather than by other analgesics or caffeine.

[A case of renal pelvic tumor due to phenacetin abuse].

A 65-year-old female had been taking analgesics containing phenacetin, because of severe headaches since 1958. The total dose of phenacetin that she had taken was calculated to be 8.0 kg. She visited the department of urology in our hospital in August, 1999 complaining of gross hematuria. A solid mass was detected in her left renal pelvis on the abdominal computed tomographic (CT) scan. Under the diagnosis of a left renal pelvic tumor, nephrouretectomy was performed in September, 1999. Histopathological diagnosis was grade 2 transitional cell carcinoma. Interstitial nephritis was also observed. Our case is the twenty-second report of an urinary tract tumor associated with phenacetin abuse in Japan.

The onset of action and the analgesic efficacy of Saridon (a propyphenazone/paracetamol/ caffeine combination) in comparison with paracetamol, ibuprofen, aspirin and placebo (pooled statistical analysis).

The objective was to evaluate the onset of action, analgesic efficacy and tolerability of Saridon*, a propyphenazone 150 mg/paracetamol 250 mg/caffeine 50 mg combination, in comparison with paracetamol 500 mg, aspirin 500 mg, ibuprofen 200 mg and placebo, by a pooled statistical analysis of eight studies. Out of 500 generally healthy patients (55.2% men, 44.8% women), average age 43.5 years, 329 (65.8%) had moderate and 171 (34.2%) severe acute dentoalveolar pain. More Saridon-treated patients reported 'pain gone/partly gone' and less 'pain unchanged or worse' compared with paracetamol, aspirin and placebo 30min (p = 0.009, p < 0.001, p = 0.001, respectively) and 60 min after dosing (p < 0.0001 for all). The difference with ibuprofen was observed 60 min after dosing (p < 0.01). Pain intensity differences 30 min and 60 min after dosing infer that Saridon has a faster onset of action than all of the other medications that it was compared with (ibuprofen at only 60 min after dosing). Total pain relief scores four hours after dosing were higher in the Saridon group compared with the paracetamol, ibuprofen, placebo (p < 0.0001 for all) and aspirin groups (p < 0.01). At the end of the study, patients assessed Saridon as more efficacious than the other study medications (p < 0.0001 for all). No serious adverse events were observed with any of the drugs studied. All medications were well tolerated. Twenty patients (4.0%) reported adverse events with no significant differences between groups. The most common adverse events were gastrointestinal disorders, followed by nervous system, skin, subcutaneous tissue, respiratory, cardiac and general disorders. Saridon is an effective analgesic that combines the advantage of fast onset and effective analgesia as compared with paracetamol alone, ibuprofen, aspirin or placebo. The results of this pooled analysis of eight studies should be confirmed in a double-blind study, since seven of the studies included in this analysis were single blind.