CORONARY EFFECT OF FIBRATES ON PROTEINS AND ENZYMES WHICH HYDROLYZE TRIACYLGLYCEROLS.

Clofibric acid derivatives called fibrates, are quite commonly used lipid-lowering drugs, so it is necessary to know beneficial and adverse effects of these compounds on the body. The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that benefits of four fibrates such as: bezafibrate, ciprofibrate, fenofibrate and gemfibrozil continue outweigh their risk in treatment of people with blood lipid disorders. According to recommendations of the CHMP fibrates should not be used as first-line drugs, except in patients with severe hypertriglyceridemia and patients who cannot use statins. In this paper, we focused on effect of clofibric acid derivatives on lipid metabolism, in particular on apoproteins and regulatory enzymes.

Fibrates: no ACCORD on their use in the treatment of dyslipidaemia.

PURPOSE OF REVIEW: New data have emerged over the last few years about the role of fibrates in treatment of microvascular and macrovascular disease. RECENT FINDINGS: Endpoint studies have been conducted with fibrates in coronary heart disease since 1971 and results have been contradictory. Fibrates have shown benefits in patients with low HDL-cholesterol and low LDL-cholesterol. Fibrates remain topical, given their actions on the lipid triad present in the metabolic syndrome and in diabetes. In the Fenofibrate Intervention in Endpoint Lowering in Diabetes study of mixed primary and secondary prevention cohorts, fenofibrate therapy resulted in an 11% reduction in coronary or cardiovascular events in monotherapy. Despite frequent use, there was little endpoint data on fibrate-statin combination therapy until recently. The Action to Control Cardiovascular Risk in Diabetes trial of fenofibrate added to baseline simvastatin therapy in diabetes showed a nonsignificant 8% reduction in cardiovascular events. The benefits were concentrated in men, and women did slightly worse with fibrate therapy. In post-hoc analysis, slight beneficial effects of fenofibrate were seen in patients with moderate hypertriglyceridaemia (>2.3 mmol/l) and low HDL-cholesterol (<0.88 mmol/l). The safety profile of fibrate-simvastatin combination was good. SUMMARY: Fenofibrate and bezafibrate are reasonable second-line therapies for dyslipidaemia and in diabetes. They are safe in combination therapy with statins but add little endpoint benefit except possibly in patients with a significant degree of atherogenic dyslipidaemia (high triglycerides and low HDL-cholesterol). The benefits of fibrates on microvascular disease remain to be fully explored.

Iatrogenic severe depression of high-density lipoprotein cholesterol.

The authors present 5 cases of paradoxical depression of high-density lipoprotein (HDL) cholesterol induced by fibrate drugs. In a 24-month review of all cases seen in one physician's practice at the Winnipeg Health Sciences Centre Lipid Clinic, 492 patients made a total of 1187 visits. Sixty-eight of them were given a fibrate drug (14%). Ten patients had HDL cholesterol levels that were less than 0.5 mmol/L (2%), and of these, 5 cases were due to exposure to fenofibrate (1%). These 5 cases comprised 7.4% of the 68 patients who were given any fibrate drug during that period. Mean levels were as follows: HDL cholesterol on fenofibrate 0.27, off fenofibrate 1.0 mmol/L and apo A1 on fenofibrate 0.41, off fenofibrate 1.17 g/L. A literature review revealed documented cases in 37 patients involving fibrates alone or in combination with other drugs known to cause decreased HDL cholesterol levels. In 13 patients, exposure was to fibrate therapy alone; in those exposed to combinations, the effect was clearly attributable to fibrates in 9; in 14, the nonfibrates (mostly rosiglitazone) were the attributable drugs; and in 1, it was impossible to tell. Thus, fibrate therapy should always be suspected as a cause of profoundly depressed HDL cholesterol.

Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine.

PURPOSE: Betaine is an osmolyte, supplies methyl groups, and controls plasma homocysteine. Abnormal urinary loss of betaine is common in patients with the metabolic syndrome or diabetes mellitus. These patients are often treated with fibrates which alter renal function and raise plasma homocysteine concentrations. We suggest there is a connection between fibrate treatment and betaine excretion. METHODS: We identified 32 fibrate-treated patients in several studies (total of 740 subjects) and compared the betaine excretion by these with the excretion by other patients, both in the separate studies and in the combined group. We investigated the correlation of betaine excretion with homocysteine in these groups. RESULTS: Patients taking bezafibrate had higher betaine excretion than patients not taking fibrates, p < 0.00001 in some studies with n < 10. Of 32 patients taking bezafibrate, 20 had abnormal (>97.5 %-ile) betaine excretion. Plasma homocysteine correlated positively with betaine excretion in male patients with lipid disorders who were not taking fibrate (n = 68, p = 0.043), but the relationship was stronger if patients taking bezafibrate were included (n = 76, p < 0.00001). In elderly (>65 years) subjects with hypertension there was a similar correlation (n = 19, p = 0.047), which was stronger when a subject taking bezafibrate was included (n = 20, p = 0.013). CONCLUSIONS: Abnormal betaine excretion is common in patients treated with bezafibrate. Bezafibrate appears to exacerbate betaine loss, which will cause a rise in plasma homocysteine. Betaine supplementation could be considered in conjunction with fibrate therapy.

[Fibrate-induced deterioration of renal function]. / Deterioro de la función renal inducido por fibratos.

INTRODUCTION: Fibrates represent one of the medications used to treat patients with hyperlipemia. Deterioration in renal function is not a very known adverse effect of fibric acid derivates. In the last 26 months we have detected thirteen patients with acute renal failure associated to fibrates in our outpatients' clinic. SUBJECTS AND METHODS: The aim of our study is to analyze our experience in deterioration in renal function associated to fibrates use. This is a retrospective charts review. RESULTS: From the thirteen patients (8 males/5 females) with mean age of 65.5 +/- 12.2 years, ten received Fenofibrate (FN), one Bezafibrate (BZ) and two Gemfibrozil (GF). Six cases had previously normal renal function and the seven remaining had mild chronic renal failure (CRF). The increase of serum Creatinine (Crs) value was higher than 74%. Acute renal failure was reversible in 9 patients (group 1), but the other 4 did not recover their previous renal function (group 2). The average of Crs before fibrate treatment was 1.33 +/- 0.36 mg/dl (Creatinine clearance 63.2 +/- 26.6 ml/min) and the highest average of Crs during the treatment was 2.22 +/- 0.49 mg/d (Creatinine clearance 37.3 +/- 11.9 ml/min). The average time until acute renal failure diagnosis was 6.7 +/- 5.8 months and the recovery of renal function was delayed an average of 3.8 +/- 3.5 months after fibrates withdrawn. Group 2 patients had a higuer Crs and longer time with fibrates than group 1 patients. CPK values were normal in all cases. In two patients renal biopsy was performed and no significant lesions were detected. CONCLUSION: The fibrate treatment can induce an acute renal failure. Four patients (30.8%) did not recover their basal renal function. When fibrate treatment begins a renal function should be monitored specially in patients with CRF.

[Efficacy and safety of etofibrate in patients with non-proliferative diabetic retinopathy]. / Wirksamkeit und Sicherheit von Etofibrat bei Patienten mit nicht proliferativer diabetischer Retinopathie.

INTRODUCTION: Diabetic retinopathy is the leading cause of vision loss or blindeness in working-age adults in the developed and developing countries. No curative treatments are available for diabetic retinopathy and the most common symptomatic treatment, laser photocoagulation, provides only partial and temporary relief from the progressive vascular damage caused by this disease. Etofibrate (Lipo-Merz) is an orally-administered treatment for lipid disorders that combines fibrate and nicotinic acid in a slow-release formulation. PATIENTS AND METHODS: This report describes the results of a double-blind, randomised, placebo-controlled study, performed to evaluate the efficacy and safety of etofibrat in patients with type 2 diabetes mellitus and concomitant diabetic retinopathy. They received either placebo or 1000 mg/day etofibrate for up to 12 months. Efficacy analyses were based on visual acuity assessment and blinded expert ratings of ocular fundus pathology, as well as laboratory analyses of serum lipid parameters. RESULTS: The evaluable population comprised 296 patients, 148 in each treatment group, of whom 89% completed the study and 73% completed according to protocol. After 12 months of treatment, a significantly larger population of etofibrate-treated patients than placebo-treated patients showed improvements in ocular pathology (46% versus 32%, respectively, p < 0.001); similar findings were already apparent after 6 months of treatment (43% versus 31%, respectively p < 0.001). Etofibrate treatment also produced significant improvements in total cholesterol, LDL-cholesterol and HDL-cholesterol in comparison to the placebo treatment group. Safety evaluations (adverse events, laboratory parameters) did not reveal any clinically significant adverse effects of etofibrate in comparison to placebo. CONCLUSION: Etofibrate provides a safe and effective treatment for ocular pathology resulting from type 2 diabetes mellitus.

[Treatment of dyslipidemia in patients with metabolic syndrome and chronic kidney disease]. / Lécba dyslipidemie u pacientu s metabolickým syndromem a chronickým onemocnením ledvin.

Dyslipidemia, often present in patients with metabolic syndrome and chronic kidney disease, contributes to increased cardiovascular risk and progression of renal impairment. In these patients, the probability of death from cardiovascular complications is higher than death consequent to terminal renal failure. Positive neuroprotective effects ofstatins and fibrates are being attributed to hypolipidemic as well as other, lipid-unrelated, properties. Statins are able to slow down the decline in glomerular filtration rate and may decrease proteinuria. Nevertheless, conclusive evidence that statins decrease the incidence of cardiovascular complications in patients with advanced chronic kidney disease is still lacking. Through their effect on albuminuria, fibrates contribute to slowing down ofthe progression of diabetic nephropathy. Controlled trials and clinical practice have shown that monotherapy with statins as well as fibrates is safe. Management of combined dyslipidemia requires, apart from the selection of a suitable statin-fibrate combination, careful monitoring of potential adverse effects and treatment tolerability and compliance. The results of the Czecho-Slovakian pivot study KOLCHRI have demonstrated the efficacy and safety of fenofibrate combined with low dose statin in patients with metabolic syndrome and stage 2-4 chronic kidney disease.

Use of statins and the risk of Parkinson's disease: a retrospective case-control study in the UK.

BACKGROUND: Case reports have related the use of HMG-CoA reductase inhibitors ('statins') to Parkinson's disease (PD). Paradoxically, however, statins may have potentially beneficial effects on neurodegenerative diseases due to their anti-inflammatory properties. OBJECTIVE: To explore the risk of the development of PD in association with untreated hyperlipidaemia and with hyperlipidaemia treated with lipid-lowering drugs in the UK primary care setting. METHODS: We conducted a case-control analysis using the UK-based General Practice Research Database (GPRD). Cases were incident PD cases > or =40 years of age between 1994 and 2005. One control was matched to each PD case based on age, sex, general practice and index date. Lipid-lowering drug use was assessed by exposure timing (current vs past use) and by exposure duration (1-9, 10-29 or > or =30 prescriptions) prior to the index date for both cases and controls. Odds ratios (OR) were calculated using conditional logistic regression, adjusted for body mass index, smoking and various cardiovascular, metabolic and psychiatric co-morbidities. RESULTS: We identified 3637 cases with an incident idiopathic PD diagnosis, and the same number of controls. Compared with patients without hyperlipidaemia, those with untreated hyperlipidaemia did not have an altered relative PD risk (adjusted OR 0.98, 95% CI 0.74, 1.30). The adjusted ORs for current use of > or =30 prescriptions for statins or fibrates compared with non-use of statins or fibrates were 1.06 (95% CI 0.75, 1.51) and 1.25 (95% CI 0.51, 3.06), respectively. CONCLUSIONS: In this observational study, the long-term use of statins or fibrates was not associated with a substantially altered relative risk of developing PD.

Differential associations between lipid-lowering drugs, statins and fibrates, and venous thromboembolism: role of drug induced homocysteinemia?

BACKGROUND: Previous studies reported that statin use was associated with a decreased risk of venous thromboembolism (VTE), whereas no association was found between fibrate use and VTE. This report aims to test the hypothesis that part of these contrasting associations is related to total homocysteine level (tHcy). MATERIALS AND METHODS: This report from a case-control study included 677 cases hospitalised with confirmed VTE and no major acquired risk factor of VTE and their 677 controls. Statin and fibrate exposure was defined as a current use of drugs at admission. Fasting serum tHcy was measured in all patients. RESULTS: The estimated odds ratio for VTE related to statin use was 0.53 (CI 95% 0.37-0.78), whereas it was 1.88 (CI 95% 1.29-2.74) for fibrate use. No difference was found for tHcy levels between patients who were current users of statin compared to non users (17.7 micromol/L+/-7.3 in users vs 18.4 micromol/L+/-8.4 in non users, p=0.50). In contrast, fibrate users had a significant higher mean level of tHcy than non users (23.2 micromol/L+/-8.7 in users vs 18.4 micromol/L+/-8.4 in non users, p<0.0001). Nevertheless, adjustment on tHcy level did not alter significance and strength of the association between fibrates and VTE (1.66, CI 95% 1.07-2.59). CONCLUSIONS: Statin use was associated with a significant decreased risk of VTE, whereas fibrate use was associated with a significant increased risk of VTE. This last association was independent of tHcy levels.

Therapeutic effects of fibrates in postprandial lipemia.

Hypertriglyceridemia is observed in many metabolic diseases such as the metabolic syndrome, diabetes mellitus, or mixed dyslipidemia frequently leading to premature coronary heart disease (CHD). Additionally, several studies have shown that postprandial hypertriglyceridemia is pronounced in patients with CHD, metabolic syndrome, hypertension, and other pathologic conditions. The triglyceride-rich lipoprotein remnants accumulating in the postprandial state seem to be involved in atherogenesis and in events leading to thrombosis. Since abnormal postprandial lipemia is associated with pathologic conditions, its treatment is of clinical importance.Fibrates are of significant help in managing hypertriglyceridemia. This review summarizes the effect of fibric acid derivatives on postprandial lipemia. Fibrates decrease the production of and enhance the catabolism of triglyceride-rich lipoproteins through the activation of peroxisome proliferator-activated receptor-alpha. Results of clinical studies with fibrates have confirmed their action in decreasing postprandial triglyceride levels by increasing lipoprotein lipase activity, decreasing apolipoprotein CIII production, and by increasing fatty acid oxidation in the liver.It is concluded that fibrates are effective agents in lowering the postprandial increase in remnant lipoprotein particles and retinyl palmitate. Furthermore, fibrates can also affect the postprandial lipid profile by increasing hepatic lipase levels and in some cases, by reducing cholesterol ester transfer protein activity. The main target of fibrate therapy is to improve fasting hypertriglyceridemia, which is an essential component associated with improving postprandial lipemia. Fibrates are well tolerated by patients and adverse effects have been reported rarely after their administration.

Behaviour and biomarkers of oxidative stress in Gambusia holbrooki after acute exposure to widely used pharmaceuticals and a detergent.

Pharmaceuticals are continuously dispersed into the environment, as a result of human and veterinary use, and have become a relevant environmental concern. In the present study, the acute toxicity of three therapeutic agents (diazepam, clofibrate, and clofibric acid) and a detergent, sodium dodecylsulphate (SDS), to the euryhaline fish Gambusia holbrooki was evaluated. Special attention was devoted to oxidative stress parameters. G. holbrooki males, captured in the estuary of the Minho River (NW Portugal), were exposed for 96 h to the selected compounds. The following oxidative stress biomarkers were evaluated in gills and liver tissues: reduced and oxidised glutathione, lipid peroxidation, and several antioxidant enzymes, namely (1) total and selenium-dependent glutathione peroxidase (GPx), (2) glutathione reductase (GRed), (3) copper-zinc superoxide dismutase (Cu-ZnSOD) and manganese superoxide dismutase (MnSOD), and (4) glutathione-S-transferases (GSTs). In the particular case of diazepam, swimming behaviour was also evaluated. The obtained results indicate an overall diminished oxidative stress response caused by SDS and diazepam. Oxidative-based alterations were observed after exposure to clofibrate and clofibric acid, with modifications of several enzymatic activities. Diazepam caused evident behavioural changes: animals showed dark pigmentation and also abnormal postures, namely lethargy and anomalous movement.

A case of rhabdomyolysis and thromboembolic event secondary to fibrate monotherapy.

Fibrates either alone or in combination with statins have been commonly used for the treatment of high non-HDL-cholesterol levels. In addition, this type of therapy is also associated with some adverse events like rhabdomyolysis. We present the first case in the literature describing the development of both rhabdomyolysis-induced acute renal failure and thromboembolic event under the treatment of fibrate monotherapy.

Colchicine: serious interactions.

(1) Renal failure, either pre-existing or induced by a nephrotoxic drug, increases the risk of adverse effects in patients taking colchicine; (2) Combining colchicines with a macrolide (except for spiramycin) carries a risk of life-threatening pancytopenia; (3) Ciclosporin co-administration can aggravate the neuromuscular adverse effects of colchicine; (4) Combining colchicine with lipid-lowering drugs (statins and fibrates) can cause myopathy; (5) Several mechanisms have been implicated: competition for cytochrome P450 or P-glycoprotein, additive adverse effects (especially on muscle), and colchicine accumulation due to a reduction in its renal excretion; (6) Patients with gout should use colchicine only after failure of symptomatic treatment: ice application, paracetamol, and possibly ibuprofen, a nonsteroidal antiinflammatory drug with well-documented adverse effects; (7) If colchicine is nevertheless used, it should be at the minimum effective dose. Close clinical monitoring is required in order to detect early signs of adverse effects, especially diarrhoea, the earliest sign in patients with renal failure and in the elderly.

Expert commentary: the safety of fibrates in lipid-lowering therapy.

The use of fibrates in the management of lipoprotein disorders has a history dating back to the mid-1960s. This group of drugs has now been tested in several large long-term trials with cardiovascular end points. Overall, there is good evidence for the reduction of cardiovascular disease in primary prevention studies and in those of subjects with manifest disease. More recent trials have suffered from high interference due to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) introduction, particularly in their placebo control groups. However, there is very good evidence for overall safety from a combined study of >20,000 patients in these controlled clinical trials lasting approximately 5 years. Abdominal pain has been observed more frequently in the statin vs placebo group. Myopathy, liver enzyme elevations, and cholecystitis have been potential adverse reactions of interest. However, these have occurred at a very low rate and are rarely found to be statistically more frequent in the active-treatment group compared with the subjects taking placebo. The recent Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study found a slightly higher incidence of pancreatitis, deep venous thrombosis, and pulmonary embolism. Small creatinine and homocysteine elevations are observed in many patients taking fibrates, and the effect of this on long-term outcomes is under study. The FIELD study also described a significant reduction in the rates of progression of proteinuria and vascular retinopathy with fibrate therapy. To date, there has been no study exclusive to patients with elevated triglycerides, raising the question of the potential benefit of these drugs in patients with the lipid abnormalities most effectively treated with fibrates.

Safety considerations with fibrate therapy.

Fibrates are an important class of drugs for the management of dyslipidemia. This class of drugs is generally well tolerated but is infrequently associated with several safety issues. Fibrates, most likely by an effect mediated by peroxisome proliferator-activated receptor-alpha, may reversibly increase creatinine and homocysteine but are not associated with an increased risk for renal failure in clinical trials. Fibrates are associated with a slightly increased risk (<1.0%) for myopathy, cholelithiasis, and venous thrombosis. In clinical trials, patients without elevated triglycerides and/or low high-density lipoprotein cholesterol (HDL) levels, fibrates are associated with an increase in noncardiovascular mortality. In combination with statins, gemfibrozil generally should be avoided. The preferred option is fenofibrate, which is not associated with an inhibition of statin metabolism. Clinicians are advised to measure serum creatinine before fibrate use and adjust the dose accordingly for renal impairment. Routine monitoring of creatinine is not required, but if a patient has a clinically important increase in creatinine, and other potential causes of creatinine increase have been excluded, consideration should be given to discontinuing fibrate therapy or reducing the dose.

Statin and statin-fibrate use was significantly associated with increased myositis risk in a managed care population.

OBJECTIVE: We quantified the risk of myositis associated with statin and fibrate drug use with other covariates within a managed care organization (MCO) population. STUDY DESIGN AND SETTING: The study spanned the years 1999-2003. Myositis cases had creatine kinase (CK) >or=10x upper limit of normal and a myopathy diagnosis. Exposures of statins, fibrates, and other drugs were assessed with age, gender, and indicators of suspected myopathy risk. Exposures were first analyzed within a cohort with CK monitoring and then within a more general secondary cohort. Adjusted relative risks (RRs) and incidence rates of myositis were generated by Poisson regression. RESULTS: Myositis was significantly associated with statin monotherapy (RR 2.8 [95% confidence interval, CI=1.3-5.9]), statin-fibrate combination therapy (9.1 [95% CI=3.5-23]), comorbid liver disease (4.3 [95% CI=1.5-13], and/or renal disease (2.5 [95% CI=1.3-5.0]). Myositis rates per covariate pattern ranged from 33 to 6,400 per 100,000 person-years. The mean time to event was 1.7 years for statin-fibrate use, 2.0 years for statins alone, and 2.1 years for unexposed. Within the secondary cohort, RRs increased up to 10 times further away from the null. CONCLUSION: Statins, with or without fibrates, and liver and renal disease were significantly associated with increased myositis risk in an MCO population.

[Influence of combined, hypolipemic therapy on lipids and non-lipid atherosclerosis risk factors]. / Wplyw skojarzonej terapii hipolipemicznej na lipidy osocza i pozalipidowe czynniki ryzyka miazdzycy.

It is very difficult to reach therapeutic goals of lipids concentrations n patients with very high and high risk development of coronary heart disease during statin monotherapy. Treatment with high doses of statins is associated with significantly increase of serious adverse events, especially rhabdomiolysis. Therefore are taken much more often trials of the combined hypolipemic therapy. In this article, we briefly review the clinical trial data on the efficacy, safety and influence on non-lipid atherosclerosis factors of combined therapy statin with fibrates, statin with nicotinic acid and statin with ezetimibe.

Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials.

OBJECTIVES: The aim of this research was to estimate the efficacy and safety of current high-density lipoprotein cholesterol (HDL-C)-increasing drugs. BACKGROUND: Epidemiologic evidence has shown that HDL-C is inversely related to coronary heart disease (CHD) risk. However, the evidence for reducing CHD risk by raising HDL-C is thin, predominantly due to the paucity of effective and safe HDL-increasing drugs. METHODS: Randomized controlled trials with fibrates and niacin, published between 1966 through February 2004 (MEDLINE), were retrieved. Information on treatment, baseline characteristics, serum lipids, end points, and side-effects were independently abstracted by two authors using a standardized protocol. RESULTS: Data from 53 trials (16,802 subjects) using fibrates and 30 trials (4,749 subjects) using niacin were included. Random-effects model showed 11% versus 10% reduction in total cholesterol, 36% versus 20% reduction in triglycerides, 8% versus 14% reduction in low-density lipoprotein cholesterol, and 10% versus 16% increase in HDL-C for fibrates and niacin, respectively. Apart from flushes in the niacin group, both fibrates and niacin were shown to be well-tolerated and safe. Fibrates reduced the risk for major coronary events by 25% (95% confidence interval 10% to 38%), whereas current available data for niacin indicate a 27% reduction. CONCLUSIONS: Fibrates reduce major coronary events and increase HDL-C levels without significant toxicity. Niacin has a more potent effect on HDL-C levels, whereas data on cardiovascular event rate reduction are limited. Future studies need to evaluate whether additional HDL increase by fibrates or particularly newer niacin formulations on top of statin therapy translates into further event reduction in high-risk subjects, without significant toxicity.

Statin safety: a systematic review.

A systematic review of cohort studies, randomized trials, voluntary notifications to national regulatory authorities, and published case reports was undertaken to assess the incidence and characteristics of adverse effects in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins. For statins other than cerivastatin, the incidence of rhabdomyolysis in 2 cohort studies was 3.4 (1.6 to 6.5) per 100,000 person-years, an estimate supported by data from 20 randomized controlled trials. Case fatality was 10%. Incidence was about 10 times greater when gemfibrozil was used in combination with statins. Incidence was higher (4.2 per 100,000 person-years) with lovastatin, simvastatin, or atorvastatin (which are oxidized by cytochrome P450 3A4 [CYP3A4], which is inhibited by many drugs) than pravastatin or fluvastatin (which are not oxidized by CYP3A4). In persons taking simvastatin, lovastatin, or atorvastatin, 60% of cases involved drugs known to inhibit CYP3A4 (especially erythromycin and azole antifungals), and 19% involved fibrates, principally gemfibrozil. The incidence of myopathy in patients treated with statins, estimated from cohort studies supported by randomized trials, was 11 per 100,000 person-years. For liver disease, randomized trials reported fewer hepatobiliary disorders in patients allocated statins than in those allocated placebo. The notification rate of liver failure to regulatory authorities was about 1 per million person-years of statin use. Randomized trials show no excess of renal disease or proteinuria in statin-allocated participants, and the decline in glomerular filtration rate was smaller with statins than with placebo. Evidence from 4 cohort studies and case reports suggests that statins cause peripheral neuropathy, but the attributable risk is small (12 per 100,000 person-years). No change in cognitive function was found in randomized trials of statins in elderly patients.

Aryloxoalcanoic compounds induce resistance to antibiotic therapy in urinary tract infection caused by Escherichia coli.

Clofibric acid (CL) is a compound used to control hypertriglyceridemia, and ethacrynic acid (ET) is administered to enhance diuresis. These compounds are structurally analogous to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), as they have a chlorinated phenoxy moiety. As these agents are mainly excreted by the renal route, they could potentially coexist with Escherichia coli in the urinary tract of infected patients. Induction of the in vitro resistance of E. coli to hydrophilic antibiotics was determined by increasing the values of the minimum inhibitory concentration (2-40-fold). These results correlated with drastically inhibited expression of the hydrophilic bacterial channel OmpF. In vivo assays were performed in ascending urinary tract infection in female BALB/c mice. Treatment with the hydrophilic antibiotic cephalexin 25 mg kg(-1) day(-1) by the oral route diminished renal infection. The CFU mean values in the kidneys were between 75% and 89% lower than those in animals without treatment. Simultaneous exposure to CL (at a therapeutic dose, 28.6 mg kg(-1) day(-1)) did not change the effect of the treatment. In contrast, ET at 2.9 mg kg(-1) day(-1) or 2,4-D at 70 mg kg(-1) day(-1) inhibited the antibiotic therapeutic effect. Moreover, 2,4-D dramatically increased bacterial infection after 9 days of exposure.