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By analysis of the data from the Toxicogenomics Database (TG-GATEs), histidine decarboxylase gene (Hdc) was identified as largely and commonly upregulated by three fibrates, clofibrate, fenofibrate, and WY-14,643, which are known to induce hepatocellular hypertrophy and proliferation via stimulation of peroxisome proliferator-activated receptor α (PPARα) in rodents. As histamine has been reported to be involved in the proliferation of liver cells, the present study was conducted to focus on Hdc. Among other genes related to histidine and histamine, the expression of the gene of histamine ammonia lyase (Hal) was exclusively mobilized by the three fibrates. The expression of Hdc, which was usually very low in the liver, was increased with the repeated administration of fibrates, and concomitantly, the constitutive expression of Hal was suppressed. An interpretation is that the formation of urocanic acid from histidine under the normal condition switches to the formation of histamine. The mobilization of gene expression of Hdc and Hal by PPARα agonists could not be reproduced in primary cultured hepatocytes. The Hdc mRNA appeared to be translated to a protein which is processed differently from brain but similarly to gastric mucosa. Surprisingly, the fibrates caused hepatic hypertrophy but no induction of Hdc mRNA at all in mice. These results revealed that the changes in the histidine catabolism by PPARα agonists might be partially, but not directly, involved in the hepatocyte proliferation in rats, and there is a large genetic distance even between rat and mouse.

Lipid metabolism involves complex pathways, which are regulated in a similar way across vertebrates. Hormonal and hypolipidemic deregulations cause lipid imbalance from fish to humans, but the underlying mechanisms are far from understood. This study explores the potential of using juvenile brown trout to evaluate the in vivo interferences caused by estrogenic (17α-ethinylestradiol - EE2), androgenic (testosterone - T), and hypolipidemic (clofibrate - CLF) compounds in lipidic and/or peroxisomal pathways. Studied endpoints were from blood/plasma biochemistry, plasma fatty acid profile, ultrastructure of hepatocytes and abundance of their peroxisomes to mRNA expression in the liver. Both T and CLF caused minimal effects when compared to EE2. Estrogenized fish had significantly higher hepatosomatic indexes, increased triglycerides and very-low density lipoproteins (VLDL) in plasma, compared with solvent control. Morphologically, EE2 fish showed increased lipid droplets in hepatocytes, and EE2 and T reduced volume density of peroxisomes in relation to the hepatic parenchyma. Polyunsaturated fatty acids (PUFA) in plasma, namely n-3 PUFA, increased with EE2. EE2 animals had increased mRNA levels of vitellogenin A (VtgA), estrogen receptor alpha (ERα), peroxisome proliferator-activated receptor alpha (PPARα), PPARαBa and acyl-CoA long chain synthetase 1 (Acsl1), while ERβ-1, acyl-CoA oxidase 1-3I (Acox1-3I), Acox3, PPARγ, catalase (Cat), urate oxidase (Uox), fatty acid binding protein 1 (Fabp1) and apolipoprotein AI (ApoAI) were down-regulated. In summary, in vivo EE2 exposure altered lipid metabolism and peroxisome dynamics in brown trout, namely by changing the mRNA levels of several genes. Our model can be used to study possible organism-level impacts, viz. in gonadogenesis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Clofibrate is a known rodent hepatotoxicant classically associated with hepatocellular hypertrophy and increased serum activities of cellular alanine aminotransferase/aspartate aminotransferase (ALT/AST) in the absence of microscopic hepatocellular degeneration. At toxic dose, clofibrate induces liver and skeletal muscle injury. The objective of this study was to assess novel liver and skeletal muscle biomarkers following clofibrate administration in Wistar rats at different dose levels for 7 days. In addition to classical biomarkers, liver injury was assessed by cytokeratin 18 (CK18) cleaved form, high-mobility group box 1, arginase 1 (ARG1), microRNA 122 (miR-122), and glutamate dehydrogenase. Skeletal muscle injury was evaluated with fatty acid binding protein 3 (Fabp3) and myosin light chain 3 (Myl3). Clofibrate-induced hepatocellular hypertrophy and skeletal muscle degeneration (type I rich muscles) were noted microscopically. CK, Fabp3, and Myl3 elevations correlated to myofiber degeneration. Fabp3 and Myl3 outperformed CK for detection of myofiber degeneration of minimal severity. miR-122 and ARG1 results were significantly correlated and indicated the absence of liver toxicity at low doses of clofibrate, despite increased ALT/AST activities. Moreover, combining classical and novel biomarkers (Fabp3, Myl3, ARG1, and miR-122) can be considered a valuable strategy for differentiating increased transaminases due to liver toxicity from skeletal muscle toxicity.

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA 1 to LPA 6 ) mediates a variety of cellular functions, including cell motility. In the present study, we investigated the effects of LPA receptors on cell motile activity during multi-stage hepatocarcinogenesis in rat liver epithelial WB-F344 cells treated with chemical liver carcinogens. Cells were treated with a initiator (N-nitrosodiethylamine (DEN)) and three promoters (phenobarbital (PB), okadaic acid (OA) and clofibrate) every 24 h for 2 days. Cell motile activity was elevated by DEN, correlating with Lpar3 expression. PB, OA, and clofibrate elevated Lpar1 expression and inhibited cell motile activity. To evaluate the effects of long-term treatment on cell motility, cells were treated with DEN and/or PB for at least 6 months. Lpar3 expression and cell motile activity were significantly elevated by the long-term DEN treatment with or without further PB treatment. In contrast, long-term PB treatment with or without further DEN elevated Lpar1 expression and inhibited cell motility. When the synthesis of extracellular LPA was blocked by a potent ATX inhibitor S32826 before cell motility assay, the cell motility induced by DEN and PB was markedly suppressed. These results suggest that activation of the different LPA receptors may regulate the biological functions of cells treated with chemical carcinogens. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Background: Though topical corticosteroids (TC) are used for treating atopic dermatitis (AD) as a standard, there exist several problems including topical steroid addiction (TSA) or Red skin syndrome. Moreover, the number of patients, who refrain from using TC because of steroid-phobia, is increasing. Recently, topical PPAR alpha ligand application has been reported to improve experimental allergic dermatitis. The purpose of this study was to investigate the short-term efficacy and safety of topical clofibrate, one of PPAR alpha ligand, in such steroid-phobic patients with AD., Methods: This study was conducted as a double-blind design to investigate the effects of random administration of topical clofibrate and base (placebo) on skin manifestation and blood parameters of patients for 2 weeks. Severity was digitized using severity scoring systems for atopic dermatitis by the Japanese Dermatological Association (SSS-JDA) before and after two weeks. Subjective severity of patients was evaluated using visual analog scale (Pt-VAS). Serum thymus and activation-regulated chemokine (TARC) and immunoglobulin E (IgE) were also investigated., Results: Twenty patients were enrolled, and 19 of 20 patients completed the study. In 19 patients, the value of severity score using SSS-JDA was decreased significantly after administration of topical clofibrate (P=0.001). Subjective evaluation using Pt-VAS (P=0.008) and serum TARC levels (P=0.03) were also significantly decreased after two weeks of topical clofibrate. There was not a significant difference in serum IgE levels. No adverse effect was observed., Conclusions: Topical clofibrate is useful for patients with AD especially who are reluctant to use topical steroids.

Background: Treatment of hyperlipidemic patients with fibrates, agonists of peroxisome proliferator-activated receptor α (PPARα), provokes muscle atrophy as a side effect. The molecular mechanism underlying this phenomenon is still unknown. We tested the hypothesis that activation of PPARα leads to an up-regulation of the ubiquitin proteasome system (UPS) which plays a major role in protein degradation in muscle., Methods: Rats, wild-type and PPARα-deficient mice (PPARα(-/-)) were treated with synthetic PPARα agonists (clofibrate, WY-14,643) to study their effect on the UPS and myofibrillar protein breakdown in muscle., Results: In rats and wild-type mice but not PPARα(-/-) mice, clofibrate or WY-14,643 caused increases in mRNA and protein levels of the ubiquitin ligases atrogin-1 and MuRF1 in muscle. Wild-type mice treated with WY-14,643 had a greater 3-methylhistidine release from incubated muscle and lesser muscle weights. In addition, wild-type mice but not PPARα(-/-) mice treated with WY-14,643 had higher amounts of ubiquitin-protein conjugates, a decreased activity of PI3K/Akt1 signalling, and an increased activity of FoxO1 transcription factor in muscle. Reporter gene and gel shift experiments revealed that the atrogin-1 and MuRF1 promoter do not contain functional PPARα DNA-binding sites., Conclusions: These findings indicate that fibrates stimulate ubiquitination of proteins in skeletal muscle which in turn stimulates protein degradation. Up-regulation of ubiquitin ligases is probably not mediated by PPARα-dependent gene transcription but by PPARα-dependent inhibition of the PI3K/Akt1 signalling pathway leading to activation of FoxO1., General Significance: PPARα plays a role in the regulation of the ubiquitin proteasome system., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To evaluate the effect of single oral dose of 50 mg/kg clofibrate in hyperbilirubinemia of term healthy neonates in Yazd, Iran., Methods: A parallel single- blinded randomized clinical trial, conducted on 60 healthy term neonates admitted between July and December 2007 to Shahid Sadoughi Hospital. Inclusion criteria were neonates with gestation age of 38-42 wk, birth weight of 2500-4000 g, product of normal vaginal delivery, breast-fed and total serum bilirubin (TSB) level of 17-29.9 mg/dL. Neonates with sepsis, anemia, severe asphyxia, hemolytic diseases, major congenital anomalies, indirect hyperbilirubinemia and underlying hepatic disorders were excluded. Selection of patients was based on random allocation via table of random numbers and the patients distributed into two groups. In group one, 30 neonates were treated with phototherapy alone and in 30 of other group treatment done with single dose of 50 mg/kg clofibrate and phototherapy. The primary endpoint with respect to efficacy in reducing of TSB was achieving TSB to less than 14 mg/dL as measured at the beginning, 12, 24 and 48 h after the start of phototherapy. Secondary outcomes were hospital stay days, duration of phototherapy and side effects of treatments during hospital stay and on the second day after discharge., Results: No significant differences were seen from the viewpoint of rout of delivery, gender, gestational age, birth weight, hemoglobin and bilirubin level at time of admission and weight in discharge time in the two groups. After 48 h of intervention, 27 (90%) neonates in clofibrate group and 15 (56.7%) in control group had TSB of less than 14 mg/dL (p 0.02). Mean TSB 12 h after treatment (mean ± SD: 14.82 ± 1.7 mg/dL vs. 16.67 ± 1.77 mg/dL, P 0.001), 24 h after treatment (mean ± SD: 11.97 ± 2.92 mg/dL vs. 14.61 ± 2.52 mg/dL, P 0.001) and 48 h after treatment (mean ± SD: 7.91 ± 2.45 mg/dL vs. 12.74 ± 2.21 mg/dL, P 0.0001), mean of hospital stay days (mean ± SD: 1.7 ± 0.7 days vs. 3.2 ± 1.2 days, P 0.03) and duration of phototherapy (mean ± SD: 30.2 ± 13.99 h vs. 46.2 ± 15.58 h, P 0.001] were significantly lower in clofibrate group. Only loose stool was seen in two patients of clofibrate group and no significant difference was seen from view of safety of the treatments., Conclusions: A single dose of 50 mg/kg clofibrate in treatment of neonatal hyperbilirubinemia is effective, safe and cost effective in view of reducing hospital stay days.

The biological activity of peroxisome proliferators (PPs) is mediated by a class of receptors, known as PPARs (PP-Activated Receptor), belonging to the nuclear receptor superfamily. Upon ligand binding, PPARs dimerize with retinoid receptors, translocate to the nucleus, recognize specific PP-responsive elements on DNA and transactivate a number of genes. Several processes are regulated by PPARs, such as mitochondrial and peroxisomal fatty acid uptake and beta-oxidation, inflammation, intracellular lipid trafficking, cell proliferation and death. In addition, PPARs have been proposed to act as tumor suppressors or as tumor promoters, depending on the circumstances. In particular, PPs have been extensively studied for their hepatocarcinogenic action in rodents, most often ascribed to their antiapoptotic action. Recent evidence, however, has been provided about the antiproliferative, proapoptotic, and differentiation-promoting activities displayed by PPAR ligands. The present review will focus on the cytotoxic effects exerted by several PPs, among which clofibrate, on different types of tumor cells, with particular reference to the mechanisms of cell death and to their relevance to cancer induction and progression.

Background: In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whether fibrates could also induce liver cancer in species not responsive to peroxisome proliferation. In this study the effect of clofibrate treatment on peroxisome proliferation, production of oxidative stress, gene expression of pro- and anti-apoptotic genes and proto-oncogenes was investigated in the liver of pigs, a non-proliferating species., Results: Pigs treated with clofibrate had heavier livers (+16%), higher peroxisome counts (+61%), higher mRNA concentration of acyl-CoA oxidase (+66%), a higher activity of catalase (+41%) but lower concentrations of hydrogen peroxide (-32%) in the liver than control pigs (P < 0.05); concentrations of lipid peroxidation products (thiobarbituric acid-reactive substances, conjugated dienes) and total and reduced glutathione in the liver did not differ between both groups. Clofibrate treated pigs also had higher hepatic mRNA concentrations of bax and the proto-oncogenes c-myc and c-jun and a lower mRNA concentration of bcl-XL than control pigs (P < 0.05)., Conclusion: The data of this study show that clofibrate treatment induces moderate peroxisome proliferation but does not cause oxidative stress in the liver of pigs. Gene expression analysis indicates that clofibrate treatment did not inhibit but rather stimulated apoptosis in the liver of these animals. It is also shown that clofibrate increases the expression of the proto-oncogenes c-myc and c-jun in the liver, an event which could be critical with respect to carcinogenesis. As the extent of peroxisome proliferation by clofibrate was similar to that observed in humans, the pig can be regarded as a useful model for investigating the effects of peroxisome proliferators on liver function and hepatocarcinogenesis.

Liver disease following the use of hypolipidemic drugs has been reported as a cellular damage (increases in AST or ALT enzymes) without cholestatic alterations (bilirubin and or alkaline phosphatase increases). Six mechanisms were proposed for hepatotoxicity: 1. High energy reactions on P450 cytochrome impairing calcium homeostasis with rupture of intracellular fibrils and hepatocyte lysis. 2. Impairment of transporter proteins related to the bile acids flux (mechanism proposed for fibrate liver toxicity). 3. Immune reactions due to the formation of metabolites linked to enzymes following liver metabolism of hypolipidemic drugs. 4. Hepatotoxicity by T cells with additional inflammation mediated by neutrophils. 5. Apoptosis mediated by TNF and Fas (immune mediated). 6. Oxidative stress due to damage of intracellular organelles. In addition, advanced age, alcohol in excess, high doses of hypolipidemic drugs, interaction with other drugs, and previous active liver disease might increase liver toxicity.

Hypothyroidism is common in the elderly, especially among women. It should be suspected in the presence of classic signals and symptoms, and can be detected by an elevation of serum thyroid stimulating hormone (TSH). Lipid abnormalities in the presence of subclinical hypothyroidism are of minor importance. However, the importance of specific treatment (hormone replacement) increases with the magnitude of thyroid disturbance. Some hypolipidemic agents can aggravate prior liver disease, however, recent studies have shown that statins might be useful in the presence of steatohepatitis. Some associations of hypolipidemic drugs can increase liver enzymes, and careful monitoring is recommended.

Pharmaceuticals or their metabolites are partially excreted with urine or faeces ending up in raw sewage. Many of these substances are not biodegradable and their presence in influents of municipal wastewater treatment plants may cause adverse effects to sensitive biological processes such as nitrification, while on the other hand, they may go through the activated sludge process unreacted. The second step of nitrification, i.e. oxidation of nitrite to nitrate is particularly sensitive. Inhibition of this step under uncontrolled conditions may lead to accumulation of nitrite nitrogen in the plant effluent, a form of nitrogen which is particularly toxic. The effects caused by the presence of seven different pharmaceuticals to a culture of nitrite-oxidizing bacteria isolated from activated sludge are presented. These pharmaceuticals were ofloxacin, propranolol, clofibrate, triclosan, carbamazepine, diclofenac and sulfamethoxazole. Different effects were observed for each of the pharmaceuticals tested in this study. In the cases of ofloxacin and sulfamethoxazole significant inhibition was observed. Triclosan presented a substantial inhibitory effect on the substrate (nitrite) reduction rate. The long-term effect of triclosan on nitrite oxidizers was also examined in a CSTR reactor and conclusions were drawn regarding the reversibility of the inhibition caused by this compound.

The effects of a variety of fibrates on the cell viability were examined in human embryonal rhabdomyosarcoma cells (HRMSC). Five fibrates, including fenofibrate, clofibrate, gemfibrozil, bezafibrate and ciprofibrate, all concentration-dependently reduced the cell viability determined by the mitochondrial enzyme activity. The cell injury occurred time-dependently and was marked at 24-48 h. The toxic action of fibrates was specific to HRMSC, since bezafibrate did not induce any marked changes in the viability of human microvascular endothelial cells or arterial smooth muscle cells. Synergistic cell injury was observed after a combined treatment with bezafibrate and simvastatin, although simvastatin alone reduced the cell viability. The cell injury was characterized by a typical nuclear damage, as evidenced by Hoechst 33342 staining and deoxynucleotidyl transferase dUTP nick-end label-positive staining. Similar cell-specific injury was induced by 8(S)-hydroxyeicosatetraenoic acid, a potent peroxisome proliferator-activated receptor alpha (PPARalpha) agonist. Consistent with these data, a marked expression for PPARalpha mRNA was observed in HRMSC but not in the endothelial or smooth muscle cells. Therefore, it is suggested that fibrates cause a cell-specific injury in HRMSC via activation of PPARalpha. Moreover, our present cell injury model using HRMSC may be useful for elucidating the mechanisms of clinical rhabdomyolysis induced by lipid-lowering agents.

Drug-induced myopathy and rhabdomyolysis are rare adverse drug reactions (ADR). They have been seen after the introduction of modern lipid-lowering drugs more regularly. The first description after medication with clofibrate dates back to 1968. Apparently, all fibrates can induce myopathy. It usually starts after a few days of medication, or after prolonged use, showing muscle weakness and/or pain. Concomitantly, the enzyme creatininephosphokinase (CPK) is raised dramatically. Muscular necrosis can follow leading secondarily to kidney failure, and eventually to death. For the class of statins, myopathy was more often seen after their introduction, and it became their most feared adverse effect, especially in combination of statins with other drugs (mibefradil, gemfibrozil, cyclosporin). In animal models the evolution of the disease and the mechanism of action may be elucidated. Though strong epidemiological data are lacking, the incidence of myopathy is probably similar for all lipid-lowering drugs and is in the range of 0.1-0.5% with monotherapy, increasing to 0.5-2.5% with combination therapy. Severe cases of rhabdomyolysis are rarer, but may have a significant mortality. The market success of cerivastatin within a short period has led to 100s of myopathies and some dozens of deaths. Though interactions on metabolism and ensuing high plasma levels can partially explain myopathy as intoxication, there are strong indications that other (endocrine, metabolic, genetic) factors might play a role in the pathophysiology. The patient population at risk should better be defined and withheld from myopathy-inducing drugs.

Pharmacological treatment of neonatal jaundice is again topical. At the beginning of the eighties, clofibrate was added to phenobarbital which was difficult to use and inefficient. Clofibrate is a better enhancer of glucuronosyl transferase induction than phenobarbital and causes 100% increase of hepatic bilirubin clearance within 6 hours. In the treatment of early jaundice in full term neonate, it significantly reduces bilirubinemia in 16 hours, and decreases the intensity and duration of jaundice and also phototherapy requirement. At the end of the eighties, new molecules inhibiting hepatic production of heme to bilirubin, like metalloporphyrins, were introduced. These molecules block the transformation of heme to biliverdin and bilirubin. Among them, the Sn-mesoporphyrin seems to have the best efficacy when used prophylactically in premature infants between 30 and 36 weeks of gestational age, and also curatively in full-term neonates, with minimal side effects. However the product is not yet manufactured and can not be used in pediatrics practice. Therefore clofibrate represents the only pharmacological treatment of neonatal jaundice actually available.

As some fibric acid derivatives have been reported to exhibit photosensitizing effects in vivo, the antilipemic drugs fenofibrate, bezafibrate, clofibrate, and gemfibrozil were tested for their phototoxic potential in vitro by a photohemolysis test using human erythrocytes and different irradiation sources. In this system only fenofibrate revealed strong phototoxic properties, which were dependent both on the drug concentration and the irradiation doses. Above a surface dose of 40 J/cm2 UVA of an UVA (320-400 nm)-rich irradiation source or 1.6 J/cm2 UVB/0.8 J/cm2 UVA of an UVB (280-320 nm)-rich irradiation source human red blood cells were completely photohemolysed in the presence of fenofibrate. Bezafibrate- and gemfibrozil-induced photohemolysis remained beneath 10%, and clofibrate showed no phototoxicity at all. As the phototoxic potential of fenofibrate lies in the UVB and UVA range, this might be of relevance with regard to clinical photosensitivity.

This study examined the effects of ciprofibrate therapy (100 mg/day) on plasma lipids, lipoproteins and low density lipoprotein (LDL) kinetic heterogeneity in moderately hypercholesterolaemic subjects. The drug lowered plasma triglyceride and cholesterol by 41% and 17%, respectively. Very low density lipoprotein (VLDL) cholesterol fell by 38%, LDL cholesterol fell by 22%, while the content of the lipid in high density lipoprotein (HDL) increased by 11%. LDL structural and metabolic heterogeneity were assessed before and during therapy in eight subjects. Density gradient centrifugation was used to fractionate LDL into three species. LDL-I, the least dense, was not affected by therapy whereas LDL-II and LDL-III were decreased by 28% (P < 0.01) and 31% (N.S.). Baseline turnover studies revealed that LDL catabolism was subnormal and this was the cause of the raised cholesterol in these subjects. Ciprofibrate therapy increased the apoLDL fractional catabolic rate (FCR) by 19%, principally by inducing a 38% enhancement (P < 0.03) in apoLDL removal by the receptor pathway. ApoLDL kinetics exhibited metabolic heterogeneity both before and during drug therapy. Analysis of plasma decay curves for the LDL tracer and urinary excretion data indicated that the lipoprotein comprised two metabolically distinct species, one with an FCR of about 0.50 pools/day (Pool A), the other with an FCR of about 0.18 pools/day (Pool B). Drug therapy decreased synthesis of and hence reduced the plasma mass of apoLDL in the slow metabolised pool B. This perturbation in synthesis was linked to the change in plasma triglyceride concentration. The resultant reduced proportion of pool B vs. pool A material accounted for the observed promotion of LDL receptor-mediated clearance. Ciprofibrate, therefore, produced beneficial changes in the plasma levels of VLDL, LDL and HDL and in the metabolism of LDL.

At present, it is very difficult, if not impossible, to draw reliable conclusions about the long-term risks of lipid lowering therapy. Many so-called "long-term" trials only cover a few years of treatment, comparative studies versus placebo are very rare and the notification of acute events in the context of pharmacovigilance does not provide information about the long-term risk. However, analysis of large scale primary or secondary prevention trials, the Lipid Research Clinics study with cholestyramine, the Helsinki cardiological study with gemfibrozil, the Coronary Drug Project with clofibrate and nicotinic acid, has not shown any significant differences between the treatment and control groups, in particular with regards to the prevalence of malignant disease. These reassuring observations contradict those of the WHO study with clofibrate: a significant increase in the incidence of cancer, especially gastrointestinal, is observed in the treatment group. Therefore, despite the absence of confirmed long-term clinical or biological adverse effects of lipid lowering drugs (apart from the WHO clofibrate study), the physician must remain vigilant, especially as the long-term risks are difficult to assess.

The authors describe the neurological manifestations of a female patient with hypercholesterolemia who developed myopathy in the course of her treatment with clofibrate. After the drug was tapered off, the neurological signs and symptoms disappeared. Therefore, attention is called for the importance of the differential diagnosis of iatrogenic myopathies with polymyositis.

Drug-induced myopathy has been reported with use of lovastatin, nicotinic acid, and clofibrate. A particularly severe form, often accompanied by rhabdomyolysis, has been reported with the use of lovastatin and gemfibrozil; however, as far as we know, no case has been documented with use of gemfibrozil alone. Herein, we report the first case (to our knowledge of gemfibrozil-induced myopathy, confirmed by drug rechallenge.

Acute muscle pain with stiffness developed in a patient with latent hypothyroidism after administration of clofibrate. Serum creatine kinase (CK), aspartate aminotransferase, and lactate dehydrogenase were markedly elevated, but returned to normal one and a half months after the discontinuation of clofibrate. Clofibrate challenge (750 mg/day) for three days caused muscle pain and an elevation in serum CK. Hypothyroidism may be a predisposing factor in the development of clofibrate-induced myopathy.

The efficacy of 1-(theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (etofylline clofibrate, Duolip) was investigated in 47 hyperlipidaemic patients of type II--V in an open within-patient study. All patients were dietary adapted before the preliminary wash-out period of 4 weeks and received etofylline clofibrate in a dosage of 500 mg/day (2x1 capsule) over 4 weeks, and 750 mg/day (3 x 1 capsule) over further 4 months. Depending on type reductions of cholesterol between 15 and 23% and of triglycerides between 24 and 52% were achieved. The total lipids were reduced, too, between 14 and 31%. Except for type IIb, all reductions were statistically significant. The rate of responders was between 47 and 80%. The higher dose (750 mg) only affected the cases of type III and IV, in which a higher rate of responders was found coinciding with more pronounced lipid level reductions. However, the influence of the treatment duration on this increased activity may play an important role. Etofylline clofibrate did not show any side effects and was well tolerated. This clinical finding coinciding with the results of the preceding pilot study on the human tolerability in 10 volunteers. From all parameters tested only GPT and cholesterol showed significant alterations (reduction).

We have compared two dose levels of Clozic, a novel agent with potential anti-rheumatoid activity, to D-penicillamine and aspirin in an observer blind randomised parallel group study of 56 patients with active rheumatoid arthritis. Eight clinical assessments and 26 laboratory assessments were performed on each patient at each visit over a six month period. Results were analysed by conventional methods and also by correlation matrices constructed between clinical and laboratory variables. Patients treated with D-penicillamine (500 mg/day) responded adequately and the control group on aspirin (up to 3.6 g of enteric coated formulation/day) performed well, though the withdrawal rate from this latter group was high, predominantly because of continued disease activity. Patients receiving Clozic (100 mg/day or 300 mg/day) improved more than patients receiving penicillamine, particularly at the higher dose. Comparison of methods of analysis validates the use of correlation matrices both for detecting anti-rheumatoid activity and for determining the optimum dose of a novel compound. This trial illustrates the problems of a study of this nature, with the powerful effect on patients of being enrolled in such a closely monitored investigation. It emphasises the greater value of biochemical changes in following disease changes.

We analyzed data obtained during the Coronary Drug Project to discover the influence of the drugs used on the frequency of gallbladder disease. Of 2680 placebo-treated men who had had myocardial infarction, gallbladder disease developed in 69. Corresponding figures for those given 2.5 mg of estrogen, 5.0 mg of estrogen and 1.8 g of clofibrate per day were 46 of 1061, 47 of 1081 and 42 of 1051, respectively. Each treatment group differed from placebo by over twice the standard error of the difference, life-table analysis yielding P less than 0.05 for each drug-placebo comparison. Forty-five variables, including age, body weight, blood pressure, serum lipids and blood sugar, were evaluated as risk factors. Age significantly correlated with prevalence of known gallbladder disease at entry (r = 0.066, P less than 0.001). No variable yielded a strong and consistent correlation with the incidence of subsequent new gallbladder disease. Gallstone formation is a risk whenever clofibrate or estrogen is prescribed.

Male F344 rats were given diethylnitrosamine in drinking water at a concentration of 40 p.p.m. for 5 weeks. One week later, the rats were fed diet containing clofibrate at concentrations of of 0,0.1, 0.25, 0.5, and 1% for 19 weeks. Hepatic tumors greater than 1 mm were counted. The doses of 0.1% and 0.25% clofibrate markedly enchanced the incidence of hepatic tumors, whereas 0.5% clofibrate had no effect and 1% clofibrate markedly inhibited hepatocarcinogenesis. It is clearly demonstrated in the present experiments that the lower doses of clofibrate (0.1% and 0.25%) promote hepatocarcinogenesis. The higher doses of clofibrate (0.5% and 1%) depress weight gain by lowering the intake of food. This lowered food intake might contribute to inhibition of hepatocarcinogenesis.

On the basis of the occurrence of myopathy in a clofibric acid treated child with diabetes insipidus, three other children with the same diseases were examined in order to find indications for a myopathic side-effect of the drug. When the children were found to have increased creatine phosphokinase activity and EMG changes, two of the authors took clofibric acid themselves. In both test persons subclinical myopathy was produced. After stopping the drug, transitional hypertriglyceridaemia occurred. These side-effects should serve as a warning of an uncritical application of clofibric acid and its esters.

A 70-year-old man with chronic renal failure was treated with clofibrate, 2.0 g daily for 6 days, and subsequently developed clofibrate-induced muscular syndrome (CMS), i.e., myalgia with severe muscle weakness and tenderness. Elevated muscular enzyme activities were found upon examination of his blood. Electron microscopic studies revealed atrophy of some muscle fibers and massive degenerative changes. The atrophic fibers were associated with damaged neuromuscular junctions. A literature survey of 44 cases with CMS is included.