Deficiency or activation of peroxisome proliferator-activated receptor α reduces the tissue concentrations of endogenously synthesized docosahexaenoic acid in C57BL/6J mice

BACKGROUND/OBJECTIVES: Docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid (LCPUFA), is acquired by dietary intake or the in vivo conversion of α-linolenic acid. Many enzymes participating in LCPUFA synthesis are regulated by peroxisome proliferator-activated receptor alpha (PPARα). Therefore, it was hypothesized that the tissue accretion of endogenously synthesized DHA could be modified by PPARα. MATERIALS/METHODS: The tissue DHA concentrations and mRNA levels of genes participating in DHA biosynthesis were compared among PPARα homozygous (KO), heterozygous (HZ), and wild type (WT) mice (Exp I), and between WT mice treated with clofibrate (PPARα agonist) or those not treated (Exp II). In ExpII, the expression levels of the proteins associated with DHA function in the brain cortex and retina were also measured. An n3-PUFA depleted/replenished regimen was applied to mitigate the confounding effects of maternal DHA. RESULTS: PPARα ablation reduced the hepatic Acox, Fads1, and Fads2 mRNA levels, as well as the DHA concentration in the liver, but not in the brain cortex. In contrast, PPARα activation increased hepatic Acox, Fads1, Fads2 and Elovl5 mRNA levels, but reduced the DHA concentrations in the liver, retina, and phospholipid of brain cortex, and decreased mRNA and protein levels of the brain-derived neurotrophic factor in brain cortex. CONCLUSIONS: LCPUFA enzyme expression was altered by PPARα. Either PPARα deficiency or activation-decreased tissue DHA concentration is a stimulus for further studies to determine the functional significance.

Biological evaluation of a siliconized analog of clofibrate [silafibrate] in rodents

Silicon is the element very similar to carbon, and bioactive siliconized compounds have therefore received much attention. Siliconization of a compound enhances its biological activities. In the present study the hypolipidemic effect and toxicity of clofibrate and its siliconized analog, silafibrate, were compared. The experiments were performed in hypercholesterolemic Wistar rats. Animals received high fat diet with 62.75% normal chow, 2% cholesterol, 0.25% cholic acid, 15% lard oil, 10% wheat flour and 10% sucrose. Silafibrate[40 mg/kg/day] produced a predominant reduction in the serum levels of total cholesterol [28.4%, p < 0.001], triglycerides [62%, p < 0.0001] and low-density lipoproteins [27%, p < 0.001] being more effective than the reference drug clofibrate [20%, 40%, 14.5%; p < 0.05]. Similarly, it increased the total antioxidant levels in serum by 40% [p < 0.05]. Simultaneously, treatment with silafibrate also reduced the malondialdehyde [MDA] concentration by 41% [p < 0.05]. LD[50] of silafibrate, given orally, was greater than 2000 mg/kg body weight in albino mice while LD[50] for clofibrate was calculated to be 1220 mg/kg. Thirty-day subacute toxicity was also evaluated with oral daily dose at 25, 50 and 100 mg/kg body weight in Wistar rats. No significant changes in body weight, food intake, behavior, mortality, hematology, blood biochemistry, vital organ weight were detected. The results of this study indicate that the effectiveness and safety of the hypolipidemic drug, clofibrate, were enhanced remarkably by replacing chlorine atom in its phenoxy ring with trimethylsilyl

[ effect of clofibrate and phototherapy on physiological jaundice in term newborns]

Clofibrate is an effective anti lipid agent that induces glucuronyltransferase could increase bilirubin conjugation. The aim of this study was to evaluate effect of clofibrate on neonatal physiologic jaundice. Randomized clinical trial sampling method used and 60 healthy term neonates which were admitted in Imam Reza Hospital of Kermanshah-Iran because of indirect hyperbilirubinemia enrolled into the study. 30 neonates [case group] were treated with single oral dose of clofibrate [100/mg] plus phototherapy and 30 neonates [control group] received only phototherapy. Serum total and direct bilirubin levels were measured at admission, 12 hours later, and then every 24 hours until 96 hours. There were no significant difference between two groups regarding to gender, age, weight and total serum bilirubin level at the admission. Mean values for total bilirubin of serum in case group 12, 24 and 48 hours after admission were significantly lower than control group [P<0.001]. The mean of needed time for phototherapy in case group was significantly less than the control group [P<0.00l]. It seems that clofibrate plus phototherapy is effective for treatment of neonatal physiologic jaundice in healthy term newborns, although further studies are necessary for evaluation of clofibrate safety as a routine treatments

effect of clofibrate on decreasing serum bilirubin in healthy term neonates under home phototherapy

This study was designed to determine the effect of clofibrate on neonatal uncomplicated jaundice treated with home phototherapy. This clinical trial study was performed on 60 newborns with jaundice that received home phototherapy. Inclusion criteria were body weight between 2500 to 4000 gr, breastfed, I total serum bilirubin [TSB] between 14 to 20 mg/dl, aged over 72 hours. The neonates were randomly divided into two groups. All received home phototherapy. Group I received a single dose of 50 mg/kg clofibrate and the other group served as control group. Total serum bilirubin level was measured every 24 hours. Two groups were matched regarding weight, sex, age and first TSB. At 24 and 48 hours of treatment, the mean values of TSB in the clofibrate group were 13.72 [1.56], 9.5 [0.56] and in the control group 15.30 [1.44], 12.6 [1.44]. The results show that TSB was significantly decreased after 24 and 48 hours in clofibrate group [P<0.001]. The mean duration of phototherapy in group I was 72[0.0] hours and in the control group 76.80 [ +/- 9.76] hours. The duration of phototherapy was significantly shorter in clofibrate group [P<0.001]. Clofibrate is effective for outpatients with neonatal hyperbilirubinemia who are under home phototherapy. Of course, further studies are needed for approved routine use of this drug in the treatment of neonatal jaundice

The effect of clofibrate with phototherapy in late pre-term newborns with non-hemolytic jaundice.

Background : Despite an understanding of the enzymatic pathways leading to bilirubin production and degradation, very few pharmacologic interventions are utilized and the mainstay of treatment remains phototherapy. Aims : To evaluate the efficacy of clofibrate in reducing total serum bilirubin levels in late pre-term neonates with non-hemolytic jaundice. Design and Setting : Double-blind, placebo-controlled, randomized trial; tertiary level neonatal unit. Materials and Methods : A randomized controlled study was carried out in the neonatal ward of Children's Hospital, Tabriz, Iran, over a 1-year period. Sixty-eight healthy late pre-term infants readmitted with non-hemolytic hyperbilirubinemia were randomized to receive phototherapy and clofibrate (n= 35) or phototherapy and placebo (n= 33). Statistical Analysis Used : Chi-square test and independent sample 't' test. Results : There were no significant differences in the weight, gender, modes of delivery and age of neonates between the two groups. Similarly the mean total serum bilirubin (TSB) level at the time of admission was not significantly different between the two groups [mean± SD: 19.72 ± 1.79 (95% confidence interval: 19.12-20.54 mg/dL) vs. 20.05 ± 2.82 (95% confidence interval, 19.54-22.04 mg/dL), P= 0.57]. The mean TSB 48 hours after phototherapy [mean± SD: 8.06± 1.34 (95% confidence interval: 7.94-10.18 mg/dL) vs.10.94 ± 2.87 (95% confidence interval: 9.92-12.16 mg/dL), P= 0.02] and the mean duration of phototherapy [mean± SD: 64.32 ± 12.48 (95% confidence interval: 60-81.6 hours) vs. 87.84 ± 29.76 (95% confidence interval: 79.2-108 hours), P< 0.001] were significantly lower in the clofibrate-treated group. Conclusions : Clofibrate is an effective adjunctive drug in neonatal hyperbilirubinemia, which results in decreased TSB level and reduced duration of phototherapy in late pre-term newborns.

Advances in the study of regulation of novel organic cation transporter-2 / 药学学报

Novel organic cation transporter-2 (OCTN2), a member of the organic cation transporter family, may transport carnitine and multiple organic cationic drugs. Thus OCTN2 possesses substantial roles in physiology and pharmacology. A number of researches have proven that many factors can regulate the expression and/or function of OCTN2 via different pathways, and then may affect the homeostasis and disposition of drugs. This paper reviews recent progresses in this field.

Efficacy of clofibrate on severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency (a randomized clinical trial).

Glucose-6-phosphate dehydrogenase (G6PD) deficiency may cause severe hyperbilirubinemia with bilirubin encephalopathy unless intervention is initiated. The aim of this study was to assess the efficacy of clofibrate in full term G6PD deficient neonates with jaundice. A randomized clinical trial study was performed in two groups of full-term G6PD deficient jaundiced neonates (clofibrate treated group, n = 21; control group, n = 19). Infants in the clofibrate group received a single oral dose of 100 mg/kg clofibrate, whereas control group received nothing. Both groups were treated with phototherapy. Serum total and direct bilirubin levels were measured at the onset of treatments, 16, 24 and 48 hours later. On enrollment, the mean total serum bilirubin (TSB) level in the clofibrate treated group was 18.40 +/- 2.41 and in the control group was 17.49 +/- 1.03 (p = 0.401). At 16, 24 and 48 hours of treatment, the mean TSB in the clofibrate group were 15.2 +/- 1.9, 12.6 +/- 2.4, and 10.1 +/- 2.4 and in the control group were 16.5 +/- 1.2, 13.3 +/- 2.2 and 11.4 +/- 2.4, respectively (p = 0.047). At 48 hours, 7 (33%) cases in the clofibrate group and one (5%) case in the control group were discharged with a TSB < 10 mg/dl (p = 0.031). No side effects were observed on serial examinations during hospitalization, or on the 1st and 7th days after discharge. The results show that clofibrate induces a faster decline in serum total bilirubin level, a shorter duration of phototherapy, and hospitalization with no side effects in full-term G6PD deficient neonates with jaundice.

Effect of clofibrate in non-hemolytic indirect hyperbiliru-binemia in full term neonates.

OBJECTIVE: Jaundice is a common clinical problem in neonatal period which may result in brain damage even in healthy full term newborns, when it is severe. The aim of this study was to characterize the therapeutic effect of clofibrate in full term neonates who present with nonhemolytic jaundice. METHODS: A clinical controlled study was performed on 60 full term neonates who presented with non- hemolytic jaundice. 30 neonates were treated with a single oral dose of clofibrate (100 mg/Kg) plus phototherapy (case group), while 30 neonates received only phototherapy (control group). Both groups were compared in regard to post therapeutic mean total and indirect plasma bilirubin levels, admission duration and the rate of exchange transfusion. RESULTS: The reduction rate of total and indirect plasma bilirubin levels were significantly higher in the clofibrate- treated group as compared with the control group (P< 0.05). The mean duration of admission was found to be reduced from 2.9 +/- 0.9 days in the control groupl to 2.2 +/- 0.6 days in clofibrate- treated group (P=0.002). The mean plasma total bilirubin level was lower in the clofibrate- treated group. No cases required phototherapy after 48 hour in clofibrate- treated group, while 9 neonates (30%) and 2 neonates (6.7%) required phototherapy after 72 hour and 96 hour respectively in the control group. There was no difference between both the groups for sex, the time of developing jaundice and the rate of exchange transfusion. CONCLUSION: A single dose of clofibrate (100 mg/Kg) along with phototherapy is more effective than phototherapy alone in treating non-hemolytic hyperbilirubinemia in term healthy newborn infants.

Determination of effect of low dose vs moderate dose of clofibrate on the decreasing in serum bilirubin level in the healthy neonate

This study was performed to determine the effect of low doses [25 mg/Kg] vs. moderate doses [50 mg/Kg] of clofibrate in treatment of non-hemolytic hyperbilirubinemia in healthy term neonates. A clinical randomized controlled trial was performed in three groups of healthy term neonates. One group was treated with a single low dose of clofibrate [25 mg/Kg] while another group received a single moderate dose [50mg/kg] both orally plus phototherapy; the results were compared with those of a control group that received only phototherapy. The mean total serum bilirubin [TSB] levels of 12th and 24th hours were significantly lower in the two clofibrate-treated groups as compared with the control group [P=0.002 and P=0.003, respectively]. There was no statistically significant difference between the mean of TSB levels in the two clofibrate-treated groups. Treatment with clofibrate also resulted in a shorter duration of jaundice and a decreased use of phototherapy [P=0.01]. No side effects were observed. The present study demonstrated that there was no significant difference between a low [25mg/Kg] and moderate [50mg/Kg] doses of clofibrate in reducing TSB levels and also decreased need of phototherapy in healthy breastfed term newborns with marked hyperbilirubinemia [TSB>16 mg/dL]

Hypolipidemic activity of Indan--1--acetic acids.

To study the hyoplipidemic activity of non-methoxy and methoxy substituted--alkyl indan acetic acids in normogenic and hypergenic animal models. The hyoplipidemic activity was evaluated using normogenic and hypergenic rat models. Indan acids synthesized in our laboratory (50 mg/kg) and the standard drug clofibrate (50 mg/kg) were used for this study. Dimethoxy substituted -methyl and -ethyl indan acetic acids (9 & 10) exhibited significant hypocholesterolemic activity in both animal models. Clofibrate showed cholesterol lowering activity of 18% in normogenic rats while test agents 9 and 10 produced a similar activity of 20% and 17% respectively. Liver cholesterol and liver weight of the animals tested were found normal in case of the test compounds while liver weight was increased by 15% in clofibrate treated rats. LDL and VLDL cholesterol levels were also affected by compounds No. 9 and 10. Compounds having a smaller alkyl groups (R = CH3, C2H5) at--carbon atom of the acetic acid moiety exhibited significant hypocholesterolemic activity.

Treatment of jaundice in full term newborn infants with clofibrate

Clofibrate is an antilipidemic agent and a glucuronosyl transferase inducer. The aim of this study was to test the therapeutic effect ofclofibrate in full term neonates with non-hemolytic jaundice. A case control study was performed on 60 full term neonates with non-hemolytic hyperbilirubinemia. Thirty neonales were treated with a single oral dose of clofibrate [100 mg/kg] plus phototherapy [clofibrate group] while 30 other neonates [control group] received only phototherapy. The mean total serum bilirubin levels at 12th, 24th and 48 hours of treatment were significantly [p<0.001] lower in the clofibrate group [15.5 +/- 2.7, 12.5 +/- 2.9, 10.6 +/- 1.9mg/dl] as compared with the control group [22.4 +/- 3.3, 18.6 +/- 3.1, 15.3i2.3mg/dl]. The mean duration of phototherapy was significantly reduced with clofibrate administration from 53'16.8 hours in the control group to 29 +/- 13 hours in the clofibrate group [p<0.0001]. No side effects were observed during the treatment and 2 days after discharge Clofibrate could be used effectively in non-hemolytic neonatal hyperbilirubinemia without any apparent side effects. However, the widespread use of this drug needs to be confirmed by further larger and longitudinal follow up studies.

Mecanismos de hepatotoxicidade / Mechanisms of hepatotoxicity

Hepatopatia relacionada ao uso de drogas hipolipemiantes tem sido definida como um dano celular (aumento das enzimas AST e ALT) sem alterações colestáticas (aumento de bilirrubinas e/ou fosfatase alcalina). Seis mecanismos são propostos para a hepatopatia: 1. Reações de alta energia no citocromo P450 comprometendo a homeostase do cálcio com a ruptura de fibrilas intracelulares e lise de hepatócitos. 2. Disfunção de proteínas transportadoras relacionadas com o fluxo de ácidos biliares (mecanismo proposto para a toxicidade hepática dos fibratos). 3. Reações imunes geradas pela formação de metabólitos das drogas hipolipemiantes formados no fígado. 4. Hepatoxicidade promovida por células T com inflamação adicional mediada por neutrófilos. 5. Apoptose mediada por TNF e Fas (imune-mediada). 6. Estresse oxidativo gerado por dano a organelas intracelulares. Ainda, idade avançada, consumo excessivo de álcool, altas doses de drogas hipolipemiantes, interação com outros fármacos, e doença hepática ativa prévia podem aumentar a hepatotoxidade.

Farmacologia do fibratos / Pharmacology of fibrates

Os fibratos são as drogas de escolha nas hipertrigliceridemias. Após sua absorção, os fibratos são metabolizados pelo fígado, utilizando isoenzimas P450 não compartilhadas pelas estatinas. Entretanto, para alguns fibratos, como o genfibrozil, uma interação com estatinas pode ocorrer durante a sua glucuronidação, ou pelo deslocamento de frações livres de estatina ligadas às proteínas plasmáticas. A vida-média plasmática é variável entre os fibratos (2-80 h). Recentemente, foi demonstrado que os fibratos promovem suas ações lipídicas pelo estímulo dos PPAR-alfa. Através dessa ação, existe um incremento na transcrição de alguns genes relacionados com o metabolismo lipídico, como a LLP, APOAI, APOAII, ABCA-1, bem como uma diminuição na expressão da APOCIII, e muitas outras ações.

Terapia hipolipemiante em situações especiais: hipotireoidismo e hepatopatias / Hypolipidemic therapy in special situations: hypothyroidism and liver disease

O hipotireoidismo é comum entre pessoas idosas, especialmente entre as mulheres. A suspeita diagnóstica deve se basear na presença de sinais e sintomas clássicos e a detecção pode ser feita pela elevação dos níveis do hormônio tireo-estimulante (TSH). Anormalidades lipídicas na presença de hipotireoidismo sub-clínico são de menor impacto. Entretanto, a reposição específica de hormônio tireoideano é tão mais importante quanto a magnitude do distúrbio glandular. Na vigência de doença hepática, alguns agentes hipolipemiantes podem levar a um agravamento do quadro, entretanto, estudos recentes têm mostrado que as estatinas podem ser utilizadas na presença de esteatose hepática. Terapia hipolipemiante combinada pode induzir aumentos de enzimas hepáticas e o monitoramento cuidadoso é recomendado nestes pacientes.

Effect of clofibrate in jaundiced term newborns.

OBJECTIVE: Clofibrate is a glucuronosyl transferase inducer that has been proposed to increase the elimination of bilirubin in neonates with hyperbilirubinemia. The aim of this study was to characterize the therapeutic effect of clofibrate in neonates born at full term and present with non-hemolytic jaundice. METHODS: A clinical controlled study was performed in two groups of healthy full term neonates. Thirty neonates were treated with a single oral dose of clofibrate (100 mg/kg) plus phototherapy (clofibrate-treated group) while another 30 neonates (control group) received only phototherapy. RESULT: The mean plasma total bilirubin levels of 12th, 24th and 48th hours were significantly lower in the clofibrate-treated group as compared with the control group (P < 0.0001, P < 0.0001 and P = 0.004, respectively). Treatment with clofibrate also resulted in a shorter duration of jaundice and a decreased use of phototherapy (P < 0.0001). No side effects were observed. CONCLUSION: Although other pharmacological agents such as metalloporphyrins and Sn-mesoporphyrin also seem to be effective in decreasing bilirubin production, these products are not available for routine use and cannot be used because the safety of these drugs has to be confirmed prior to their widespread use. Therefore, clofibrate is now the only available pharmacological treatment of neonatal jaundice.

A Case of Bezafibrate induced Rhabdomyolysis / 대한내분비학회지

Bezafibrate, a fibric acid derivative related to clofibrate, is being used increasingly in the treatment of hypertriglycemia. It is relatively well tolerated at usual dosage, and has a low incidence of adverse reactions. But we had recently observed a reversible deterioration of renal function requiring hemodialysis, presumed to be caused by bezafibrate treatment in a patient with diabetic nephropathy. A 55 year old man was admitted with complaints of general weakness and painful lower extremities. He had taken bezafibrate (200 mg every 12 hours) for the previous 4 months because of hypertriglycemia. After admission, the drug was withdrawn, and he was treated conservatively management with hydration and diuretics for bezafibrate induced rhabdomyolysis. Nevertheless, his symptom was not improved, so he was taken even hemodialysis. These findings suggested that bezafibrate should be admistered with great caution to patient with renal insufficiency. When it is admistered, CK, LDH, aldolase, and sGOT levels have to be checked for early detection of potential side effect.