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The Journal of Clinical Investigation Mar 1973Normal subjects and patients with antidiuretic hormone (ADH) deficiency were studied to determine the mechanism of the antidiuretic action of clofibrate. Before...
Normal subjects and patients with antidiuretic hormone (ADH) deficiency were studied to determine the mechanism of the antidiuretic action of clofibrate. Before clofibrate treatment, the patients' ability to concentrate urine with a standardized dehydration procedure correlated with the amount of ADH which was excreted. During clofibrate administration all six patients with ADH deficiency developed an antidiuresis which was like that of ADH, since there was no change in sodium, potassium, total solute, or creatinine excretion. There was a correlation between the patients' ability to concentrate urine during dehydration and the subsequent response to clofibrate, and the excretion of ADH during dehydration correlated with the excretion of ADH on clofibrate therapy. Clofibrate-induced antidiuresis in these patients was partially overcome by ethanol and by water loading. Clofibrate interfered with the ability of patients and subjects to excrete a water load and prevented the water load from inhibiting ADH excretion in the normal subjects. These studies suggested that clofibrate was acting through endogenous ADH and this thesis was supported by the failure of clofibrate to produce an antidiuresis when injected into rats with total ADH deficiency (Brattleboro strain) although an antidiuresis was produced in water-loaded normal rats. When the drug was injected into Brattleboro rats with exogenous ADH, clofibrate either did not alter or it inhibited the action of the ADH. The data demonstrate that clofibrate has a significant ADH-like action. This action appears to be mediated through the release of endogenous ADH.
Topics: Adult; Animals; Clofibrate; Creatinine; Dehydration; Diabetes Insipidus; Diuresis; Drinking; Ethanol; Female; Humans; Male; Middle Aged; Osmolar Concentration; Potassium; Rats; Sodium; Urination; Vasopressins
PubMed: 4685079
DOI: 10.1172/JCI107213 -
Kidney International Nov 1974
Review
Topics: Adrenal Glands; Animals; Antineoplastic Agents; Anura; Biological Transport; Calcium; Cell Membrane Permeability; Chlorpropamide; Clofibrate; Cyclic AMP; Diabetes Insipidus; Dogs; Humans; Models, Biological; Molecular Conformation; Osmolar Concentration; Oxytocin; Pituitary Hormones, Posterior; Prostaglandins; Radioimmunoassay; Receptors, Cell Surface; Sodium; Thiazines; Vasopressins; Water
PubMed: 4372455
DOI: 10.1038/ki.1974.116 -
Archives of Cardiovascular Diseases Sep 2008
Topics: Anticholesteremic Agents; Clofibric Acid; Drug Utilization; Guideline Adherence; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipids; Practice Guidelines as Topic; Practice Patterns, Physicians'; Registries; Treatment Outcome
PubMed: 19041834
DOI: 10.1016/j.acvd.2008.09.002 -
The Cochrane Database of Systematic... Dec 2012There are many pathological conditions leading to an elevated unconjugated bilirubin level (hyperbilirubinaemia) in neonates. Currently the standard therapies for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There are many pathological conditions leading to an elevated unconjugated bilirubin level (hyperbilirubinaemia) in neonates. Currently the standard therapies for unconjugated hyperbilirubinaemia include phototherapy and exchange transfusion. In addition to phototherapy, clofibrate has been studied as a treatment for hyperbilirubinaemia in several countries.
OBJECTIVES
To determine the efficacy and safety of clofibrate in combination with phototherapy versus phototherapy alone in unconjugated neonatal hyperbilirubinaemia.
SEARCH METHODS
Randomised controlled trials were identified by searching MEDLINE (1950 to April 2012) before being translated for use in The Cochrane Library, EMBASE 1980 to April 2012 and CINAHL databases. All searches were re-run on 2 April 2012.
SELECTION CRITERIA
We included trials where neonates with hyperbilirubinaemia received either clofibrate in combination with phototherapy or phototherapy alone or placebo in combination with phototherapy.
DATA COLLECTION AND ANALYSIS
Data were extracted and analysed independently by two review authors (MG and HM). Treatment effects on the following outcomes were determined: mean change in bilirubin levels, mean duration of treatment with phototherapy, number of exchange transfusions needed, adverse effects of clofibrate, bilirubin encephalopathy and neonatal mortality. Study authors were contacted for additional information. Studies were analysed for methodological quality in a 'Risk of bias' table.
MAIN RESULTS
Fifteen studies (two including preterm neonates and 13 including term neonates) were included in this review. All but one of the included studies were conducted in Iran. For preterm neonates, there was a significantly lower bilirubin level in the 100 mg/kg clofibrate group compared to the control group with a mean difference of -1.37 mg/dL (95% CI -2.19 mg/dL to -0.55 mg/dL) (-23 µmol/L; 95% CI -36 µmol/L to -9 µmol/L) after 48 hours. For the term neonates, there were significantly lower bilirubin levels in the clofibrate group compared to the control group after both 24 and 48 hours of treatment with a weighted mean difference of -2.14 mg/dL (95% CI -2.53 mg/dL to -1.75 mg/dL) (-37 µmol/L; 95% CI -43 µmol/L to -30 µmol/L] and -1.82 mg/dL (95% CI -2.25 mg/dL to -1.38 mg/dL) (-31 µmol/L; 95% CI -38 µmol/L to -24 µmol/L), respectively.There was a significantly lower duration of phototherapy in the clofibrate group compared to the control group for both preterm and term neonates with a weighted mean difference of -23.82 hours (95% CI -30.46 hours to -17.18 hours) and -25.40 hours (95% CI -28.94 hours to -21.86 hours), respectively.None of the studies reported on bilirubin encephalopathy rates, neonatal mortality rates, or the levels of parental or staff satisfactions with the interventions.
AUTHORS' CONCLUSIONS
There are insufficient data from different countries on the use of clofibrate in combination with phototherapy for hyperbilirubinaemia to make recommendations for practice. There is a need for larger trials to determine how effective clofibrate is in reducing the need for, and duration of, phototherapy in term and preterm infants with hyperbilirubinaemia.
Topics: Clofibrate; Combined Modality Therapy; Humans; Hyperbilirubinemia, Neonatal; Infant, Newborn; Phototherapy; Randomized Controlled Trials as Topic
PubMed: 23235669
DOI: 10.1002/14651858.CD009017.pub2 -
British Medical Journal Dec 1978
Topics: Adult; Cholesterol; Clofibrate; Coronary Disease; Humans; Male; Middle Aged; Myocardial Infarction
PubMed: 728731
DOI: 10.1136/bmj.2.6152.1585 -
Indian Pediatrics Jan 2012To evaluate the effect of clofibrate for unconjugated hyperbilirubinemia in neonates. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To evaluate the effect of clofibrate for unconjugated hyperbilirubinemia in neonates.
METHODS
A systematic review with meta-analysis of randomized controlled trials or quasi-randomized controlled trials was conducted to evaluate the clofibrate treatment in neonates with unconjugated hyperbilirubinemia. We followed the guidelines from the Cochrane review group and the PRISMA statement.
RESULTS
Of 148 studies identified, a total of 13 studies on 867 infants were included. A single oral administration of clofibrate was associated with decreased need of phototherapy (RR:.38, 95% CI: 0.21 to 0.68), shortened duration of phototherapy (mean duration: 23.88 h, 95% CI: 33.03 to -14.72 h) and reduced peak total serum bilirubin (mean duration: -1.62 mg/dL, 95% CI: 2.13 to -1.11 mg/dL). These effects were especially obvious in term infants and infants without hemolytic diseases. Data regarding mortality or kernicterus were not available from included studies.
CONCLUSIONS
Clofibrate may have short-term benefits for the infants with hyperbilirubinaemia, especially for population of term infants and infants without hemolytic diseases. Large RCTs with long-term followup are required to verify the safety of clofibrate and assess its long-term effects.
Topics: Bilirubin; Clofibrate; Humans; Hyperbilirubinemia, Neonatal; Infant, Newborn; Phototherapy; Treatment Outcome
PubMed: 22318100
DOI: 10.1007/s13312-012-0012-x -
British Medical Journal Jan 1979
Topics: Clofibrate; Humans; Hypercholesterolemia; Thyroiditis
PubMed: 421011
DOI: 10.1136/bmj.1.6157.195 -
British Medical Journal Apr 1971
Topics: Anticholesteremic Agents; Clofibrate; Humans; Lipids; Propionates; Time Factors
PubMed: 5575963
DOI: 10.1136/bmj.2.5755.223-a -
British Medical Journal Sep 1970
Topics: Anticholesteremic Agents; Clofibrate; Humans; Hypercholesterolemia; Hyperglycemia; Hyperlipidemias; Propionates
PubMed: 5470094
DOI: No ID Found -
The Journal of Toxicological Sciences Aug 2008Toxicokinetics (TK) is usually performed by measurement of the total drug concentrations in plasma. However, free drug concentrations in plasma are considered to...
Toxicokinetics (TK) is usually performed by measurement of the total drug concentrations in plasma. However, free drug concentrations in plasma are considered to correlate directly with toxicodynamics (TD). In the present study, to evaluate the applicability of TK/TD analysis based on free drug concentrations, we investigated the TK/TD of clofibrate, which binds to albumin with a higher ratio, using an albumin-deficient mutant strain, Nagase analbuminemia rats (NAR). TK, blood chemistry, histopathology, drug and fatty acid metabolizing enzymes and microarray analysis in the liver were examined after a 4-day oral administration of clofibrate. Compared to Sprague-Dawley (SD) rats, the parent strain of NAR, 4.1-fold higher AUC(0-24hr) based on free drug concentrations (3445 versus 844 microg.hr/ml) was observed in NAR when both rats showed the same level of AUC(0-24hr) based on the total drug concentrations (4436 versus 4237microg.hr/ml). Additionally, more severe hepatocellular hypertrophy, increase in aspartate transaminase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), decrease in total cholesterol (T.CHO), phospholipid (PL), triglyceride (TG), and non-esterified fatty acid (NEFA), and increase in the mRNA levels of fatty acid metabolizing enzymes (FAOS, CAT, and CPT) were observed in NAR at the same dose. These results demonstrated that NAR developed more severe toxicities and pharmacological effects than SD rats correlating with the higher AUC of the free drug concentrations. The results also suggested that TK/TD analysis based on the free drug concentration is appropriate to interpret the relationship between exposure and toxicity in cases of protein binding saturation including protein decrease or species differences on protein binding, especially when drugs showing a higher protein binding ratio are dosed.
Topics: Animals; Clofibrate; Cytochrome P-450 Enzyme System; Fatty Acids; Male; Protein Binding; Rats; Rats, Sprague-Dawley; Serum Albumin
PubMed: 18670166
DOI: 10.2131/jts.33.349