Structural simplification and bioisostere principle lead to Bis-benzodioxole-fibrate derivatives as potential hypolipidemic and hepatoprotective agents.

The bis-benzodioxole-fibrate hybrids were designed by structural simplification and bioisostere principle. Lipids lowering activity was preliminarily screened by Triton WR 1339 induced hyperlipidemia mice model, in which T3 showed the best hypolipidemia, decreasing plasma triglyceride (TG) and total cholesterol (TC), which were better than sesamin and fenofibrate (FF). T3 was also found to significantly reduce TG, TC and low density lipoprotein cholesterin (LDL-C) both in plasma and liver tissue of high fat diet (HFD) induced hyperlipidemic mice. In addition, T3 showed hepatoprotective activity, which the noteworthy amelioration in liver aminotransferases (AST and ALT) was evaluated and the histopathological observation exhibited that T3 inhibited lipids accumulation in the hepatic and alleviated liver damage. The expression of PPAR-α receptor involved lipids metabolism in liver tissue significantly increased after T3 supplementation. Other potent activity, such as antioxidation and anti-inflammation, was also observed. The molecular docking study revealed that T3 has good affinity activity toward to the active site of PPAR-α receptor. Based on these findings, T3 may serve as an effective hypolipidemic agent with hepatoprotection.

[Effects of Fibrates on Risk of Development of Diabetic Retinopathy in Japanese Working Age Patients with Type 2 Diabetes and Dyslipidemia: a Retrospective Cohort Study].

The aims of the present study were to investigate the effects of fenofibrate and bezafibrate on the risk of development of diabetic retinopathy (DR) in patients with type 2 diabetes and dyslipidemia. Japanese working age patients with type 2 diabetes and dyslipidemia were extracted from the Nihon University School of Medicine Clinical Data Warehouse. These patients were divided into three groups: control group (n=2549), fenofibrate group (n=40), and bezafibrate group (n=135). Multivariate logistic regression analysis was performed to assess the association between fibrates and the development of DR. After adjustment for covariates, fenofibrate showed no association with the risk of DR [adjusted odds ratio (OR), 0.160; 95% CI, 0.021-1.209; p=0.0758]. Bezafibrate also showed no association with the risk of DR (adjusted OR, 0.731; 95% CI, 0.411-1.299; p=0.2855). However, poor control of hemoglobin A1c (HbA1c ≥8.0%; adjusted OR, 3.623; 95% CI, 2.649-4.956; p<0.0001) and high low-density lipoprotein cholesterol (LDL-C ≥140 mg/dL; adjusted OR, 1.399; 95% CI, 1.013-1.932; p=0.0415) within the follow-up period of type 2 diabetes and dyslipidemia increased the risk of DR. Our results suggested that to prevent development of DR in patients with type 2 diabetes and dyslipidemia, controlling LDL-C levels as well as HbA1c levels under coexistence type 2 diabetes and dyslipidemia is more important than the selection of fibrate.

Treatment of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive fibro-stenotic strictures and destruction of the biliary tree. Currently, there is no effective treatment which can delay its progression or ameliorate the transplant-free survival. Moreover, a major chontroversy in PSC is whether to use UDCA. More recently, novel pharmacological agents emerged aiming at: i) modulation of bile composition; ii) immunomodulation; iii) targeting the gut microbiome; iv) targeting fibrosis. Successful PSC therapy, however, will be most likely a personalized combination of different drugs plus endoscopic treatment. This review aims at offering an overview on the experimental pharmacological strategies currently exploited for PSC treatment.

Physician variation in the de-adoption of ineffective statin and fibrate therapy.

OBJECTIVE: To describe physicians' variation in de-adopting concurrent statin and fibrate therapy for type 2 diabetic patients following a reversal in clinical evidence. DATA SOURCES: We analyzed 2007-2015 claims data from OptumLabs® Data Warehouse, a longitudinal, real-world data asset with de-identified administrative claims and electronic health record data. STUDY DESIGN: We modeled fibrate use among Medicare Advantage and commercially insured type 2 diabetic statin users before and after the publication of the ACCORD lipid trial, which found statins and fibrates were no more effective than statins alone in reducing cardiovascular events among type 2 diabetic patients. We modeled fibrate use trends with physician random effects and physician characteristics such as age and specialty. DATA EXTRACTION: We identified patient-year-quarters with one year of continuous insurance enrollment, type 2 diabetes diagnoses, and fibrate use. We designated the physician most responsible for patients' diabetes care based on evaluation and management visits and prescriptions of glucose-lowering drugs. PRINCIPAL FINDINGS: Fibrate use increased by 0.12 percentage points per quarter among commercial patients (95% CI, 0.10 to 0.14) and 0.17 percentage points per quarter among Medicare Advantage patients (95% CI, 0.13 to 0.20) before the trial and then decreased by 0.16 percentage points per quarter among commercial patients (95% CI, -0.18 to -0.15) and 0.05 percentage points per quarter among Medicare Advantage patients (95% CI, -0.06 to -0.03) after the trial. However, 45% of physicians treating commercial patients and 48% of physicians treating Medicare Advantage patients had positive trends in prescribing following the trial. Physicians' characteristics did not explain their variation (pseudo R2  = 0.000). CONCLUSION: On average, physicians decreased fibrate prescribing following the ACCORD lipid trial. However, many physicians increased prescribing following the trial. Observable physician characteristics did not explain variations in prescribing. Future research should examine whether physicians vary similarly in other de-adoption settings.

Establishment and characterization of a mouse model of rhabdomyolysis by coadministration of statin and fibrate.

Rhabdomyolysis is characterized by elevation of plasma creatine phosphokinase (CPK) level, and multiple organ disorders, especially renal failure, as well as approximately 50% of acquired rhabdomyolysis are caused by pharmaceuticals. Statins are known to cause rhabdomyolysis, and its incidence is ≥10 times higher with coadministration of statin and fibrate. The purpose of this study is to establish a mouse model of drug-induced rhabdomyolysis by coadministration of statin and fibrate to clarify the mechanisms of its myotoxicity. We administered lovastatin (LV) and gemfibrozil (GF) with a glutathione synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), to C57BL/6 J female mice once daily for 3 days. The plasma levels of CPK and aspartate aminotransferase (AST) were prominently increased, and the increase in plasma miR-206-3p and miR-133-3p levels, not the increase of miR-122-5p and miR-208-3p levels, suggested skeletal muscle-specific toxicity. The caspase 3/7 activity and mRNA levels of oxidative stress-related factors were elevated in skeletal muscle. Pharmacokinetic parameters showed that blood levels of statin were significantly increased by coadministered GF. The possibility of kidney injury was examined as in clinical rhabdomyolysis. In histological examination, vacuoles were observed in renal proximal tubules, and the plasma renal injury marker, lipocalin 2/neutrophil gelatinase-associated lipocalin (Lcn2/Ngal), was markedly increased in the mice coadministered LV and GF, suggesting mild complications of acute kidney injury. A quantitative comparison of the myotoxic potential of various statins was successfully performed using the present method. In this study, a rhabdomyolysis mouse model was established by coadministration of the clinically using statin and fibrate. This mouse model may be useful to identify drugs that have high risk for rhabdomyolysis.

Risk of diabetes with fibrates and statins: a pharmacoepidemiological study in VigiBase®.

In contrast to statins, the risk of diabetes with fibrates was not clearly studied. This study investigates a putative signal of diabetes associated with the use of fibrates using the World Health Organization (WHO) global individual case safety reports database, VigiBase® . We included all reports registered until the 31st December 2017 in VigiBase® to measure the risk of reporting 'hyperglycemia or new onset of diabetes' (SMQ term) compared with all other reports [as a reporting odds ratio (ROR 95% CI)] for fibrates, statins, and the combination fibrates + statins. The likelihood that diabetes resulted from statin-fibrate interaction was also estimated. According to the interaction additive model, a ROR value for coexposure exceeding the sum of the RORs estimated for each individual class of drug supports a potential drug-drug interaction (DDI). To assess the stability of our results, we performed several sensitivity analyses, according to outcome definition and after exclusion of putative competitive (hyperglycemic) drugs. We included 19 149 patients exposed to fibrates (without statins), 177 323 to statins (without fibrates) and 3 247 to statins plus fibrates. In contrast to statins (ROR = 1.75, 95% CI 1.72-1.78), no association was found for fibrates (ROR = 0.76, 95% CI 0.71-0.82). The ROR value was lower for the combination statins plus fibrates (ROR = 1.46, 95% CI 1.28-1.67). Similar trends were found in sensitivity analyses. This study, performed in the real conditions of use, failed to find a signal of diabetes with fibrates. It strengths the association previously described with statin without any evidence for a statin-fibrate DDI.

Association between venous thromboembolism events and fibrates: A comparative study.

AIM: Previous studies highlighted a significant association between fibrates and venous thromboembolism (VTE) events in dyslipidemia diabetic patients. Studies in non-diabetic patients are divergent. The present study investigated the association between VTE events and fibrates in diabetic and non-diabetic patients. METHODS: Two approaches were used: (1) a disproportionality analysis using the World health organization pharmacovigilance database VigiBase® was used to evaluate the reporting odds-ratio (ROR) of fibrates for VTE events. Clinical and demographic characterizations of patients with fibrates-related VTE reports are described; (2) a case control-study was performed using the Caen university hospital medical information database between January 2008 and December 2012. Cases were dyslipidemia patients who were hospitalized for VTE without an evident provoking factor. Up to four controls per case were selected in dyslipidemia patients hospitalized for a non-VTE event. Controls were matched to cases by age, gender, date of hospitalization, diabetes, chronic kidney disease and hospitalization department. A multivariate conditional logistic regression was performed. RESULTS: Disproportionality analysis: a total of 946 notifications were identified in VigiBase® (32.9% of diabetic patients). Fibrates were significantly associated with an increased report of VTE (ROR 1.14, CI 1.07-1.22). Case-control study: a total of 163 cases (21.5% of diabetic patients) and 514 matched controls were recruited. Fibrates were significantly associated with a higher risk of VTE events that required hospitalization in multivariate analysis (odds-ratio (OR) 3.67, CI 1.82-7.37, P=0.0003). The association was only significant for fenofibrate in both approaches. CONCLUSION: Fenofibrate was associated with a higher incidence of VTE events in diabetic and non-diabetic patients.

A review of the studies on food-derived factors which regulate energy metabolism via the modulation of lipid-sensing nuclear receptors.

Obesity is one of the most important risk factors for chronic metabolic disorders. Molecular mechanisms underlying obesity-related metabolic disorders have not been completely elucidated. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and are key metabolic regulators of the whole-body energy metabolism. Certain enzymes involved in carbohydrate and lipid metabolism are directly regulated by PPARs via their interaction with specific response elements in their gene promoters. Many food factors act as ligands of PPARs and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors, leading to the attenuation of obesity-related metabolic disorders. In this review, we describe our current knowledge of the role of PPARs in the regulation of whole-body energy metabolism and several examples of food factors that act as ligands of PPARs, which may be useful in the management of obesity and the accompanying energy metabolism abnormalities. Abbreviations: WAT: white adipose tissue; PPAR: Peroxisome proliferators-activated receptor; RXR: retinoid X receptors; mTORC1: mechanistic target of rapamycin complex 1; PPRE: PPAR-responsive regulatory elements; NAFLD: nonalcoholic fatty liver disease; LPL: lipoprotein lipase; FGF21: fibroblast growth factor 21; BAT: brown adipose tissue; UCP1: uncoupling protein 1; LPC(16:0): 1-palmitoyl lysophosphatidylcholine; C/EBP: CCAAT-enhancer binding proteins; STAT5A: signal transduction and activator of transcription 5A; APO apolipoptotein; CBP: cAMP response element-binding protein-binding protein; PGC1A: PPARγ coactivator protein 1a; HFD: high-fat diet; TG: triglyceride; VLDL: very low density lipoprotein; HDL: high density lipoprotein.

Fibrates in primary prevention of cardiovascular disease. Comments on the results of a systematic review of the Cochrane Collaboration. / Los fibratos en la prevención primaria de la enfermedad cardiovascular. Comentarios a los resultados de una revisión sistemática de la Colaboración Cochrane.

Fibrates are drugs that reduce triglycerides, elevate high-density lipoproteins, as well as decrease small, dense LDL particles. The results of a study have recently been published by the Cochrane Collaboration on fibrates efficacy and safety in the primary prevention of cardiovascular disease. This study includes a systematic review and a meta-analysis of 6 studies (16,135 patients) that evaluated the clinical benefits of fibrates compared to placebo use or other lipid-lowering drugs. This review showed evidence of a protective effect of the fibrates compared with placebo as regards a reduction 16% of a compound objective of death due to cardiovascular disease, non-fatal myocardial infarction, or non-fatal cerebrovascular accident (NNT: 112), and that reduce coronary morbidity and mortality by 21% (NNT: 125). In addition, fibrates could reduce previously established diabetic retinopathy. However, fibrates do not influence total mortality, or non-cardiovascular mortality. Its joint use with statins does not benefit patients without established cardiovascular disease, compared to the use of statins in monotherapy. Fibrates are safe, although they can elevate serum creatinine levels.

The influence of fibrate initiation on INR and warfarin dose in patients receiving chronic warfarin therapy.

Several drug interaction compendia report a risk of warfarin potentiation after initiation of a fibrate; however, the evidence of this interaction is limited. The objective of this study was to evaluate warfarin dose and international normalized ratio (INR) response among a large sample of patients receiving chronic warfarin who initiated a fibrate. This was a retrospective, one-sample, pre-to-post study. Adult patients who were receiving chronic warfarin therapy at the time of gemfibrozil or fenofibrate dispensing between 1/1/2000 and 3/31/2016 were included. Patients had at least one and two therapeutic INRs during the 90 days prior to (baseline) and after (follow-up), respectively, fibrate initiation. Comparison of stable warfarin dose:INR ratio between the baseline and follow-up periods and assessment of safety outcomes during follow-up were performed. There were 321 patients included. Patients were predominantly male (62.6%) with an indication of atrial fibrillation (44.2%). The mean warfarin dose:INR ratio was equivalent between the baseline and follow-up periods (13.4 mg/INR [± 6.9] vs. 13.5 mg/INR [± 7.5], respectively, p = 0.711). Rates of thromboembolism, bleeding, and all-cause mortality in the 90-day follow up were 0, 0.6, and 1.2%, respectively. Although individual patients may have labile INRs after fibrate initiation, no significant interaction between fibrate and warfarin in a large sample of real world patients was identified. The utility of additional INR monitoring after fibrate initiation in otherwise stable patients receiving chronic warfarin therapy is unclear.

[New name and new treatments for primary biliary cholangitits].

The name of chronic liver disease: primary biliary cirrhosis, has been changed to: primary biliary cholangitis, primarily because of the stigma associated with the word "cirrhosis", as only a minority of the patients develop cirrhosis. In this review we present data on epidemiology and discuss the current treatments with focus on ursodeoxycholic acid and the newly described effects of the farnesoid receptor agonist obeticholic acid.

[Fibrates and risk of venous thromboembolism: Case/no-case study in French pharmacovigilance database]. / Fibrates et risques thrombo-emboliques veineux : étude cas/non-cas dans la base nationale de pharmacovigilance.

INTRODUCTION: Several studies have investigated the occurrence of venous thromboembolic events (phlebitis and pulmonary embolism) [VTE] and fibrates. Fibrates could be associated with VTE although published data are contradictory. The objective of this study is to confirm the link between VTE and fibrates. MATERIALS AND METHODS: Retrospective disproportionality analysis (case/non-case method) from observations recorded consecutively in the French pharmacovigilance database between 1985 and 2016. Cases were defined as embolic and thrombotic events, thrombophlebitis; Non-cases were other adverse events reported over the same period. We measured the disproportionality of exposure to each fibrate among cases and no-cases. The analysis was validated with a positive control (drospirenone) and a negative control (paracetamol). RESULTS: We compared 19,436 cases (including 161 mentioning fibrates) to 563,310 non-cases (including 3228 fibrates). Reports of VTE were significantly associated with fenofibrate (ROR=1.83; 95% CI=[1.53; 2.2]) but not with other fibrates: bézafibrate (ROR=0.44; 95% CI=[0.2; 0.99]), ciprofibrate (ROR=1.15; 95% CI=[0.76; 1.73]) and gemfibrozil (ROR=0.91; 95% CI=[0.45; 1.84]). CONCLUSION: With this study, we confirm the link between VTE and fenofibrate. It is therefore advisable to remain cautious when prescribing fenofibrate, in particular in case of past history of VTE and to declare systematically any venous thromboembolic adverse events observed with these drugs.

Comparison of the effects of fibrates versus statins on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of head-to-head randomized controlled trials.

BACKGROUND: Raised plasma lipoprotein(a) (Lp(a)) concentration is an independent and causal risk factor for atherosclerotic cardiovascular disease. Several types of pharmacological approaches are under evaluation for their potential to reduce plasma Lp(a) levels. There is suggestive evidence that statins and fibrates, two frequently employed lipid-lowering drugs, can lower plasma Lp(a). The present study aims to compare the efficacy of fibrates and statins in reducing plasma concentrations of Lp(a) using a meta-analysis of randomized head-to-head trials. METHODS: Medline and Scopus databases were searched to identify randomized head-to-head comparative trials investigating the efficacy of fibrates versus statins in reducing plasma Lp(a) levels. Meta-analysis was performed using a random-effects model, with inverse variance weighted mean differences (WMDs) and 95% confidence intervals (CIs) as summary statistics. The impact of putative confounders on the estimated effect size was explored using random effects meta-regression. RESULTS: Sixteen head-to-head comparative trials with a total of 1388 subjects met the eligibility criteria and were selected for this meta-analysis. Meta-analysis revealed a significantly greater effect of fibrates versus statins in reducing plasma Lp(a) concentrations (WMD, -2.70 mg/dL; 95% CI, -4.56 to -0.84; P = 0.004). Combination therapy with fibrates and statins had a significantly greater effect compared with statin monotherapy (WMD, -1.60 mg/dL; 95% CI, -2.93 to -0.26; P = 0.019) but not fibrate monotherapy (WMD, -1.76 mg/dL; 95% CI, -5.44 to +1.92; P = 0.349) in reducing plasma Lp(a) concentrations. The impact of fibrates versus statins in reducing plasma Lp(a) concentrations was not found to be significantly associated with treatment duration (P = 0.788). CONCLUSIONS: Fibrates have a significantly greater effect in reducing plasma Lp(a) concentrations than statins. Addition of fibrates to statins can enhance the Lp(a)-lowering effect of statins.

Novel Treatment Strategies for Primary Biliary Cholangitis.

Despite the presumed immunological pathogenesis of primary biliary cholangitis, no clear or even harmful consequences have resulted from treatments designed to modify the immunological condition. Ursodeoxycholic acid (13-16 mg/kg/d) has, however, clear favorable effects that not only improve biochemical cholestasis, but also delay histological progression. Long-term treatment with ursodeoxycholic acid is associated with excellent transplant-free survival in cases showing a biochemical response at 1 year. Data on the effects of obeticholic acid and fibrates are encouraging. Moreover, recent pilot studies evaluating several biological agents targeting immunity such as different monoclonal antibodies and other drugs that modulate cholestasis are under investigation, although with limited results at present.

Omega-3 fatty acids supplementation improves endothelial function and arterial stiffness in hypertensive patients with hypertriglyceridemia and high cardiovascular risk.

Association between hypertriglyceridemia and cardiovascular (CV) disease is still controversial. The purpose of this study was to compare omega-3 and ciprofibrate effects on the vascular structure and function in low and high CV risk hypertensive patients with hypertriglyceridemia. Twenty-nine adults with triglycerides 150-499 mg/dL were divided into low (<7.5%) and high (≥7.5%) CV risk, randomized to receive omega-3 fatty acids 1800 mg/d or ciprofibrate 100 mg/d for 12 weeks. Treatment was switched after 8-week washout. Clinical evaluation and vascular tests were assessed at baseline and after intervention. Peripheral (131 ± 3 to 125 ± 3 mm Hg, P < .05) and aortic (124 ± 3 to 118 ± 2 mg/dL, P < .05) systolic blood pressure were decreased by ciprofibrate in low-risk patients. In high-risk patients, pulse wave velocity was reduced (10.4 ± 0.4 to 9.4 ± 0.3 m/s, P < .05) and flow-mediated dilation was increased (11.1 ± 1.6 to 13.5 ± 1.2%, P < .05) by omega-3. In conclusion, omega-3 improved arterial stiffness and endothelial function, pointing out the beneficial effect of this therapy on vascular aging, in high-risk patients.

[Fibrates therapy: Rational use fenofibrate 2016. Executive summary]. / Terapia con fibratos: uso racional del fenofibrato 2016. Resumen ejecutivo.

To control lipid factors risk, beyond proper management of LDL cholesterol according to individual risk, detection and treatment of atherogenic dyslipidemia and abnormal levels of triglycerides or HDL cholesterol it should be considered for address a global cardiovascular protection, both in primary and secondary prevention. In this sense, these recommendations collect data on efficacy and safety about the combination statin with fibrates, often necessary for total control of dyslipidemia, particularly in patients with metabolic disorders such as diabetes mellitus, metabolic syndrome or visceral obesity. Reference to control and monitoring of treatment is also done, as well as benefits of fenofibrate not linked directly to their lipid-lowering effect.

Serum concentrations of fibroblast growth factor 21 are elevated in patients with congenital or acquired lipodystrophy.

OBJECTIVE: Patients with lipodystrophy (LD) suffer from loss of subcutaneous adipose tissue accompanied by dysregulation of several adipocyte-secreted factors. However, regulation of adipocyte-expressed fibroblast growth factor (FGF) 21 which acts in an insulin-mimetic, lipid-lowering, and anti-atherogenic manner has not been investigated in non-human immunodeficiency virus (HIV) LD. MATERIAL AND METHODS: Circulating serum FGF21 levels were quantified in 37 patients with non-HIV LD and 37 controls matched for age, gender, and body mass index. Moreover, FGF21 plasma levels and mRNA expression were measured in LD mice and control animals. Additionally, serum FGF21 levels were assessed in 10 LD patients before and during metreleptin therapy. RESULTS: Median FGF21 serum concentrations were significantly higher in LD patients (381.2ng/l) as compared to the control group (231.2ng/l; p=0.023). There was an independent and positive association between circulating FGF21 and serum triglycerides (TG), as well as fibrate treatment, in multiple linear regression analysis. LD mice showed significantly upregulated FGF21 plasma levels (4.5-fold), as well as mRNA expression in various adipose tissue depots and liver as compared to controls (p<0.05). Metreleptin treatment did not significantly alter circulating FGF21 levels in human subjects. CONCLUSIONS: Serum concentrations of FGF21 are elevated in patients with non-HIV LD with adipose tissue and liver being potential sources of increased production. TG and fibrate treatment are independent positive predictors of circulating FGF21.

[Drug-induced Nonalcoholic Steatohepatitis].

Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease characterized by intense liver steatosis accompanied by hepatocyte destruction, inflammation and fibrous, despite little or no history of alcoholic consumption. There are also cases of drug-induced secondary steatohepatitis. Drug-induced steatohepatitis is a relatively rare type of drug-induced liver disease, but close attention to the possible onset of steatohepatitis is needed when drugs with the potential to induce fatty liver are prescribed for long term use. Estrogen is a factor indispensable to smooth fatty acid ß-oxidation in hepatocytes. However, treatment with Tamoxifen markedly suppresses fatty acid ß-oxidation in the liver. As free fatty acids are toxic, their accumulation results in the activation of alternative fatty acid oxidation pathways mediated by CYP2E1 in cytosol and lipid peroxidases in peroxisomes in hepatocytes. CYP2E1 enhances lipid peroxidation and dicarboxylic acid synthesis via the activation of fatty acid ω-oxidation that injures mitochondria and results in the emergence of ballooned hepatocytes. In such cases, the attenuation of alternative fatty acid oxidation pathways could have some beneficial effects on mitochondrial injury, since fibrates (PPAR-α ligands) are potent enough to stimulate neutral fat consumption through the activation of peroxisomal fatty acid ß-oxidation. Fortunately, fibrates attenuate serum estrogen levels by affecting estrogen receptor expression, so the co-administration of fibrates with Tamoxifen is expected to exert higher efficacy in breast cancer patients with Tamoxifen-induced hepatic steatosis.

Evaluation of a fibrate, specific stimulant of PPARα, as a therapeutic alternative to the treatment of clinical ovine pregnancy toxaemia.

Ovine pregnancy toxaemia is a metabolic disorder affecting sheep in their last 6 weeks of pregnancy as a result of their inability to maintain adequate energy homoeostasis. Different alternative treatments are available with variable results. The aim of this research was to evaluate a peroxisome proliferator-activated receptor alpha (PPARα) stimulant as an alternative to treat clinical pregnancy toxaemia. Thirty-three adult sheep, with known gestation date and carrying a single foetus, were fasted from day 130 of gestation until animals showed clinical disease. From that moment onwards, sheep were treated during 6 days with three different therapeutic alternatives: 10 mg/kg of 2-methyl-2-phenoxy-propionic acid; 10 mg/kg of 2-methyl-2-phenoxy-propionic acid + 100 mL of propylene glycol oral; or 100 mL of propylene glycol oral. Glycaemia and serum ß-hydroxybutyrate (BHOB) were determined daily. Liver biopsies were taken at day 130 of gestation, at the beginning and end of treatments and at 5 days postpartum, evaluating the extent and degree of the steatosis lesion. Even though in sheep treated with 2-methyl-2-phenoxy-propionic acid, serum concentrations of glucose and BHOB recovered more slowly, we conclude that 2-methyl-2-phenoxy-propionic acid alone or combined with propylene glycol can be used as an alternative to effectively treat fatty liver, and therefore pregnancy toxaemia.