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Objectives: Metabolic syndrome (MS) is the concurrence of at least three of five medical conditions: obesity, high blood pressure, insulin resistance, high serum triglyceride (TG) and low serum high‐density lipoprotein levels. While fibrates are used to treat disorders other than the lowering serum TG, the mechanism by which fibrates decrease MS has not been established. Methods: In this study, wild‐type and Ppara‐null mice fed a medium‐fat diet (MFD) were administered gemfibrozil and fenofibrate for 3 months respectively, to explore the effect and action mechanism. Key findings: In Ppara‐null mice, MFD treatment increased body weight, adipose tissue, serum TG and impaired glucose tolerance. These phenotypes were attenuated in two groups treated with gemfibrozil and fenofibrate. The STAT3 pathway was activated in adipose and hepatic tissues in positive control, and inhibited in groups treated with gemfibrozil and fenofibrate. The above phenotypes and inflammation were not observed in any wild‐type group. In 3T3‐L1 adipogenic stem cells treated with high glucose, STAT3 knockdown greatly decreased the number of lipid droplets. Conclusions: Low dose of clinical fibrates was effective against MS development independent of PPARα, and this action was mediated by STAT3 signalling inhibition in adipose tissue and, to a lesser extent, in hepatic tissues. [ABSTRACT FROM AUTHOR]

Objective. To study the effect of sesquiterpene γ-lactone achillin on the lipid content and mRNA expression of key genes of lipid metabolism in the hepatoma tissue cell line HTC in the experimental hyperlipidemia. Materials and methods. The experimental hyperlipidaemia in HTC cells simulated by adding fat emulsion Lipofundin MCT/LCT at a final concentration 0.05 % to the incubation medium. After 48 h of incubating cell culture with achillin at the final concentration 500 μM the cell viability was investigated by using the MTT assay and assessed level of lipids by fluorescent vital stain Nile Red and the content of triacylglycerols (TAG) and cholesterol by enzymatic method. RNA was isolated from cells using the set Illustra RNAspin Mini RNA Isolation Kit («GE Healthcare»). The level of mRNA expression of key genes in lipid metabolism was assessed using a real-time quantitative polymerase chain reaction with reverse transcription by TaqMan technology. Results. Incubation cells with Lipofundin MCT/LCT (0.05%) resulted in an increase in the fluorescence intensity of Nile Red and increase the levels of TAG in cells. Achill (500 µM) had no cytotoxic effect on HTC cell and led to reduction of cholesterol and TAG in cells with hyperlipidemia induced by Lipofundin. This was accompanied by a decrease in fluorescence intensity of Nile Red dye in the cells. In the hepatoma culture achillin increased gene expression of carnitine palmitoyltransferase 1 (Cpt1a) and 2 (Cpt2) , 7-alpha-hydroxylase (Cyp7a1) and 3-hydroxy-3-methylglutaryl CoA reductase (Hmgcr) . On expression of gene acetyl-CoA cholesterol acyltransferase (Soat1) achill had an inhibitory effect. Conclusion. Lowering of cholesterol, TAG and Nile Red fluorescence intensity in hepatoma cells in experimental hyperlipidemia under the action of achillin in the final concentration 500 µM could be caused by increase of gene expression carnitine palmitoyltransferase 1 and 2; 7-alpha-hydroxylase, which contributes to increase the transport of fatty acids into the mitochondria, and synthesis of bile acids from cholesterol. In addition, inhibition of acetyl-CoA cholesterol acyltransferase helps to reduce the formation of cholesterol esters and their accumulation in the hepatocytes.

The hypolipidemic action of sesquiterpene γ-lactones ludartin and grosshemin was studied in vivo experiments on the model of acute hyperlipidemia induced by Triton WR 1339. Hyperlipemia model induced by Triton WR 1339, characterized by a sharp increase in the content in the serum of triacylglycerides and total cholesterol, mainly due to the increase of cholesterol in proatherogenic fractions of lipoproteins (low density). Hypolipidemic action of ludartin and grosshemin on the background of triton WR 1339 induced hyperlipemia, and drug comparison of phenofibrate, evident decrease in the content of triacylglycerides and pro-atherogenic cholesterol in low density lipoproteins in the blood serum, as well as reducing the amount of triacylglycerides and cholesterol in the liver of rats.

Introduction: Hypertriglyceridemia (HTG) is a physiological condition of pregnancy. However, in some patients, it could be harmful due to possible complications such as pancreatitis. Treating this clinical condition during pregnancy is controversial as many drugs are not allowed in different trimesters. The current report discussed 2 cases of HTG and their outcomes during pregnancy. Case Presentation: The 1st patient had twin pregnancy and a “milky” blood sample raised suspicion on abnormal lipid profile (LP) during the pregnancy screening tests. There was a positive history of HTG and the available laboratory results showed triglyceride (TG) 3920 mg/dL, cholesterol (Chol) 1370 mg/dL, and normal amylase and lipase serum levels. The patient received daily LP and blood glucose monitoring as well as insulin, gemfibrozil, and fish oil prescription. In the 30th week of gestation, one of the fetuses was lost and a cesarean section, because of preterm uterine contractures, was performed. Mother and baby were discharged in good conditions. The 2nd patient presented with nausea, vomiting, and abdominal pain in the 22nd week of gestation. The patient had gestational diabetes without the history of HTG. Laboratory results were as follows: TG 878 mg/dL, Chol 249 mg/dL, amylase 251 U/L, and lipase 29 U/L. The patient was treated as pancreatitis induced by HTG. Therefore, gemfibrozil and fish oil were prescribed in addition to hydration and low fat diet. A healthy term baby was the result of pregnancy. Conclusions: Establishing prompt medical treatment and controlling comorbid conditions are essential in gestational HTG. Although there are controversial reports about using medications such as fibrates and fish oil, gemfibrozil and fish oil were recommended as an effective treatment for the patients with gestational HTG.

Peroxisome proliferator-activated receptor α (PPARα) shows promising potential to enhance host defenses against Mycobacterium tuberculosis infection. Herein we evaluated the protective effect of PPARα against nontuberculous mycobacterial (NTM) infections. Using a rapidly growing NTM species, Mycobacterium abscessus (Mabc), we found that the intracellular bacterial load and histopathological damage were increased in PPARα-null mice in vivo. In addition, PPARα deficiency led to excessive production of proinflammatory cytokines and chemokines after infection of the lung and macrophages. Notably, administration of gemfibrozil (GEM), a PPARα activator, significantly reduced the in vivo Mabc load and inflammatory response in mice. Transcription factor EB was required for the antimicrobial response against Mabc infection. Collectively, these results suggest that manipulation of PPARα activation has promising potential as a therapeutic strategy for NTM disease.

Abstract Background Although rare, familial hypertriglyceridemia can cause acute and life-threatening complications in pregnancy. Cases The first patient's pregnancy was complicated by multiple admissions for pancreatitis due to hypertriglyceridemia and noncompliance with gemfibrozil. In her second pregnancy, she was compliant with gemfibrozil and only experienced pancreatitis episodes toward the end of pregnancy. The second patient had diabetes mellitus and familial hypertriglyceridemia. She required multiple hospitalizations for diabetic ketoacidosis secondary to insulin noncompliance. In both pregnancies, she was compliant with gemfibrozil and had no complications related to hypertriglyceridemia. Conclusion Treatment with gemfibrozil in pregnancies complicated by hypertriglyceridemia may prevent complications without adverse maternal or fetal effects and could be considered in treating pregnant patients with severe hypertriglyceridemia. These cases also demonstrate the importance of medication compliance in the prevention of poor outcomes.

Typha latifolia is widely used as a phytoremediation model plant for organic compounds. However, the dynamic uptake and translocation of pharmaceutical and personal care products (PPCPs) and their relationship with physicochemical properties, such as lipophilicity (LogKow), ionization behavior (pKa), pH-dependent lipophilicity (LogDow), exposure time and transpiration, are scarcely studied. In the current study, hydroponically grown T. latifolia was exposed to carbamazepine, fluoxetine, gemfibrozil, and triclosan at environmentally relevant concentrations (20 μg/L each). Eighteen out of thirty-six plants were exposed to the PPCPs and the other eighteen were untreated. Plants were harvested at 7, 14, 21, 28, 35, and 42 days and separated into root, rhizome, sprouts, stem, and lower, middle, and upper leaf sections. Dry tissue biomass was determined. PPCP tissue concentrations were analyzed by LC-MS/MS. PPCP mass per tissue type was calculated for each individual compound and for the sum of all compounds during each exposure time. Carbamazepine, fluoxetine, and triclosan were detected in all tissues, while gemfibrozil was detected only in roots and rhizomes. In roots, triclosan and gemfibrozil mass surpassed 80% of the PPCP mass, while in leaf carbamazepine and fluoxetine mass represented 90%. Fluoxetine accumulated mainly in the stem and the lower and middle leaf, while carbamazepine accumulated in the upper leaf. The PPCP mass in roots and rhizome was strongly positively correlated with LogDow, while in leaf it was correlated with water transpired and pKa. PPCP uptake and translocation in T. latifolia is a dynamic process determined by the properties of contaminants and plants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Graphical abstract Highlights • Decrease in IDR with an increase in chain length of the counterion observed using UV-imaging. • Developed interfacial area ratio (Sdr) showed significant surface gains for the compacts for IDR determination. • Particulates on surface compacts and observed cracks responsible for inflated IDR values. • Imaging of surface should be taken into consideration prior IDR determination. Abstract The optimisation of the pharmaceutical properties of carboxylic acid drugs is often conducted by salt formation. Often, the salt with the best solubility is not chosen due to other factors such as stability, solubility, dissolution and bioavailability that are taken into consideration during the preformulation stage. This work uses advanced imaging techniques to give insights into the preformulation properties that can aid in the empirical approach often used in industry for the selection of salts. Gemfibrozil (GEM) was used as a model poorly soluble drug. Four salts of GEM were made using cyclopropylamine (CPROP), cyclobutylamine (CBUT), cyclopentylamine (CPENT) and cyclohexylamine (CHEX) as counterions. DSC, XRD and SEM were used to confirm and characterise salt formation. IDR obtained using UV-imaging up to 10 min for all the salts showed that an increase in the chain length of the counterion caused a decrease in the IDR. Past the 10 min mark, there was an increase in the IDR value for the CPROP salt, which was visualised using UV-imaging. The developed interfacial (surface) area ratio (Sdr) showed significant surface gains for the compacts. Full dosage form (capsule) imaging showed an improvement over the GEM for all the salts with an increase in chain length of the counterion bringing about a decrease in dissolution which correlated with the obtained UV-imaging IDR data. [ABSTRACT FROM AUTHOR]

Pharmaceuticals are ubiquitously detected in the marine environment at the ng-μg/L range. Given their biological activity, these compounds are known to induce detrimental effects on biota at relatively low exposure levels; however, whether they affect early life stages of marine species is still unclear. In this study, a set of bioassays was performed to assess the effects of propranolol (PROP), 17-α ethinylestradiol (EE2), and gemfibrozil (GEM) on gamete fertilization and embryonic development of mussels (Mytilus galloprovincialis) and sea urchins (Paracentrotus lividus), and on the survival of seabream (Sparus aurata) larvae. Treatments of PROP (500, 5000, 50,000 ng/L), EE2 (5, 50, 500 ng/L), and GEM (50, 500, 5000 ng/L) were selected to encompass levels comparable or superior to environmental concentrations. Obtained data were tested for dose-response curve fitting and the lowest EC10/LC10 used to calculate risk quotients (RQs) based on the MEC/PNEC. No alteration was induced by PROP on the mussel gamete fertilization, while inhibitory effects were observed at environmental levels of EE2 (500 ng/L) and GEM (5000 ng/L). Fertilization was significantly reduced in sea urchin at all PROP and EE2 dosages. The 48-h exposure to all pharmaceuticals induced the onset of morphological abnormalities in either mussel or sea urchin embryos. Alterations were generally observed at environmentally relevant dosages, except for PROP in mussels, in which alterations occurred only at 50,000 ng/L. A decreased survival of seabream larvae was recorded after 96-h exposure to PROP (all treatments), EE2 (50-500 ng/L), and GEM (500 ng/L). A median RQ > 1 was obtained for all pharmaceuticals, assigning a high risk to their occurrence in marine environments. Overall, results showed that current levels of contamination by pharmaceuticals can impact early stages of marine species, which represent critical junctures in the resilience of coastal ecosystems. [ABSTRACT FROM AUTHOR]

Background/aim: Cisplatin-induced nephrotoxicity in large proportion of patients. The aim of this work is to clarify the effect of combination of sildenafil and gemfibrozil on cisplatin-induced nephrotoxicity either before or after cisplatin treatment and determination of nephrotoxicity predictors among the measured tissue markers. Methods: Thirty two adult male albino rats were divided into four equal groups (G) GI control, GII received cisplatin, GIII received sildenafil and gemfibrozil before cisplatin, GIV received sildenafil and gemfibrozil after cisplatin. Creatinine and urea were measured and animals were sacrificed and kidney was taken for histopathology. The following tissue markers were measured, heme oxygenase-1 (HO-1) activity, reduced glutathione, quantitative (real-time polymerase chain reaction) RT-PCR for gene expression of tumor necrosis factor alpha (TNF-α) and endothelial nitric oxide synthase (ENOS) level. Results: GII developed AKI demonstrated by significantly high urea and creatinine and severe diffuse (80-90%) tubular necrosis. TNF-α was highly and significantly elevated while the rest of tissue markers were significantly reduced in GI1 compared to other groups. GIV showed better results compared to GIII. There was a significant positive correlation between creatinine and TNF-α when combining GI and GII while there were significant negative correlation between creatinine and other tissue markers in same groups. Linear regression analysis demonstrated that HO-1 was the independent predictor of AKI demonstrated by elevated creatinine among GI and GII. Conclusions: Combination of sildenafil and gemfibrozil can be used in treatment of cisplatin-induced nephrotoxicity. HO-1 is a promising target for prevention and/or treatment of cisplatin-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

To better understand the performance of constructed wetlands (CWs) to remove acidic pharmaceuticals (APs) in wastewaters in subtropical areas and to optimize CW design criteria, six small-scale CWs under different design configurations were operated. The factors (environmental parameters, water quality, and seasonality) influencing the APs removal were also analyzed to illustrate the removal mechanisms. The results indicated that the best performances of CWs were up to 80–90%. Subsurface flow (SSF) CWs showed high removal efficiency for ibuprofen, gemfibrozil and naproxen, but surface flow (SF) CWs performed better for ketoprofen and diclofenac. The positive relationship between the removal efficiencies of ibuprofen, gemfibrozil, and naproxen with dissolved oxygen and ammonia nitrogen reveals that SSF CWs under aerobic conditions benefit the biodegradation, while the favorable conditions created by SF CWs for receiving solar radiation promote the effective photolysis of ketoprofen and diclofenac. Planted SSF CWs had significantly higher removal efficiencies of ibuprofen and gemfibrozil than the unplanted controls had in all seasons. The removal of all APs was higher in summer and autumn than those in winter. Furthermore, an inverse relationship between removal efficiency and the distribution coefficient (log D ow) was observed in SF CWs. Overall, CWs that provide aerobic degradation and photolysis would benefit APs removal in subtropical areas in the south of China. [ABSTRACT FROM AUTHOR]

Aim: Several drugs have been used for treating non-alcoholic fatty liver disease (NAFLD). The present study is a network meta-analysis of such drugs.Design, Setting and Patients: Randomised clinical trials comparing drug interventions in patients with NAFLD were analysed. OR and weighted mean difference (95 % CI) were the effect estimates for categorical and numerical outcomes, respectively. Random-effects model was used to generate pooled estimates. Surface under the cumulative ranking curve was used to rank the treatments.Main Outcome Measures: Proportion of responders was the primary outcome measure and non-alcoholic steatohepatitis scores, liver enzymes, lipid profile, body mass index, homeostatic model assessment of insulin resistance, intrahepatic fat and adverse events were the key secondary outcomes.Results: 116 studies were included in the systematic review and 106 in the meta-analysis. Elafibranor, gemfibrozil, metadoxine, obeticholic acid, pentoxifylline, pioglitazone, probiotics, telmisartan, vildagliptin and vitamin E significantly increased the response rate than standard of care. Various other drugs were observed to modify the secondary outcomes favourably. Probiotics was found with a better response in children; and elafibranor, obeticholic acid, pentoxifylline and pioglitazone in patients with type 2 diabetes mellitus. The quality of evidence observed was either low or very low.Conclusion: In patients with NAFLD, several drugs have been shown to have variable therapeutic benefit. However, the estimates and the inferences should be considered with extreme caution as it might change with the advent of future head-to-head clinical trials. [ABSTRACT FROM AUTHOR]

Previous pre-clinical studies demonstrated a promising role of alpha-type peroxisome proliferator-activated receptors (PPARα) agonists in decreasing nicotine self-administration and nicotine-seeking behavior in animals. Our goal was to investigate the potential of gemfibrozil, a PPARα agonist, on reducing tobacco smoking in humans. Methods: This was a double-blind, placebo-controlled, crossover study evaluating the effects of gemfibrozil (1200 mg/day) on smoking in 27 treatment-seeking smokers. The study had two 2-week phases separated by a washout period of at least 1 week. In each phase and after 1 week on medication, participants underwent a lab session where cue reactivity and forced choice paradigms were conducted. Physiological responses and self-reported craving were monitored during the presentation of smoking and neutral cues. In addition, two types of cigarettes were used in the forced choice paradigms: the Nicotinized cigarettes (Nic) and the Denicotinized cigarettes (Denic). The goal of the forced choice was to calculate the percentage of choice of Nic cigarettes while taking gemfibrozil or placebo. The number of quit days was calculated during the two quit attempts weeks (one while taking gemfibrozil and one while taking placebo) of the study. Results: There were no significant differences between gemfibrozil and placebo groups in the percentage of choice of Nic cigarettes, the cue-reactivity (both physiological and subjective measures), or in the number of days of abstinence. Conclusions: Although preclinical studies with PPAR α agonists showed promising results, this preliminary study did not demonstrate positive effect of gemfibrozil on tobacco use and cessation indices. [ABSTRACT FROM AUTHOR]

Abstract We describe a case of a 36-year-old woman with severe hypertriglyceridemia likely caused by double heterozygosity of a known pathogenic APOA5 nonsense variant (p.Q275X) and a novel CREB3L3 nonsense variant (p.C296X) on a background of very strong polygenic susceptibility. Her clinical course worsened with development of eruptive xanthomata after oral administration of 2 mg estradiol twice daily for 2 weeks as part of a medical protocol for intrauterine embryo transfer following in vitro fertilization. Her triglyceride levels decreased to baseline and xanthomata resolved without treatment after discontinuation of hormonal therapy, which also resulted in termination of pregnancy. Before undergoing a second embryo transfer using her natural cycle and no exogenous hormones, the patient started combination therapy with eicosapentaenoic acid ethyl ester and gemfibrozil, leading to an ∼80% decrease in triglyceride levels. She continued treatment throughout pregnancy, which progressed to term with the delivery of healthy twins. Highlights • Severe hypertriglyceridemia (HTG) can be either a monogenic or polygenic trait. • Several pathogenic APOA5 alleles are associated with severe HTG. • CREB-H encoded by CREB3L3 regulates lipid metabolism genes including APOA5. • A patient with severe HTG had nonsense variants in both CREB3L3 and APOA5 genes. • In this patient, HTG was exacerbated by a high polygenic burden plus estrogen use. [ABSTRACT FROM AUTHOR]

The assessment of vulnerability in karst systems reveals to be extremely challenging since it varies significantly with time and highly depends on the identification of diffuse and concentrated infiltration from surface karst features. The origin, consumed loads, and transport mode of selected micropollutants (MPs) including two artificial sweeteners (ASWs) Sucralose (SUC) and Acesulfame-K (ACE-K), in addition to other less investigated pharmaceuticals such as the lipid regulator Gemfibrozil (GEM), and the contrast media Iohexol (IOX) were investigated in a karst system under dynamic conditions. A detailed analysis of selected spring responses' chemograph and hydrograph following a multi precipitation event shows that three of the tracked MPs, especially ACE-K, and to the exception of IOX, can be used as specific indicators for point source domestic wastewater in karst systems. They have revealed to be persistent, source specific, conservative, and highly correlated with in-situ parameters easily measurable at the spring (chloride and turbidity). Even if the selected MPs are found in the system during low flow periods, they are mostly transported to the spring through fast flow pathways from flushed wastewater with surface water or flood rainwater. The highest mass inflow of ACE-K, IOX and GEM originated from a sinking stream, while SUC infiltrated exclusively through fast infiltration points (dolines). Their breakthrough curves coincide with the arrival of new waters and turbidity peaks. Unlike IOX, the mass fluxes of ASWs, and GEM to a lesser extent, can be linearly correlated with chloride mass fluxes and turbidity flux. Moreover, the variance of the normalized breakthrough curves of the MPs with respect to a mean transit time, increases in that order IOX

Aqueous micellar solubilization of ibuprofen and gemfibrozil drugs was investigated at constant temperature (25.0 ± 0.1) °C and atmospheric pressure using shake-flask and UV–vis spectrophotometric techniques. The solubility measurement was done in presence of three surfactants possessing different head groups, namely sodium dodecylsulfate (anionic SDS), cethyltrimethylammonium bromide (cationic CTAB) and polyethylene glycol dodecyl ether (non-ionic Brij 35) as well as their binary mixtures. The micellar solubility descriptors of χ (molar solubilization capacity), K (micelle–water partition coefficient), and Δ G s ∘ (standard free energy of solubilization) were obtained to estimate quantitatively the solubilization efficiency of the surfactant systems. Moreover, the octanol-water partition coefficient of these drugs was also evaluated in the micellar solutions. The results obtained in the aqueous micellar system demonstrate that, irrespective of the surfactant type, the solubility of drugs increases with increasing the concentration of micelles. It was found that the solubility of ibuprofen and gemfibrozil in Brij 35 and CTAB solutions, respectively is higher compared to that in the other surfactants. However, the partition coefficients of these drugs show an inverse trend with solubility data. Finally, the effect of the surfactant type on solubility enhancement of the drugs is explained in terms of possible interactions between the drug and the micelle. [ABSTRACT FROM AUTHOR]

Lipid regulators are among the most prescribed human pharmaceuticals worldwide. Gemfibrozil, which belongs to this class of pharmaceuticals, is one of the most frequently encountered in the aquatic environment. However, there is limited information concerning the mechanisms involved in gemfibrozil effects to aquatic organisms, particularly to marine organisms. Based on this knowledge gap, the current study aimed to assess biochemical and behavioral effects following a sublethal exposure to gemfibrozil (1.5, 15, 150, 1500 and 15,000 μg L −1 ) in the estuarine/marine fish Sparus aurata . After the exposure to 1.5 μg L −1 of gemfibrozil, fish had reduced ability to swim against a water flow and increased lipid peroxidation in the liver. At concentrations between 15–15,000 μg L −1 , the activities of some enzymes involved in antioxidant defense were induced, appearing to be sufficient to prevent oxidative damage. Depending on the organ, different responses to gemfibrozil were displayed, with enzymes like catalase being more stimulated in gills, whereas glutathione peroxidase was more activated in liver. Although there were no obvious concentration-response relationships, the integrated biomarker response version 2 (IBRv2) analysis revealed that the highest concentrations of gemfibrozil (between 150–15,000 μg L −1 ) caused more alterations. All the tested concentrations of gemfibrozil induced effects in S. aurata , in terms of behavior and/or oxidative stress responses. Oxidative damage was found at a concentration that is considered environmentally relevant, suggesting a potential of this pharmaceutical to impact fish populations. [ABSTRACT FROM AUTHOR]

Abstract: The effects of parental exposure to pharmaceuticals on sexual differentiation in F1 offspring were examined in zebrafish (Danio rerio). Adult zebrafish were exposed to 0 or 10 μg/L of carbamazepine or gemfibrozil for 6 wk and bred in pairwise crosses to generate 7 distinct lineages. Lineages were formed with both parents from the same treatment group or with only one parent exposed, to delineate between maternal and paternal effects. The F1 offspring from each lineage were reared in clean water and sampled at 45 and 60 d post fertilization (dpf). Gonadal differentiation was assessed by histology. The morphological stages of the gonads were converted to a quantitative day‐equivalent based on data from offspring of untreated parents sampled from 15 to 75 dpf, which enabled a quantitative statistical analysis on the timing of sexual differentiation. Paternal, but not maternal, exposure to carbamazepine resulted in significantly faster sexual differentiation and a male‐biased sex ratio; these effects were not observed when both parents were exposed. Combined paternal and maternal exposure to gemfibrozil resulted in significantly faster sexual differentiation, and paternal, but not maternal, exposure to gemfibrozil led to male‐biased sex ratios. The present study demonstrates the ability of parental exposure to pharmaceuticals to disrupt sexual differentiation in the F1 offspring and also shows that effects may be uniquely influenced by which parent was exposed. Environ Toxicol Chem 2018;37:1696–1706. © 2018 SETAC [ABSTRACT FROM AUTHOR]

Gemfibrozil (GEM) and carbamazepine (CBZ) are two environmentally relevant pharmaceuticals and chronic exposure of fish to these compounds has decreased androgen levels and fish reproduction in laboratory studies. The main focus of this study was to examine the effects of GEM and CBZ on testicular steroid production, using zebrafish as a model species. Chronic water borne exposures of adult zebrafish to 10 μg/L of GEM and CBZ were conducted and the dosing was confirmed by chemical analysis of water as 17.5 ± 1.78 and 11.2 ± 1.08 μg/L respectively. A 67 day exposure led to reduced reproductive output and lowered whole body, plasma, and testicular 11-ketotestosterone (11-KT). Testicular production of 11-KT was examined post exposure (42 days) using ex vivo cultures to determine basal and stimulated steroid production. The goal was to ascertain the step impaired in the steroidogenic pathway by each compound. Ex vivo 11-KT production in testes from males chronically exposed to GEM and CBZ was lower than that from unexposed males. Although hCG, 25-OH cholesterol, and pregnenolone stimulation increased 11-KT production in all treatment groups over basal levels, hCG stimulated 11-KT production remained significantly less in testes from exposed males compared to controls. 25-OH cholesterol and pregnenolone stimulated 11-KT production was similar between GEM and control groups but the CBZ group had lower 11-KT production than controls with both stimulants. We therefore propose that chronic GEM and CBZ exposure can reduce production of 11-KT in testes through direct effects independent of mediation through HPG axis. The biochemical processes for steroid production appear un-impacted by GEM exposure; while CBZ exposure may influence steroidogenic enzyme expression or function. [ABSTRACT FROM AUTHOR]

Herein we report on the interactions between two common pharmaceuticals and wheat (Triticum aestivum L.) plants. Pharmaceuticals and personal care products (PPCPs) enter wastewater treatment plants from industrial and household sewers. These chemicals are not completely removed during wastewater processing, and in many countries, are being found in drinking water sources and in surface waters downstream of wastewater treatment plants. If treated wastewater effluent is re-used to irrigate crops, the potential adverse interactions between PPCPs and plants needs to be understood. β-estradiol and gemfibrozil appeared to affect wheat seedlings through oxidative stress, as indicated by increases in lipid peroxidation, hydrogen peroxide, carotenoid, and antioxidant enzyme activities. Additionally, plant cell damage in wheat seedlings was indicated by an increase in electrolyte leakage. Although our study was not designed to elucidate possible mechanisms, the changes in activity of plant enzymes in response to some pharmaceuticals is likely the consequence of oxidative stress and the initiation of pathways to protect the plant from further cell damage. [ABSTRACT FROM AUTHOR]

The present study focussed on potential application of river bank filtration (RBF) for the effective removal of pharmaceutically active compounds (PhACs), namely, atenolol, ciprofloxacin and gemfibrozil. Experiments on RBF were performed in a pilot scale reactor (3.0 m × 1.0 m × 0.5 m) in which two dimensional unconfined aquifer flow conditions were induced by pumping to depict realistic field conditions. Initially, experiments were carried out in a reactor filled with natural river bed material. The natural attenuation efficiencies were found to be 21, 35 and 8% for atenolol, ciprofloxacin and gemfibrozil, respectively. Pumping experiments conducted through clean sand in RBF indicated that PhACs were highly mobile with minimal degradation. In order to improve the treatment efficiency of RBF, biofilm coated clay composite adsorbent was synthesized and used in a reactive barrier. The reactive barrier could significantly eliminate PhACs up to 80, 90, 75% for atenolol, ciprofloxacin and gemfibrozil, respectively, at the extracting well (located at 125 cm from the inlet) even after 150 h. Pumping experiments showed that 20 cm thick barrier was able to contain the movement of contaminant plume up to 4 h when water was pumped at a rate of 0.0075 L/s and up to 3.2 h when the pumping rate was 0.01 L/s. Further, a 2D reactive transport model was developed and validated based on the experimental data. The transport model would be useful for developing a management model for the optimal design of reactive barrier for enhancing the performance of RBF. [ABSTRACT FROM AUTHOR]

Major depressive disorder has become one of the most serious neuropsychiatric disorders worldwide. However, currently available antidepressants used in clinical practice are ineffective for a substantial proportion of patients and always have side effects. Besides being a lipid-regulating agent, gemfibrozil is an agonist of peroxisome proliferator-activated receptor-α (PPAR-α). We investigated the antidepressant effects of gemfibrozil on C57BL/6J mice using the forced swim test (FST) and tail suspension test (TST), as well as the chronic unpredictable mild stress (CUMS) model of depression. The changes in brain-derived neurotrophic factor (BDNF) signaling cascade in the brain after CUMS and gemfibrozil treatment were further assessed. Pharmacological inhibitors and lentivirus-expressed short hairpin RNA (shRNA) were also used to clarify the antidepressant mechanisms of gemfibrozil. Gemfibrozil exhibited significant antidepressant actions in the FST and TST without affecting the locomotor activity of mice. Chronic gemfibrozil administration fully reversed CUMS-induced depressive-like behaviors in the FST, TST and sucrose preference test. Gemfibrozil treatment also restored CUMS-induced inhibition of the hippocampal BDNF signaling pathway. Blocking PPAR-α and BDNF but not the serotonergic system abolished the antidepressant effects of gemfibrozil on mice. Gemfibrozil produced antidepressant effects in mice by promoting the hippocampal BDNF system. [ABSTRACT FROM AUTHOR]

Purpose: Gemfibrozil (GEM) apart from agonist activity at peroxisome proliferator-activated receptor-alpha (PPAR-a) has antioxidant and anti-inflammatory properties. Accordingly, the present study was designed to investigate the protective effect of GEM on acute liver toxicity induced by acetaminophen (APAP) in mice. Methods: In this study, mice divided in seven groups include, control group, APAP group, GEM group, three APAP groups pretreated with GEM at the doses of 25, 50 and 100 mg/kg respectively and APAP group pretreated with N-Acetyl cysteine. GEM, NAC or vehicle were administered for 10 days. In last day, GEM and NAC were gavaged 1 h before and 1 h after APAP injection. Twenty four hours after APAP, mice were sacrificed. Serum parameters include alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver tissue markers including catalase enzyme activity, reactive oxygen species (ROS), malondialdehyde and reduced glutathione (GSH) levels determined and histopathological parameters measured. Results: GEM led to significant decrease in serum ALT and AST activities and increase in catalase activity and hepatic GSH level and reduces malondialdehyde and ROS levels in the liver tissue. In confirmation, histopathological findings revealed that GEM decrease degeneration, vacuolation and necrosis of hepatocytes and infiltration of inflammatory cells. Conclusion: Present data demonstrated that GEM has antioxidant properties and can protect the liver from APAP toxicity, just in the same pathway that toxicity occurs by toxic ROS and that GEM may be an alternative therapeutic agent to NAC in APAP toxicity. [ABSTRACT FROM AUTHOR]

Gemfibrozil, a common lipid regulator, enters aquatic environments through treated municipal wastewater effluent that fails to remove it completely from effluent streams. When exposed to gemfibrozil concentrations of 50, 500, 5,000, and 50,000 ng L −1 , Daphnia magna showed increased lipid reserves by 14–21% (significant at 500 ng L −1 ), increased length by 9–13% (significant at 50 ng L −1 ), increased mass by 6–13% (significant at 50 ng L −1 ) and increased neonate production by 57–74% (significant at 50 ng L −1 ). Gemfibrozil-exposed Daphnia held under conditions where food availability was low, grew and reproduced as well as those in the control. Taken together, these results suggest that gemfibrozil exposure within environmentally relevant concentration ranges is not toxic to Daphnia magna but has the potential to be beneficial to the species under these conditions. [ABSTRACT FROM AUTHOR]

Pharmaceutical compounds are known to be persistent. Their presence after conventional treatments in sewage treatment plants may harm aquatic environments. The simultaneous degradation of the pharmaceuticals gemfibrozil, hydrochlorothiazide and naproxen involving photo-Fenton processes was evaluated using different sources and concentrations of iron (Fe 2+ , Fe 3+ and the iron complexes of oxalate – FeOx), initial pH (2.6, 5.0 and 7.0) and concentrations of H 2 O 2 . The classic photo-Fenton reaction (at initial pH 2.6, using Fe 2+ and Fe 3+ ) showed a limited efficiency in promoting gemfibrozil degradation, which, based on evidence provided by LC–MS measurements, is related to the formation of associations between this compound and iron ions. The simultaneous degradation of gemfibrozil and the other compounds was improved using FeOx (1.0 mg L −1 in iron) at an initial pH of 2.6 and 2.0 mg L −1 H 2 O 2 . In addition, using this catalyst it was possible to efficiently degrade the pharmaceuticals at an initial pH of 5.0, reaching complete degradation of these compounds with a treatment time varying between 20 and 60 min and generating a low toxicity effluent. These results highlight the potential applicability of ferrioxalate as a photocatalyst in the photo-Fenton process as an alternative method to degrade this kind of pollutant at a pH near neutrality. [ABSTRACT FROM AUTHOR]

BACKGROUND: Statins are widely used lipid-lowering drugs used for the prevention of cardiovascular disease. Statins are known to cause myopathy, an adverse drug reaction with various clinical features rhabdomyolysis. OBJECTIVE: To describe clinical characteristics of statin-treated individuals who experienced myopathy and identify risk factors of statinassociated myopathy. METHODS: A retrospective study was conducted on cases of statin-associated myopathy reported to the Swedish Medical Products Agency. Clinical factors were compared between cases and statin-treated controls not diagnosed with myopathy. Statistical methods were univariate and multivariate logistic regression and results were presented as odds ratio (OR) with 95% confidence interval (CI). To correct for multiple comparisons, the cutoff for statistical significance was set to P < .0017. RESULTS: In total, 47 cases of statin-associated myopathy were compared with 3871 treated controls. Rhabdomyolysis was diagnosed in 51% of the cases. Markers for cardiovascular disease were more common in cases than controls. Statistical analysis revealed the following independent risk factors for myopathy: high statin dose (OR = 1.54, calculated using the standard deviation 19.82, 95% CI = 1.32-1.80, P < .0001), and concomitant treatment with fusidic acid (OR = 1002, 95% CI = 54.55-18 410, P < .0001), cyclosporine (OR = 34.10, 95% CI = 4.43-262.45, P = .0007), and gemfibrozil (OR = 12.35, 95% CI = 2.38-64.10, P = .0028). CONCLUSIONS: The risk of myopathy increases with statin dose and cotreatment with cyclosporine and gemfibrozil. Concomitant fusidic acid has previously only been noted in a few case reports. Considering that use of fusidic acid may become more frequent, it is important to remind of this risk factor for statin-associated myopathy. [ABSTRACT FROM AUTHOR]

Gemfibrozil is a pharmaceutical commonly found in the aquatic compartment and its presence together with a mixture of several other biologically-active drugs raises concern about the possible long-term adverse effects on biota chronically exposed. Most research focus on its effect/degradation in wastewater treatment plant, while few investigations take into account its persistence in receiving aquatic ecosystems and its effects on natural microbial communities. In this context, the present work aims to evaluate gemfibrozil biodegradation, alone or in the co-presence of naproxen, comparing its persistence in the presence/absence of the river natural microbial community. For this purpose, water samples were collected from a river Tiber stretch inside the city of Rome and located downstream from a wastewater treatment plant and used for degradation experiments. Microbiologically active or sterile water microcosms were set up and treated with 100 μg L − 1 of gemfibrozil alone or in the co-presence of naproxen (100 μg L − 1 ), in order to evaluate gemfibrozil degradation in the different conditions. At fixed times water samplings were collected for both chemical and microbiological analysis. Moreover, the effects of the pharmaceuticals on the microbial community structure in terms of variations in its abundance and composition were also assessed. The overall results showed gemfibrozil to be a quite persistent molecule in the river water microcosms and the natural microbial community had a key role in its biodegradation. The co-presence of naproxen, a non-steroidal anti-inflammatory drug commonly co-occurring with gemfibrozil, increased its persistence and affected negatively some bacterial groups presence. [ABSTRACT FROM AUTHOR]

Aims Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor, and rifampicin, an inducer of CYP2C8. Methods The study consisted of two independent parts, each conducted according to an open-label, randomized, crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (part I) or rifampicin (part II) in healthy male subjects. Results Gemfibrozil had comparatively small effects on selexipag (less than 2-fold difference in any pharmacokinetic variable) but, with respect to ACT-333679, increased the maximum plasma concentration (Cmax) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration-time curve from zero to infinity (AUC0-∞) 11.1-fold (90% CI 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of the pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea and vomiting. Coadministration of rifampicin increased the Cmax of selexipag 1.8-fold (90% CI 1.4, 2.2) and its AUC0-∞ 1.3-fold (90% CI 1.1, 1.4); its effects on ACT-333679 were to increase its Cmax 1.3-fold (90% CI 1.1, 1.6), shorten its half-life by 63% and reduce its AUC0-∞ by half (90% CI 0.45, 0.59). Conclusion Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided, whereas when coadministered with inducers of CYP2C8, dose adjustments of selexipag should be envisaged. [ABSTRACT FROM AUTHOR]

Gemfibrozil is a fibrate drug used widely for dyslipidemia associated with atherosclerosis. Clinically, both gemfibrozil and its phase II metabolite gemfibrozil 1-O-β-glucuronide (gem-glu) are involved in drug-drug interaction (DDI). But the DDI risk caused by gem-glu between human and mice has not been compared. In this study, six volunteers were recruited and took a therapeutic dose of gemfibrozil for 3 days for examination of the gemfibrozil and gem-glu level in human. Male mice were fed a gemfibrozil diet (0.75%) for 7 days, following which a cocktail-based inhibitory DDI experiment was performed. Plasma samples and liver tissues from mice were collected for determination of gemfibrozil, gem-glu concentration and cytochrome p450 enzyme (P450) induction analysis. In human, the molar ratio of gem-glu/gemfibrozil was 15% and 10% at the trough concentration and the concentration at 1.5 h after the 6th dose. In contrast, this molar ratio at steady state in mice was 91%, demonstrating a 6- to 9-fold difference compared with that in human. Interestingly, a net induction of P450 activity and in vivo inductive DDI potential in mice was revealed. The P450 activity was not inhibited although the gem-glu concentration was high. These data suggested species difference of relative gem-glu exposure between human and mice, as well as a net inductive DDI potential of gemfibrozil in mouse model. [ABSTRACT FROM AUTHOR]

The presence and fate of pharmaceutical residues in environmental samples are of great interest. There is a vast number of studies published regarding their input, presence, effects and risks in ecosystems. Moreover, it has been demonstrated that the primary source of input of these contaminants in the environment is from Wastewater Treatment Plants (WWTPs). It is therefore essential to evaluate the efficiency of commonly used treatments and the necessity of applying novel purification processes in order to eliminate or reduce the concentration of pharmaceuticals from wastewater or from the effluent of WWTPs. The aim of this work was to quantify twenty-three pharmaceutical compounds in the aqueous phase at different stages of a conventional and a natural WWTP situated in Gran Canaria (Spain). The results indicate concentration levels in the range of 0.004 ± 0.001 to 59.2 ± 11.7 μg L − 1 and 0.018 ± 0.001 to 148 ± 14.7 μg L − 1 from conventional and natural WWTPs, respectively. Better efficiency was, however, offered by the conventional WWTP with a removal median of 99.7%. In addition, the impact on different aquatic organisms (algae, daphnids and fish) was assessed in terms of risk quotients. The results reveal a possible highly harmful effect towards organisms by gemfibrozil, ibuprofen and ofloxacin. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR), an antineoplastic drug, is widely used to treat different types of cancers. Yet, the usage is limited because of its severe side effects on testis. On the other hand, gemfibrozil (GEM), as an anti-hyperlipidemic drug, has other pharmacological effects independent of lipid- lowering activity including anti-inflammatory and antioxidant properties. The present experiment was designed to investigate the effect of GEM on ADR-induced testicular injury in male rats. A total of 28 male Wistar rats were divided into 4 equal groups: Control; ADR; ADR + GEM; GEM. Serum level of testosterone, luteinizing hormone and follicle stimulating hormone were assessed. Also, testicular tissue oxidant/antioxidant markers (malondialdehyde, total antioxidant capacity, nitric oxide, superoxide dismutase, catalase, glutathione peroxidase and glutathione) and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) were measured. Histopathological studies were conducted on testes. GEM improved hormonal profile and antioxidant defenses in comparison with ADR-treated animals. GEM, significantly reduced the production of proinflammatory cytokines compared with ADR-treated animals. Hormonal and biochemical results were further supported by testicular histopathological findings. Thus, GEM might represent a promising therapeutic modality for the attenuation of testicular injury induced by ADR in clinic. • ADR induces oxidative and inflammatory damages in testes. • ADR induces hormonal disturbances as well as histopathological lesions in testes. • GEM, as an anti-hyperlipidemic drug, has anti-inflammatory and antioxidant effects. • GEM improves ADR-induced alternations in oxidative and inflammatory parameters. • GEM attenuated the histopathological lesions which induced by ADR in testes. [ABSTRACT FROM AUTHOR]