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The occurrence of pharmaceuticals in surface water has been barely studied in Latin America. This work aimed to i) develop a multi-residue liquid chromatography- triple quadrupole mass spectrometry (LC–MS/MS) method for the determination of pharmaceutical active compounds (PhACs); ii) monitor 70 PhACs in three urban-influenced rivers in San José, Costa Rica; and iii) perform the risk assessment of detected compounds and ecotoxicological evaluation on water samples. Caffeine, 1,7-dimethylxanthine, naproxen, gemfibrozil and ibuprofen were the most frequent among 23 detected compounds. Concentrations ranged from 0.013 μg/L to 53.8 μg/L (62 % detections between 0.1 μg/L–1 μg/L), and the highest values corresponded to caffeine, 1,7-dimethylxanthine, ofloxacin, gemfibrozil and cephalexin. The environmental risk estimated using the hazard quotient (HQ) approach, revealed four and eleven compounds with medium and high risk, respectively. The highest risk (HQ >10) was determined for diphenhydramine, risperidone, fluoxetine, trimethoprim, ofloxacin and azithromycin; nonetheless, high risk (HQ >1) was also estimated for caffeine, diclofenac, clarithromycin, gemfibrozil and ibuprofen. Total HQ sample values (ΣHQ), calculated as the sum of individual HQs for each detected compound, revealed the highest hazard in surface water near wastewater treatment plant discharges, followed by the locations of higher urban influence (in the Virilla river). Ecotoxicological evaluation showed no acute toxicity towards Daphnia magna and Vibrio fischeri in surface water samples; on the contrary, toxicity towards Lactuca sativa (germination tests) showed a similar pattern to that determined with the ΣHQ, although the highest toxicity was observed downstream with respect to the urban influence of the metropolitan area. These findings help to visualize the importance of pharmaceutical residues in the overall toxicity of surface water samples, and remark the relevance of monitoring these compounds, as an input for the implementation of future mitigation actions. Universidad de Costa Rica/[802-B7-A09]/UCR/Costa Rica Universidad de Costa Rica/[802-B8-510]/UCR/Costa Rica Universidad de Costa Rica/[802-B8-144]/UCR/Costa Rica Universidad de Costa Rica/[802-B8-145]/UCR/Costa Rica Ministerio de Ciencia, Tecnología y Telecomunicaciones/[FI-197B-17]/MICITT/Costa Rica Ministerio de Ciencia, Tecnología y Telecomunicaciones/[FI-056B-17]/MICITT/Costa Rica UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro en Investigación en Contaminación Ambiental (CICA) UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiología

Objective Severe hypertriglyceridemia carries increased health risks, including the development of pancreatitis. The objective of this study was to report on management of 2 cases with severe gestational hypertriglyceridemia. Cases In case 1, a 33-year-old pregnant woman presented with serum triglyceride level of 14 000 mg/dL after discontinuing hypolipidemic medications. She was treated with Lovaza 12 g/day, and serum triglyceride remained near normal at level of less than 800 mg mg/dL until delivery. In case 2, a 28-year-old patient (29th week gestation) presented with acute pancreatitis and triglycerides >4000 mg/dL. She was treated with Gemfibrozil, Lovaza, insulin infusion, subcutaneous heparin, and escalated to plasmapheresis. She successfully delivered a baby at the week of 36th and her triglyceride level was 304 mg/dL after that. Discussion Case 1 was treated with high-dose Lovaza and case 2 was treated with plasmapheresis successfully. Triglyceride levels were reduced to less than 500 mg/dL until delivery of healthy babies in both cases. Conclusion Omega-3 fatty acids and plasmapheresis may be effective and safe to treat pregnant women with severe hypertriglyceridemia and pancreatitis.

Photochemical transformation of pharmaceuticals plays an important role in their natural attenuation, especially in lagoon-based wastewater treatment plants and surface waters receiving substantial sunlight. In this study, the photodegradation of five important pharmaceuticals was studied in samples obtained from a wastewater treatment plant and surface water sources. Batch photodegradation studies for a mixture of pharmaceuticals (diclofenac, sulfamethoxazole, acetaminophen, carbamazepine and gemfibrozil) were carried out in a photochemical reactor. Multiple aliquots of samples removed from the reactor during the experiment were analyzed through high-performance liquid chromatography (HPLC) coupled to a photodiode array (PDA) detector. Intermediate products formed due to photodegradation were identified by ultra-high-performance liquid chromatography coupled with a time-of-flight mass spectrometry (UHPLC-MS/MS). Diclofenac and sulfamethoxazole were found to undergo direct photodegradation due to strong light absorption, whereas the indirect route of photosensitized degradation in the presence of dissolved organic matter (DOM) and model humic acid was significant for acetaminophen, carbamazepine, and gemfibrozil. The reactive radicals such as hydroxyl (OH

The removal efficiencies (REs) of nineteen pharmaceutically active compounds (PhACs) (six antibiotics-clarithromycin, ofloxacin, sulfadiazine, sulfamethazine, sulfamethoxazole and trimethoprim -, four β-blockers -atenolol, metoprolol, propranolol and sotalol-, two antihypertensives/diuretics -furosemide and hydrochlorothiazide-, three lipid regulators -bezafibrate, fenofibrate and gemfibrozil-, and four psychiatric medications -carbamazepine, diazepam, lorazepam and paroxetine) were ascertained in a pilot-scale anaerobic/anoxic/aerobic (A2O) system treating urban wastewater, long term operated during two experimental phases using different sets of environmental conditions and operating parameters. Illumina MiSeq sequencing was used to investigate the structure, diversity and population dynamics of bacteria, archaea and fungi communities in the activated sludge. The results showed that mixed liquor suspended solids (MLSS) and food-to-microorganisms ratio (F/M) were operational parameters significantly influencing the REs of five of the analyzed PhACs in the A2O system. Biota-environment (BIO-ENV) analysis revealed strong correlations between population shifts of the activated sludge community and the REs of PhACs of the different pharmaceutical families. Increased REs of clarithromycin, furosemide, bezafibrate and gemfibrozil were concomitant to higher relative abundances of bacterial phylotypes classified within the Rhodobacteraceae and Sphingomonadaceae (Alphaproteobacteria), while those of Betaproteobacteria, Chloroflexi and Methanomethylovorans (Euryarchaea) correlated positively with the REs of up to seven PhACs belonging to different therapeutic groups. © 2019 Elsevier Ltd, This work was funded by Spanish Ministerio de Economía y Competitividad (MINECO) and Fondo Europeo de Desarrollo Regional (FEDER) (CTM2014-60131-P). MINECO is also acknowledged for personal grants to P. Maza-Márquez (postdoctoral fellow) and M.J. Gallardo-Altamirano (FPI program, BES-2015-073595). Regional Government of Murcia, Spain (ESAMUR) and Murcia Water Works (EMUASA) are acknowledged for their collaboration in this research project and provision of facilities at Murcia Este Wastewater Treatment Plant (Murcia, Spain).

Aim To describe the management of atherogenic dyslipidemia (AD) in routine clinical practice in the Primary Care (PC) setting in Spain. Methods Observational, descriptive, cross-sectional study based on a structured questionnaire designed for this study and addressed to PC physicians. The questionnaire content was based on a literature review and was validated by 3 experts in AD. Results A total of 1029 PC physicians participated in the study. 96.99% indicated that AD is determinant for cardiovascular risk, even if LDL-C levels are appropriate. 88.43% evaluated residual cardiovascular risk in their clinical practice, however, only 27.89% of them evaluated it in secondary prevention. Regarding diagnosis, 82.22% reported that TC, TG, HDL-C and non-HDL-C are essential measures when evaluating AD. Almost all physicians reported that they can request fractionated cholesterol to assess HDL-C and LDL-C, however 3.69% could not. Physicians (95.63%) considered that the first step in AD treatment should be diet, regular exercise, smoking cessation and pharmaceutical treatment, if necessary. 19.1% agreed partially or completely that gemfibrozil is the most suitable fibrate to associate with statins. 74.83% completely agreed that fenofibrate is the most suitable fibrate to combine with statins. Conclusions Physicians have access to general Spanish guidelines and recommendations associated with AD management, however, it is necessary to continue rising awareness about the importance of early detection and optimal control of AD to reduce patients’ cardiovascular risk.

Gemfibrozil (GEM) is a fibrate lipid regulator and one of the most commonly occurring fresh water pharmaceuticals. The negative effects of fibrates including GEM on fish reproduction have been frequently reported including effects of F0 GEM exposure on reproduction of the unexposed F1 offspring. We predicted that chronic, direct exposure of zebrafish with low concentrations of GEM would adversely affect parental male reproduction and unexposed offspring for multiple generations. Adult zebrafish were exposed to 10 μg/L GEM for 6 weeks and a range of reproductive indices were analyzed. The F1–F4 offspring were reared in clean water from 3 distinct lineages where only a single or both parents were exposed and compared to a control lineage where parents were unexposed. Reproductive indices were examined in unexposed F1–F4 offspring to test the hypothesis of multi- or trans- generational impacts. Exposure to GEM caused a decline in breeding success and mean embryo production in F0 parents and a reduction in whole body 11-ketotestosterone (11-KT), altered male courtship, aggression and sperm morphology. Our results indicate that paternal exposure alone is sufficient to result in reproductive effects in unexposed male offspring but that effects are mostly limited to F1. We suggest that GEM may act as a reproductive endocrine disruptor in fish and that chronic exposure reduced male reproductive fitness but not over multiple generations.

Purpose To determine the relationship of illnesses and medical drug consumption with the occurrence of traffic accidents among truck and bus drivers. Methods This is a cross-sectional study on truck and bus drivers in Tehran, Iran. The criteria for participating in this study were: married males over 30 years old, driving license in grade one, five years of job experience, mental health and non-addiction license. The criterion for not participating in this study was the lack of cooperation in responding to the questions. Six months was spent to collect the latest five years data of driving accidents from 2011 to 2016. A total of 323 truck and bus drivers in Tehran city and the suburbs, Iran were chosen. Among them, 112 were responsible for accidents (accident group) while 211 were not responsible for any accidents or involved in an accident in the last five years (non-accident group). A specially designed questionnaire was used to investigate the demographic information, medical drug consumption, medical backgrounds and history of accidents. Results The results revealed that compared with healthy subjects, the occurrence of accidents among people with diabetes (OR = 2.3, p = 0.001) and vision weakness (OR = 1.7, p = 0.020) was significantly higher, while that among people with cardiac (OR = 0.5, p = 0.002) and hypertension (OR = 0.9, p = 0.048) problems was remarkably lower. Moreover, consumption of Gemfibrozil (OR = 1.8, p = 0.010) and Glibenclamide (OR = 2.2, p = 0.002) drugs resulted in significantly higher incidence of accidents than those without. Conclusion Frequencies of illnesses like cardiovascular and hypertension were not higher in accident drivers than in non-accident drivers; but diabetes, vision weakness and consumption of Gemfibrozil and Glibenclamide lead to more traffic accidents., Highlights • Vascular-cardinal and blood pressure lead to less traffic accidents. • Diabetes and vision weakness lead to more traffic accidents. • Consumption of Gemfibrozil and Glibenclamide lead to more traffic accidents.

Pharmaceuticals and analogs of bisphenol A (BPA) are increasingly threatening environmental pollutants. In this study, mixtures of selected pharmaceuticals (diclofenac sodium salt, chloramphenicol, oxytetracycline hydrochloride, fluoxetine hydrochloride, estrone, ketoprofen, progesterone, gemfibrozil and androstenedione) were prepared with BPA and its two analogs (namely, bisphenols F and S) at such ratios to reflect environmentally detectable levels. Then, the mixture solutions were studied with a XenoScreen YES/YAS assay to determine the variations in the initial hormonal response of each pharmaceutical compound due to the presence of a bisphenol analog. The results obtained were modeled with the concentration addition (CA) and independent action (IA) approaches, the trueness of which was studied with model deviation ratios (MDR). The estrogenic agonistic activity of the drugs studied was most strongly affected by the presence of BPA in solution (twenty-one cases of synergy observed for CA models versus twelve cases of antagonism in the case of IA predictions). BPS shows a strong agonistic estrogenic impact on most of the drugs studied at medium and high concentration levels; androgenic agonistic activity was also impaired with elevated concentrations of BPS. Increasing the concentration of BPF in a reaction mixture also increased the number of YES + synergism incidences (for CA modeling). Estrone, progesterone and androstenedione were mostly affected by the highest BPF concentrations studied in the case of androgenic agonistic research performed.

Previously, we proposed 12 marker genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2 and Tubb4b) to discriminate mouse genotoxic hepatocarcinogens (GTHC) from non-genotoxic hepatocarcinogens (NGTHC). This was determined by qPCR and principal component analysis (PCA), as the aim of an in vivo short-term screening for genotoxic hepatocarcinogens. For this paper, we conducted an application study of the 12 mouse marker genes to rat data, Open TG-GATEs (public data). We analyzed five typical rat GTHC (2-acetamodofluorene, aflatoxin B1, 2-nitrofluorene, N-nitrosodiethylamine and N-nitrosomorpholine), and not only seven typical rat NGTHC (clofibrate, ethanol, fenofibrate, gemfibrozil, hexachlorobenzene, phenobarbital and WY-14643) but also 11 non-genotoxic non-hepatocarcinogens (NGTNHC; allyl alcohol, aspirin, caffeine, chlorpheniramine, chlorpropamide, dexamethasone, diazepam, indomethacin, phenylbutazone, theophylline and tolbutamide) from Open TG-GATEs. The analysis was performed at 3, 6, 9 and 24 h after a single administration and 4, 8, 15 and 29 days after repeated administrations. We transferred Open TG-GATEs DNA microarray data into log2 data using the “R Project for Statistical Computing”. GTHC-specific dose-dependent gene expression changes were observed and significance assessed with the Williams test. Similar significant changes were observed during 3–24 h and 4–29 days, assessed with Welch’s t-test, except not for NGTHC or NGTNHC. Significant differential changes in gene expression were observed between GTHC and NGTHC in 11 genes (except not Tubb4b) and between GTHC and NGTNHC in all 12 genes at 24 h and 10 genes (except Ccnf and Mbd1) at 29 days, per Tukey’s test. PCA successfully discriminated GTHC from NGTHC and NGTNHC at 24 h and 29 days. The results demonstrate that 12 previously proposed mouse marker genes are useful for discriminating rat GTHC from NGTHC and NGTNHC from Open TG-GATEs.

There is an increasing need to assess animal welfare and subtle alterations that may indicate the presence of environmental stressors. Among the most widely used endpoints are the assessment of the activities of specific enzymes and the alterations of the expression levels of target genes. Enzymes associated with oxidative stress are frequently assessed but the results frequently render enzyme-dependent altered levels that make analyses difficult. In this study, Sparus aurata (gilthead sea bream) juveniles, were exposed, via water, to gemfibrozil (GEM) for a 96 h period to i) validate methods to measure total oxidative status (TOS), total antioxidant capacity (TAC), and esterase activity (EA) in gills; ii) study the relation between assessed gills’ oxidative stress responses and the mRNA levels of genes related to stress and immune function (in the gills and head kidney); iii) contribute to the knowledge of the effects of this human pharmaceutical on marine fish species. Overall, the obtained data confirmed the methodological precision and accuracy of TOS, TAC and EA measurements in the gills. GEM exposure did not alter TAC in gills but increased TOS. GEM modulated mRNA levels of genes, such as glutathione peroxidase 1 (gpx1) and interleukin 1β (il1 β) in the gills and head kidney of S. aurata.

Berberine (BBR) hydrochloride is a traditional Chinese medicine with unique hypoglycemic and lipid-lowering effects discovered in recent years. The combination of BBR with other hypoglycemic drugs and lipid-lowering drugs could become a promising treatment strategy. With the aim of evaluating the potential drug-drug interaction (DDI) based on the pharmacokinetics between BBR and simvastatin, fenofibrate, gemfibrozil, metformin, glimepiride, nateglinide, pioglitazone and sitagliptin in beagles, an UPLC-MS/MS method has been developed and validated. The analytes and internal standards were extracted from plasma samples using a magnetic solid phase extraction technique, and then separated by a Luna® Omega C18 column (20.0 × 2.0 mm, 1.6 μm) with water containing 3 mM ammonium and 0.1% formic acid and acetonitrile containing 3 mM ammonium and 0.1% formic acid as the mobile phase. Validation of the UPLC-MS/MS method was carried out following the criteria of the Chinese Pharmacopeia, mainly including specificity, carryover, calibration curve, crosstalk, precision, accuracy, dilution integrity, matrix effect, recovery and stability. The results showed that all the criteria of the method validation met the Chinese Pharmacopoeia guidelines, and the proposed UPLC-MS/MS method was proven to be sensitive, simple and specific to determine all the analytes in the beagles’ plasma samples simultaneously. Meanwhile, the potential DDI between BBR and simvastatin, fenofibrate, gemfibrozil, metformin, glimepiride, nateglinide, pioglitazone and sitagliptin was confirmed in this paper, especially for simvastatin, fenofibrate, gemfibrozil and glimepiride.

Atorvastatin (ATV) and gemfibrozil (GEM) are two typical lipid-lowering pharmaceuticals with different action modes, which are frequently detected in various water bodies owning to their wide usage. However, there is limited information about their effects on Daphnia magna. The present study addressed and compared the toxic effects of ATV and GEM on D. magna through determining the responses of the stress related genes (including Nrf2, Keap1, HO-1, GCLC, p53 and PIG3) in D. magna for 24 h and 48 h acute exposure and the changes of life history traits and swimming behaviors in a 21 days chronic exposure under different concentrations of ATV and GEM exposure (5 μg L−1, 50 μg L−1, 500 μg L−1 and 5000 μg L−1). Results showed that the expression of Nrf2, Keap1, HO-1, GCLC, p53 and PIG3 were induced to various degrees under the ATV exposure. There were similar performances for GEM. ATV and GEM caused the delay of first brooding and hatching time and decrease of eggs production number, especially in GEM exposure, reproduction of Daphnia was significantly inhibited, decreasing 38.51% compared to the control. ATV and GEM increased the heart rate of D. magna, and changed swimming behaviors of D. magna. In summary, two lipid-lowering pharmaceuticals caused oxidative stress on D. magna, subsequently brought about alterations in physiological traits. Comparatively, ATV pose more higher risks to D. magna than GEM, but the detailed action mechanisms of ATV and GEM on D. magna needs more investigations in future.

Ethnopharmacological relevance Parkinsonia aculeata L. (Cesalpineaceae) is a medium tree found in the Xingo region (semi-arid area) in Northeast of Brazil, recognised by local population as an antidiabetic agent. According information from local community, the commonly traditional preparation is prepared as an infusion of the aerial part of the plant and consumed over the day to manage diabetes-related complications. Previous studies have described Parkinsonia aculeate as a product with both hypoglycemic and hypotriglyceridemic effects. Aim of the study The objective of this study was to evaluate the effects of polar fraction obtained from the hydroethanolic extract of Parkinsonia aculeata (PfrHEPA) on the lipid profile of animals that consumed a westernized diet. Materials and methods Thirty-six Wistar rats (45–55 g) were fed either with standard control(C) or westernized diet(W) for 120 days. The food intake, body weight evolution and body size were also analyzed. From 120 to 150 days, they were orally treated according to their group with vehicle (distillated water, 10 mL/kg), PfrHEPA at three doses (35, 70 and 140 mg/kg/day) or Gemfibrozil (140 mg/kg/day) for 30 days. Results The animals fed with westernized diet showed dyslipidemia when compared to animals receiving a standard diet. Treatment with PfrHEPA (140 mg/kg), even with the continued consumption of westernized diet by animals (from 120 to 150 days) promoted a significant reduction in total cholesterol, LDL and triglyceride levels, in relation to untreated W group. PfrHEPA 140 mg/kg reduced the key serum lipids and glycaemia as well as inflammatory cytokines known as important risk factors of cardiovascular diseases. Conclusions The observed evidence may contribute to the control of metabolic parameters as dyslipidemia corroborating the ethnopharmacological information concerning the antihyperlipidemic and hypoglycemic activities of P. aculeata.

Degradation of three lipid regulators, i.e., gemfibrozil, bezafibrate and clofibric acid, by a UV/chlorine treatment was systematically investigated. The chlorine oxide radical (ClO•) played an important role in the degradation of gemfibrozil and bezafibrate with second-order rate constants of 4.2 (±0.3) × 108 M−1 s−1 and 3.6 (±0.1) × 107 M−1 s−1, respectively, whereas UV photolysis and the hydroxyl radical (HO•) mainly contributed to the degradation of clofibric acid. The first-order rate constants (k′) for the degradation of gemfibrozil and bezafibrate increased linearly with increasing chlorine dosage, primarily due to the linear increase in the ClO• concentration. The k′ values for gemfibrozil, bezafibrate, and clofibric acid degradation decreased with increasing pH from 5.0 to 8.4; however, the contribution of the reactive chlorine species (RCS) increased. Degradation of gemfibrozil and bezafibrate was enhanced in the presence of Br−, whereas it was inhibited in the presence of natural organic matter (NOM). The presence of ammonia at a chlorine: ammonia molar ratio of 1:1 resulted in decreases in the k′ values for gemfibrozil and bezafibrate of 69.7% and 7%, respectively, but led to an increase in that for clofibric acid of 61.8%. Degradation of gemfibrozil by ClO• was initiated by hydroxylation and chlorine substitution on the benzene ring. Then, subsequent hydroxylation, bond cleavage and chlorination reactions led to the formation of more stable products. Three chlorinated intermediates were identified during ClO• oxidation process. Formation of the chlorinated disinfection by-products chloral hydrate and 1,1,1-trichloropropanone was enhanced relative to that of other by-products. The acute toxicity of gemfibrozil to Vibrio fischeri increased significantly when subjected to direct UV photolysis, whereas it decreased when oxidized by ClO•. This study is the first to report the transformation pathway of a micropollutant by ClO•.

Lime amendment of biosolids can produce large quantities of hydroxyl ions and increase biosolids pH. The mobility of some pharmaceutical and personal care products (PPCPs) is closely correlated with the pH of biosolids. In this study the mobility of six PPCPs: erythromycin, fluoxetine, carbamazepine, naproxen, gemfibrozil and triclosan, was measured in unamended and lime-amended biosolids over 63days. Biosolids were equilibrated either a at pH range of 5.5-11.5 or cured over a time period up to 63days. The mobility was calculated as the proportion of PPCPs associated with the soluble phase after a given equilibrium time or a curing period. In unamended biosolids the mobility of erythromycin, fluoxetine, gemfibrozil and triclosan decreased, the mobility of naproxen increased and the mobility of carbamazepine was almost unchanged over 63days of curing. Compared to unamended biosolids, lime addition increased the mobility of erythromycin and naproxen by 21.7% and 33.8% respectively, but suppressed the mobility of carbamazepine, fluoxetine, gemfibrozil and triclosan by up to 100% after 63days. The pH influence on hydrophobicity and speciation of PPCPs correlated well with the mobility of erythromycin and fluoxetine, but only partially correlated with the mobility of the other 4 compounds over the pH of 5.5-11.5. Attenuated total reflectance Fourier transformed infrared (ATR-FTIR) and emission-excitation matrices (EEMs) provided spectroscopic evidences showing that the increases in amide and carboxylic groups, the decrease in polysaccharides, and the increases in humic substances in dissolved organic matter (DOM) may be responsible for the changes in the PPCPs' mobility. The effects of lime amendment lasted for approximately a month. The results of this work suggest that lime amendment prevents some PPCPs from being dissolved in biosolids soluble phases, but may not "lock" all PPCPs into biosolids.

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.

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.

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 (Fe2+, Fe3+ and the iron complexes of oxalate – FeOx), initial pH (2.6, 5.0 and 7.0) and concentrations of H2O2. The classic photo-Fenton reaction (at initial pH 2.6, using Fe2+and Fe3+) 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−1H2O2. 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.

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.

Summary 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: bezafibrate (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.

Previous studies demonstrated that anti-hyperlipidemic drug gemfibrozil acts as NO- and heme-independent activator of NO receptor soluble guanylyl cyclase. A series of new gemfibrozil derivatives were synthesized and evaluated for sGC activation. The structure-activity relationship study identified the positions in gemfibrozil’s scaffold that are detrimental for sGC activation and those that are amendable for optimizing modifications. Compared with gemfibrozil, compounds 7c and 15b were more potent activators of cGMP-forming activity of purified sGC and exhibited enhanced relaxation of preconstricted mouse thoracic aorta rings. These studies established the overall framework needed for futher improvement of sGC activators based on gemfibrozil scaffold.

Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exert protective effects on podocytes, whereas angiopoietin-like 3 (ANGPTL3) has been shown to exert significant pathogenic effects on these cells. This study aimed to investigate the link between the protective effects of PPARα activation and the pathogenic effects of ANGPTL3 in podocytes. Both PPARα and ANGPTL3 were expressed in cultured podocytes. PPARα mRNA and protein levels decreased whereas ANGPTL3 mRNA and protein levels increased in a time-dependent manner in podocytes treated with puromycin aminonucleoside (PAN). Gemfibrozil, a pharmacological agonist of PPARα, increased PPARα levels and activity in podocytes. The drug also decreased ANGPTL3 levels by potentially weakening ANGPTL3 promoter activity in both normal and PAN-treated podocytes. Furthermore, gemfibrozil significantly decreased PAN-induced apoptosis and F-actin rearrangement. Primary podocytes from Angptl3-knockout mice were cultured. There was no significant difference between Angptl3-/- podocytes treated with or without gemfibrozil in the lamellipodia numbers after PAN treatment. The results suggested that the protective effects of gemfibrozil on podocytes were not exerted following knockout of the Angptl3 gene. This study identified a novel mechanism of the PPARα agonist gemfibrozil that exerts its protective effects by inhibiting PAN-induced apoptosis and cytoskeleton rearrangements through inhibition of ANGPTL3 expression.

Quantitative analysis of transporter- and enzyme-mediated complex drug–drug interactions (DDIs) is challenging. Repaglinide (RPG) is transported into the liver by OATP1B1 and then is metabolized by CYP2C8 and CYP3A4. The purpose of this study was to describe the complex DDIs of RPG quantitatively based on unified physiologically based pharmacokinetic (PBPK) models using in vitro K i values for OATP1B1, CYP3A4, and CYP2C8. Cyclosporin A (CsA) or gemfibrozil (GEM) increased the blood concentrations of RPG. The time profiles of RPG and the inhibitors were analyzed by PBPK models, considering the inhibition of OATP1B1 and CYP3A4 by CsA or OATP1B1 inhibition by GEM and its glucuronide and the mechanism-based inhibition of CYP2C8 by GEM glucuronide. RPG–CsA interaction was closely predicted using a reported in vitro K i,OATP1B1 value in the presence of CsA preincubation. RPG–GEM interaction was underestimated compared with observed data, but the simulation was improved with the increase of f m,CYP2C8 . These results based on in vitro K i values for transport and metabolism suggest the possibility of a bottom–up approach with in vitro inhibition data for the prediction of complex DDIs using unified PBPK models and in vitro f m value of a substrate for multiple enzymes should be considered carefully for the prediction.

Widespread use of pharmaceuticals and suboptimal wastewater treatment have led to increased levels of these substances in aquatic ecosystems. Lipid-lowering drugs such as gemfibrozil, which are among the most abundant human pharmaceuticals in the environment, may have deleterious effects on aquatic organisms. We examined the genotoxicity of gemfibrozil in a fish species, the gilthead seabream (Sparus aurata), which is commercially important in southern Europe. Following 96-h waterborne exposure, molecular (erythrocyte DNA strand breaks) and cytogenetic (micronuclei and other nuclear abnormalities in cells) endpoints were measured. Gemfibrozil was positive in both endpoints, at environmentally relevant concentrations, a result that raises concerns about the potential genotoxic effects of the drug in recipient waters.

Despite the large number of pharmaceutically active compounds found in natural environments little is known about their transport behavior in groundwater, which is complicated by their wide range of physical and chemical properties. The transport behavior of five widely used and often detected pharmaceutical compounds and one lifestyle drug has therefore been investigated, using a set of three column experiments. The investigated compounds were the anticonvulsant carbamazepine, the lifestyle drug caffeine, the antibiotic sulfamethoxazole, the lipid regulator gemfibrozil, and the nonsteroidal anti-inflammatories ibuprofen and naproxen. The columns were filled with three different types of sand. The substrates consisted of artificially prepared iron-coated sand, artificially prepared organic carbon sand (with 5% leaf compost), and natural aquifer sand from Long Point, Ontario (Canada). The experiments were conducted simultaneously under the same hydraulic conditions and with the same input solution of about 1μg·L-1 of each compound. The transport behavior of the organic compounds differed significantly between both the different columns and the different compounds. A strong correlation was observed between the retardation factors for carbamazepine, gemfibrozil, and ibuprofen and the organic carbon content of the substrate. While the retardation increased with increasing organic carbon content, no direct relationship was observed between the organic carbon content and the removal of these compounds. In contrast, the retardation factors for sulfamethoxazole and naproxen showed no correlation with the organic carbon content but these compounds were significantly removed in the presence of organic matter. The influence of the Fe3+ surfaces in the iron-coated sand was less significant than expected, with all compounds except for sulfamethoxazole having retardation factors

Batten disease (neuronal ceroid lipofuscinosis) refers to a group of neurodegenerative lysosomal storage diseases predominantly affecting children. There are currently no effective treatments, and the functions of many of the associated gene products are unknown. Here we characterise fetal neural cultures from two genetically distinct sheep forms of Batten disease, with mutations in the lysosomal protein encoding gene CLN5 and endoplasmic reticulum membrane protein encoding gene CLN6, respectively. We found similar reductions in autophagy, acidic organelles and synaptic recycling in both forms compared to unaffected cells. We then developed a high-throughput screen and tested for correction of deficient cells with lentiviral-mediated CLN5 or CLN6 gene transfer and fibrate drugs, gemfibrozil and fenofibrate in CLN6 deficient neural cultures. These assays provide a simple system to rapidly screen candidate therapies or libraries of drugs prior to in vivo testing.

Background Drug interactions, particularly those involving warfarin, are a major clinical and public health problem. Minimizing serious bleeding caused by anticoagulants is a recent major focus of the United States (US) Department of Health and Human Services. This study quantified the risk of gastrointestinal bleeding (GIB) and intracranial hemorrhage (ICH) among concomitant users of warfarin and individual antihyperlipidemics. Methods The authors conducted a high-dimensional propensity score-adjusted cohort study of new concomitant users of warfarin and an antihyperlipidemic, among US Medicaid beneficiaries from five states during 1999–2011. Exposure was defined by concomitant use of warfarin plus one of eight antihyperlipidemics. The primary outcome measure was a composite of GIB/ICH within the first 30days of concomitant use. As a secondary outcome measure, GIB/ICH was examined within the first 180days of concomitant use. Results Among 236,691 persons newly-exposed to warfarin and an antihyperlipidemic, the crude incidence of GIB/ICH was 13.2 (95% confidence interval 12.7 to 13.8) per 100person-years. Users were predominantly older, female, and Caucasian. Adjusted hazard ratios (aHRs) for warfarin and individual statins were consistent with no association. Warfarin+gemfibrozil was associated with an 80% increased risk of GIB/ICH within the first month of concomitant use (aHR=1.8, 1.4 to 2.4). Warfarin+fenofibrate was associated with a similar increased risk (aHR=1.8, 1.2 to 2.7), yet with an onset during the second month of concomitant use. Conclusions Among warfarin-treated persons, the use of fibrates―but not statins―increases the risk of hospital presentation for GIB/ICH.

Background Although Fenofibrate (FF) is a hypolipedmic drug and one of the PPARα agonists which is a drug target for non alcoholic liver disease (NAFLD), no studies had investigated its potential hepatic effects in such cases. Aim To compare between the effect of FF and Gemfibrozil (GF) on the prognosis of NAFLD in rats. Methods Sixty four rats were used and classified into two main groups. Group I (treated for 6 weeks): naive, FF, GF groups and Group II (treated for 14 weeks and drugs were added at the last 6 weeks): Control, high fat diet (HFD) untreated, HFD + FF, HFD + FF + folic acid (FA) and HFD + GF groups. Body weight (BW), liver index (LI), renal perfusion test (RPT), glomerular filtration rate (GFR), serum creatinine (S.cr), plasma homocysteine (Hcy), liver function, non invasive markers of fibrosis and histopathology were done. Results HFD produced significant increase (P Conclusions There is preference of adding FA to FF or using GF instead in cases of NAFLD. Moreover, this work implies the enhanced liver fibrosis (ELF) panel diagnostic performance in diagnosis of any and moderate degree of fibrosis in rats with NAFLD.

Wastewater-based epidemiology (WBE) is considered as an effective tool for monitoring drug consumption, which is often obtained by back-calculation using the influent concentration and other parameters of wastewater treatment plants. Lack of information on the transformation of drugs in municipal wastewater and sewers may lead to inaccurate consumption estimation. Fourteen prescription drugs in four major categories of diseases (cardiovascular, diabetes, depression, and asthma) were selected to study their adsorption and biodegradation in wastewater and biofilm sewers under different temperatures, pH and biofilms conditions. The result demonstrated that the decay percentage of drugs in wastewater is increased with temperature. Within 72 h, eleven of these 14 drugs, such as metformin, metoprolol, bezafibrate, etc., have decay percentages below 20% in wastewater, which are considered as stable drugs; and the decay percentages of the other three, monluster, paroxetine, and sertraline, are greater than 20%, which are the most unstable drugs. In lab-scale aerobic and anaerobic sewers, the decay percentages of metformin, glipizide, metoprolol, gemfibrozil, and atorvastatin are less than 20% within 24 h. The decay percentages of venlafaxine, citalopram, fluoxetine, salmeterol, and salbutamol within 24 h are 20%–60% and paroxetine and sertraline are close to or even exceed 80% within 6 h. Biodegradation of drugs in sewers with aerobic or anaerobic biofilms is higher than that in wastewater systems without biofilms. The results showed that when the per capita consumption of drugs is estimated by using the WBE method, the stability of drugs in wastewater and different types of sewers will significantly affect their residual concentrations.

The circulating lipids of birds play essential roles for egg production and as an energy source for flight and thermogenesis. How lipid-lowering pharmaceuticals geared to prevent heart disease in humans and that are routinely released in the environment affect their metabolism is unknown. This study assesses the impact of the popular drug gemfibrozil (GEM) on the plasma phospholipids (PL), neutral lipids (NL), and nonesterified fatty acids (NEFA) of bobwhite quails (Colinus virginianus). Results show that bird lipoproteins are rapidly altered by GEM, even at environmentally-relevant doses. After 4 days of exposure, pharmacological amounts cause an 83% increase in circulating PL levels, a major decrease in average lipoprotein size measured as a 56% drop in the NL/PL ratio, and important changes in the fatty acid composition of PL and NEFA (increases in fatty acid unsaturation). The levels of PL carrying all individual fatty acids except arachidonate are strongly stimulated. The large decrease in bird lipoprotein size may reflect the effects seen in humans: lowering of LDL that can cause atherosclerosis and stimulation of HDL that promote cholesterol disposal. Lower (environmental) doses of GEM cause a reduction of %palmitate in all the plasma lipid fractions of quails, but particularly in the core triacylglycerol of lipoproteins (NL). No changes in mRNA levels of bird peroxisome proliferator-activated receptor (PPAR) could be demonstrated. The disrupting effects of GEM on circulating lipids reported here suggest that the pervasive presence of this drug in the environment could jeopardize reproduction and migratory behaviours in wild birds.

Removal of three pharmaceuticals, namely, atenolol, gemfibrozil and ciprofloxacin in three bioreactors namely, activated sludge process (ASP), submerged attached biofilter (SABF) and membrane bioreactor (MBR) was studied. Removal efficiencies at steady state for atenolol were found to be 93%, 82% and 95% in ASP, SABF and MBR, respectively. Removal efficiencies for gemfibrozil were 75%, 90% and 85%, while those for ciprofloxacin were 84%, 95% and 93% in ASP, SABF and MBR, respectively. Nearly 20% of the ciprofloxacin was found to be sorbed on the biomass in the reactors. Reduction in sludge residence time (SRT) decreased the removal of compounds in ASP and MBR, and reduction in hydraulic residence time (HRT) caused a negative impact on the performance of all the reactors. Considerable increase in easily available carbon source reduced the removal efficiency. Sorption coefficient (log K d ) of ciprofloxacin was found to be 3.86 and sorption was negligible in case of atenolol and gemfibrozil. Monod co-metabolic model could simulate biodegradation process satisfactorily. Inhibition concentrations ( K i ) of atenolol, ciprofloxacin and gemfibrozil were found to be 2.8 mg/L, 0.6 mg/L and 0.89 mg/L, respectively. Biokinetic parameters μ max , K s and Y X/S were 0.046 h −1 , 10 mg/L and 0.36, respectively. Efficiency factor ( η c ) was estimated to be 0.002, 0.0006 and 0.001 mg compound/gCOD for atenolol, ciprofloxacin and gemfibrozil, respectively.

High carbohydrate diet (HCD) can induce lipid metabolism disorder, characterized by excessive lipid in farmed fish. Peroxisome proliferator activated receptor-α (PPARα) plays an important role in lipid homeostasis. In this study, we hypothesize that PPARα can improve lipid metabolism in fish fed HCD. Fish (3.03 ± 0.11 g) were fed with three diets: control (30% carbohydrate), HCD (45% carbohydrate) and HCG (HCD supplemented with 200 mg/kg gemfibrozil, an agonist of PPARα) for eight weeks. The fish fed HCG had higher growth rate and protein effiency than those fed the HCD diet, whereas the opposite trend was observed in feed conversion ratio, hepatosomatic index and mesenteric fat index. Additionally, fish fed HCG significantly decreased lipid accumulation in the whole body, liver and adipose tissues compared to those fed the HCD diet. Furthermore, fish in the HCG group significantly increased the mRNA and protein expression and protein dephosphorylation of PPARα. The HCG group also significantly increased the mRNA level of the downstream target genes of PPARα, whereas the opposite trend occured in the mRNA level of lipolysis-related genes compared to the HCD group. Besides, fish in the HCG group remarkably decreased the contents of alanine aminotransferase, aspartate aminotransferase and malondialdehyde, whereas the opposite occured in the activities of antioxidative enzymes and anti-inflammatory cytokine genes compared to the HCD group. This study indicates that gemfibrozil can improve lipid metabolism and maintain high antioxidant and anti-inflammatory capacity through activating PPARα in Nile tilapia fed a high carbohydrate diet.

Introduction The risk of cataracts (C) associated to lipid-lowering drugs (LLD) is discussed. Following early warnings in animal models, several clinical and observational studies led to conflicting results. We assessed in real life the association between LLD and C using the WHO individual case safety reports database, VigiBase®, including reports from over 130 countries worldwide. Methods We performed a disproportionality analysis with all reports between 1/1/1988 and 31/12/2018 to measure the reporting risk of “cataract” in patients ≥ 45 years. Primary analysis compared LLD users to non-users. We performed 2 sensitivity analyses: (1) exclusion of reports with 2 LLD associated, (2) exclusion of patients with antidiabetics and glucocorticoids, known to induce C. Finally, we investigated the drugs more at risk in each class. Results We identified 14,664 reports of cataract (3,049 in users, 66% women, 66 ± 20 y). The most frequently involved LLD were statins [84%, atorvastatin (n = 1.016), simvastatin (626), rosuvastatin (392), lovastatin (343), pravastatin (268)] followed by fibrates [5.7%, fenofibrate (117), gemfibrozil (56)], nicotinic acid (3%), bile acid sequestrants (2%), herbal cholesterol and triglyceride reducers (2%) and others (15%). LLD users were associated to a greater C risk than non-users ROR: 2.47 (95%CI: 2.37–2.57). This risk was also found for statins in general, fibrates, bile sequestrants, nicotinic acid, herbal drugs and others (ezetimibe, PCSK9 inhibitors). Similar trends were observed in sensitivity analyses. The most important risk was found for statins with lovastatin followed by pravastatin and atorvastatin and for fibrates with fenofibrate. Conclusion Using a large real life database (18.5 million reports), we found for the first time a signal of cataract for all LLD, i.e. not only statins but also fibrates and other classes suggesting that a decrease in cholesterol is involved in the pathophysiology of C with LLD.

The magnetic metal-organic framework Fe3O4@(Fe-(benzene-1,3,5-tricarboxylic acid) (MMOF) was prepared, characterized and studied as a magnetic sorbent for the dispersive solid-phase extraction (DSPE) of several widely used blood lipid regulators (i.e., bezafibrate, clofibric acid, clofibrate, gemfibrozil and fenofibrate) from water samples. Characterization of the synthesized Fe3O4@Fe-BTC magnetic nanomaterial was performed by Fourier transform infrared spectroscopy, powder X-ray diffractometry, thermogravimetric analysis, scanning electron microscopy and transmission electron microscopy. The magnetic nanocomposite was found to be chemically stable and to possess a large surface area (803.62 m2/g) and pore volume (0.59 cm³/g). The concentrations of fibrates in different water samples were determined using HPLC-UV-Vis and confirmed by UPLC-MS/MS. Parameters affecting the extraction efficiency of magnetic-DSPE were studied and optimized. The maxima absorption capacities (Qmax) were determined to be (in mg/g) 197.0 for bezafibrate, 620.3 for clofibric acid, 537.6 for clofibrate, 288.7 gemfibrozil and 223.2 for fenofibrate. Validations of the optimized magnetic DSPE method for analyses at two fibrate concentrations in spiked water samples produced relative recovery values ≤ 70% for clofibrate and within the range of 80–100% for bezafibrate, clofibric acid, gemfibrozil and fenofibrate. LODs ranging from 4 μg/L for fenofibrate to 99 μg/L for gemfibrozil were obtained. The validated methodology produced recovery values ranging from 70 to 112% (relative standard deviations

In recent years, pharmaceuticals have received increasing attentions because of their potential risks to the environment, but researches focusing on their impacts on defense system of living plants are still lacking. As an important class of phytohormones, jasmonates play crucial roles in plant defense system against environmental stress. In order to investigate the effect of pharmaceuticals uptake on endogenous jasmonates, an in vivo solid phase microextraction (SPME) method was established to simultaneously detect and monitor both pharmaceuticals and jasmonates in living plants. The proposed method exhibited wide linear ranges, high sensitivity (limits of detection ranging 0.0043–0.035 ng g−1 for pharmaceuticals and 0.091–0.22 ng g−1 for jasmonates, respectively), and satisfactory reproducibility (relative standard deviation of intrafiber ranging 4.2%–8.6% and interfiber ranging 5.2%–8.2%, respectively). Subsequently, this method was successfully applied to track the concentrations of each pharmaceutical and corresponding jasmonates in living Malabar spinach plants (Basella alba. L) exposed to three common pharmaceuticals (i.e. gemfibrozil, mefenamic acid and tolfenamic acid) over 15 days. In result, all pharmaceuticals appeared to trigger intensive biosynthesis of jasmonic acid (JA) (3.1–9.4 times of control) while reduced the concentration of methyl jasmonate (MeJA) (18.3%–38.1% of control). We inferred that uptake of pharmaceuticals acted as an abiotic stress and stimulated the plant defense response because of the variation of jasmonates. To the best of our knowledge, this is the first study applying SPME to detect and track both pharmaceuticals and phytohormones in living plants, which not only provided a glimpse to the adverse effect of pharmaceuticals on plants as well as the regulation of endogenous jasmonates, but also set a promising template for future in vivo analysis of xenobiotics and plant endogenous substances.

While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug–drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the k inact and K ′ app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min −1 and 57.3 μM, respectively. In this study, the k obs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo . The k obs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min −1 and 0.0051 min −1 , respectively. The k obs, in vivo value of gemfibrozil was 0.0060 min −1 , which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo .

Background & AimsParitaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients.MethodsMechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin. Drug-drug interactions with medications commonly used in HCV-infected patients were evaluated for amlodipine, furosemide, alprazolam, zolpidem, duloxetine, escitalopram, methadone, buprenorphine/naloxone, and oral contraceptives. Ratios of geometric means with 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were used to determine the magnitude of interaction.ResultsCoadministration with the 3D regimen of OBV, PTV/r, and DSV resulted in a

Background Effects of peroxisome proliferator-activated receptor alpha (PPARα) agonists on cardiovascular outcome have been controversial. Although these agents primarily affect lipoprotein metabolism, their pleiotropic anti-inflammatory effect is one of the potential anti-atherosclerotic mechanisms. This study aimed to evaluate the effect of fenofibrate and gemfibrozil on inflammation in macrophages and reveal pathways these agents may affect. Methods and results The two PPARα agonists inhibited secretion of CXCL2, TNF-α, IL-6, activation of p65 of NF-κB, ERK, and TLR4 expression. These changes occurred simultaneously with upregulation and secretion of β-defensin 1, an inflammation-modulating peptide. To demonstrate the role of β-defensin 1, it was knocked-down by target-specific siRNA. The effects of PPARα agonists on TLR4 expression and chemokine secretion were obviously abrogated with this treatment. In experiments investigating whether β-defensin 1 acts extracellularly, inflammatory chemokines decreased significantly after the addition of recombinant β-defensin 1 or conditioned media to cells. In experiments designed to clarify if the effects of the two agents are PPARα-dependent, induction of mRNA and secretion β-defensin 1 and inhibition of chemokine release were clearly reduced with GW6471, a PPARα blocker. Conclusions Our results reveal the pathways by which fenofibrate and gemfibrozil inhibit LPS-induced inflammatory activation of macrophages. This study elucidated a novel anti-inflammatory mechanism that acts through PPARα, β-defensin 1, and TLR4 pathways.

A magnetic solid phase extraction method based on β-cyclodextrin (β-CD) grafted graphene oxide (GO)/magnetite (Fe3O4) nano-hybrid as an innovative adsorbent was developed for the separation and pre-concentration of gemfibrozil prior to its determination by spectrofluorometry. The as-prepared β-CD/GO/Fe3O4 nano-hybrid possesses the magnetism property of Fe3O4 nano-particles that makes it easily manipulated by an external magnetic field. On the other hand, the surface modification of GO by β-CD leads to selective separation of the target analyte from sample matrices. The structure and morphology of the synthesized adsorbent were characterized using powder X-ray diffraction, Fourier transform infrared spectroscopy, and field emission scanning electron microscopy. The experimental factors affecting the extraction/pre-concentration and determination of the analyte were investigated and optimized. Under the optimized experimental conditions, the calibration graph was linear in the range between 10 and 5000 pg mL(-1) with a correlation coefficient of 0.9989. The limit of detection and enrichment factor for gemfibrozil were 3 pg mL(-1) and 100, respectively. The maximum sorption capacity of the adsorbent for gemfibrozil was 49.8 mg g(-1). The method was successfully applied to monitoring gemfibrozil in human serum and pharmaceutical wastewaters samples with recoveries in the range of 96.0-104.0% for the spiked samples.

X-linked adrenoleukodystrophy (X-ALD) is a neurometabolic disease that is caused by mutations in the ABCD1 gene. ABCD1 protein deficiency impairs peroxisomal very long-chain fatty acid (VLCFA) degradation resulting in increased cytosolic VLCFA-CoA levels, which are further elongated by the VLCFA-specific elongase, ELOVL1. In adulthood, X-ALD most commonly manifests as a gradually progressive myelopathy (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1. Although, in a clinical trial, bezafibrate was unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients, inhibition of ELOVL1 remains an attractive therapeutic option. In this study, we investigated the kinetic characteristics of ELOVL1 using X-ALD fibroblasts and microsomal fractions from ELOVL1 over-expressing HEK293 cell lines and analyzed the inhibition kinetics of a series of fibrates. Our data show that the CoA esters of bezafibrate and gemfibrozil reduce chain elongation by specifically inhibiting ELOVL1. These fibrates can therefore serve as lead compounds for the development of more potent and more specific inhibitors for ELOVL1.

This study provides a first estimate of the sources, distribution, and risk presented by emerging organic contaminants (EOCs) in coastal waters off southwestern Taiwan. Ten illicit drugs, seven nonsteroidal anti-inflammatory drugs (NSAIDs), five antibiotics, two blood lipid regulators, two antiepileptic drugs, two UV filters, caffeine, atenolol, and omeprazole were analyzed by solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry (SPE–LC–MS/MS). Thirteen EOCs were detected in coastal waters, including four NSAIDs (acetaminophen, ibuprofen, ketoprofen, and codeine), three antibiotics (ampicillin, erythromycin, and cefalexin), three illicit drugs (ketamine, pseudoephedrine, and MDMA), caffeine, carbamazepine, and gemfibrozil. The median concentrations for the 13 EOCs ranged from 1.47 ng/L to 156 ng/L. Spatial variation in concentration of the 13 EOCs suggests discharge into coastal waters via ocean outfall pipes and rivers. Codeine and ampicillin have significant pollution risk quotients (RQ > 1), indicating potentially high risk to aquatic organisms in coastal waters.

With mixed dyslipidemia of the atherogenic dyslipidemia type, once the LDL-c objectives have been achieved through statin treatment, there is often a residual risk, for which the addition of a fibrate is recommended. The combination of statins and fibrates has been limited by the possibility of drug interactions, which mostly result in myopathy. Interactions between statins and other drugs are caused by pharmacokinetic mechanisms, mainly by changing the metabolism of statins in the CYP450 enzyme system, in the hepatic glucuronidation pathway or in the transporters responsible for statin distribution in tissues. The most significant adverse eff ect of statins is myopathy, which can also be induced by fibrates and is more frequent when the 2 drugs (statins and fibrates) are combined. This adverse eff ect manifests clinically as myalgia, muscle weakness, increased CK levels and, in its most severe form, rhabdomyolysis. This interaction mainly aff ects gemfibrozil due to its specific action on the CYP450 enzyme system and that interferes with the hepatic glucuronidation of statins by using the same isoenzymes and with organic anion transporters in the liver. When combining statins, we should use other fibric acid derivatives, preferably fenofibrate.

Cholesteryl ester transfer protein (CETP) is a plasma protein that reduces high density lipoprotein (HDL)-cholesterol (chol) levels and may increase atherosclerosis risk. n-3 and n-6 polyunsaturated fatty acids (PUFAs) are natural ligands, and fibrates are synthetic ligands for peroxisome proliferator activated receptor-alpha (PPARα), a transcription factor that modulates lipid metabolism. In this study, we investigated the effects of PUFA oils and fibrates on CETP expression. Hypertriglyceridemic CETP transgenic mice were treated with gemfibrozil, fenofibrate, bezafibrate or vehicle (control), and normolipidemic CETP transgenic mice were treated with fenofibrate or with fish oil (FO; n-3 PUFA rich), corn oil (CO, n-6 PUFA rich) or saline. Compared with the control treatment, only fenofibrate significantly diminished triglyceridemia (50%), whereas all fibrates decreased the HDL-chol level. Elevation of the CETP liver mRNA levels and plasma activity was observed in the fenofibrate (53%) and gemfibrozil (75%) groups. Compared with saline, FO reduced the plasma levels of nonesterified fatty acid (26%), total chol (15%) and HDL-chol (20%). Neither of the oil treatments affected the plasma triglyceride levels. Compared with saline, FO increased the plasma adiponectin level and reduced plasma leptin levels, whereas CO increased the leptin levels. FO, but not CO, significantly increased the plasma CETP mass (90%) and activity (23%) as well as increased the liver level of CETP mRNA (28%). In conclusion, fibrates and FO, but not CO, up-regulated CETP expression at both the mRNA and protein levels. We propose that these effects are mediated by the activation of PPARα, which acts on a putative PPAR response element in the CETP gene.

In this study we explored how parental exposure to pharmaceuticals influences reproduction in offspring. Adult zebrafish (Danio rerio) were exposed for 6 weeks to 10 μgL(-1) of carbamazepine (CBZ) and gemfibrozil (GEM), two commonly prescribed drugs. Embryos were collected, reared in clean water until sexual maturity and then assessed for reproductive output, courtship, sperm function and organ histology. While 34% of the control pairs produced clutches, only 11% of the fish with CBZ exposed parents or 17% of the fish with GEM exposed parents produced clutches. Reciprocal crosses indicated that exposure in males had more profound reproductive effects. When a control F1 male was crossed with either a F1 female whose parents were CBZ or GEM exposed; no differences were observed in embryo production compared to controls. However, when a control F1 female was crossed with either a CBZ or GEM F1 male, 50% less embryos were produced. Male courtship was reduced in both CBZ and GEM F1 fish but the deficits in courtship displays were drug specific. Compared to control males, the sperm from GEM F1 males had shorter head lengths and midpieces whereas sperm from CBZ F1 males had longer midpieces. Although it remains unclear how specifically these morphological differences influenced sperm velocity, the sperm from GEM F1 males and from CBZ F1 males swam faster than the sperm of control F1 at 20s post activation. No significant differences were observed in the histology of the liver, kidney and gonads across treatment groups. These data are important as they show that chronic, low dose pharmaceutical exposure of parental fish is sufficient to cause significant reproductive effects in offspring.

Statins, which are used as first-line drugs in the prevention of cardiovascular disease, are usually safe, but in some cases there may be muscular toxicity. Statin-associated myopathy, can present as myalgia, myositis or rhabdomyolysis. Only 0.44 per 10,000 treated and per year, develop rhabdomyolysis. There are many risk factors associated with the patient and with the pharmacological treatment. A risk of muscle injury of 1-5% has been reported with some statins combined with fibrates. The fibrate with the highest risk of myopathy in combination with statins is gemfibrozil, while phenofibrate seems to be the safest. The case is presented of a 60 year-old woman with clinical symptoms and laboratory findings that suggested rhabdomyolysis secondary to a combination of simvastatin and phenofibrate. This case reminds physicians of the need to closely monitor these patients, in addition to alert them to the onset of muscle pain or weakness.

The fate of pharmaceutically active compounds (PhACs) in wastewater treatment systems is an area of increasing concern. Little research has been done to understand this issue in rural or decentralized communities. The objective of this research was to examine the ability of a bench scale nitrifying recirculating biofilter (RBF) to remove four acidic PhACs: gemfibrozil, naproxen, ibuprofen and diclofenac from secondary treated municipal wastewater at concentrations of 20 and 200 μg/L. The average removals in this study were between 92 and 99% for ibuprofen, 89 and 99% for naproxen, 62 and 92% for gemfibrozil and 40 and 76% for diclofenac, which is consistent with literature. Ibuprofen and naproxen were largely removed through biological transformation; whereas gemfibrozil and diclofenac showed more variable removal, likely due to both biological transformation and sorption processes. PhAC removal in the RBFs was repeatable between trials, robust and responsive to system upsets, and the presence of PhACs as a single compound versus mixtures had no impact on PhAC removal efficiency. In summary, this study indicates that RBFs as a nitrifying stage of a multi-stage filtration process could be a viable technology for removal of some acidic pharmaceuticals in small onsite wastewater treatment facilities.

The fate and exposure risks of pharmaceutically active compounds (PhACs) and endocrine disrupting chemicals (EDCs) in marine environments are not well-understood. In this study we developed a multi-residue analytical method for quantifying concentrations of forty target compounds in seawater from Singapore. Analyses of samples (n = 24) from eight sites showed the occurrence of several compounds, including gemfibrozil (

Stress predisposes the brain to various neuropathological disorders. Fibrates like gemfibrozil, commonly used for hyperlipidemia, have not yet been examined for their protective/deteriorative potential against restraint stress-induced disturbances. Pretreatment of rats with a range of gemfibrozil concentrations showed significant protection against stress consequences at 90 mg/kg of gemfibrozil, as it resulted in the highest level of antioxidant defense system potentiation among other doses. It also reduced plasma corticosterone compared with the stressed animals. Administration of gemfibrozil (90 mg/kg) before stress induction was able to significantly induce the protein levels of some protective factors including hemeoxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone-1 (NQO-1) in the antioxidant nuclear factor erythroid-derived 2-like 2 (Nrf-2) pathway, as well as mitochondrial pro-survival proteins, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1). In parallel, the level of cleaved caspase-3 and apoptosis-inducing factor (AIF), two proteins involved in apoptotic cell death, and the number of damaged neurons detected in hematoxylin-eosin (H&E) stained hippocampus sections were suppressed in the presence of gemfibrozil. Herein, although gemfibrozil demonstrated protection against the restraint stress, considering its dose and context-dependent effects reported in the previous studies, as well as its common application in clinic, further investigations are essential to unravel its exact beneficial/deleterious effects in various neuronal contexts.