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International Journal of Molecular... Dec 2023Recent studies observed, despite an anti-hyperlipidaemic effect, a positive impact of fibrates on septic conditions. This study evaluates the effects of gemfibrozil on...
Recent studies observed, despite an anti-hyperlipidaemic effect, a positive impact of fibrates on septic conditions. This study evaluates the effects of gemfibrozil on microcirculatory variables, mitochondrial function, and lipid peroxidation levels with regard to its potential role as an indicator for oxidative stress in the colon and liver under control and septic conditions and dependencies on PPARα-mediated mechanisms of action. With the approval of the local ethics committee, 120 Wistar rats were randomly divided into 12 groups. Sham and septic animals were treated with a vehicle, gemfibrozil (30 and 100 mg/kg BW), GW 6471 (1 mg/kg BW, PPARα inhibitor), or a combination of both drugs. Sepsis was induced via the colon ascendens stent peritonitis (CASP) model. Then, 24 h post sham or CASP surgery, a re-laparotomy was performed. Measures of vital parameters (heart rate (HR), mean arterial pressure (MAP), and microcirculation (µHbO)) were recorded for 90 min. Mitochondrial respirometry and assessment of lipid peroxidation via a malondialdehyde (MDA) assay were performed on colon and liver tissues. In the untreated sham animals, microcirculation remained stable, while pre-treatment with gemfibrozil showed significant decreases in the microcirculatory oxygenation of the colon. In the CASP animals, µHbO levels in the colon and the liver were significantly decreased 90 min after laparotomy. Pre-treatment with gemfibrozil prevented the microcirculatory aberrations in both organs. Gemfibrozil did not affect mitochondrial function and lipid peroxidation levels in the sham or CASP animals. Gemfibrozil treatment influences microcirculation depending on the underlying condition. Gemfibrozil prevents sepsis-induced microcirculatory aberrances in the colon and liver PPARα-independently. In non-septic animals, gemfibrozil impairs the microcirculatory variables in the colon without affecting those in the liver.
Topics: Rats; Animals; Gemfibrozil; Microcirculation; PPAR alpha; Rats, Wistar; Communicable Diseases; Liver; Peritonitis; Gastrointestinal Diseases; Sepsis; Mitochondria; Colon
PubMed: 38203431
DOI: 10.3390/ijms25010262 -
Cardiovascular Diabetology Dec 2014The existence of an independent association between elevated triglyceride (TG) levels, cardiovascular (CV) risk and mortality has been largely controversial. The main... (Review)
Review
The existence of an independent association between elevated triglyceride (TG) levels, cardiovascular (CV) risk and mortality has been largely controversial. The main difficulty in isolating the effect of hypertriglyceridemia on CV risk is the fact that elevated triglyceride levels are commonly associated with concomitant changes in high density lipoprotein (HDL), low density lipoprotein (LDL) and other lipoproteins. As a result of this problem and in disregard of the real biological role of TG, its significance as a plausible therapeutic target was unfoundedly underestimated for many years. However, taking epidemiological data together, both moderate and severe hypertriglyceridaemia are associated with a substantially increased long term total mortality and CV risk. Plasma TG levels partially reflect the concentration of the triglyceride-carrying lipoproteins (TRL): very low density lipoprotein (VLDL), chylomicrons and their remnants. Furthermore, hypertriglyceridemia commonly leads to reduction in HDL and increase in atherogenic small dense LDL levels. TG may also stimulate atherogenesis by mechanisms, such excessive free fatty acids (FFA) release, production of proinflammatory cytokines, fibrinogen, coagulation factors and impairment of fibrinolysis. Genetic studies strongly support hypertriglyceridemia and high concentrations of TRL as causal risk factors for CV disease. The most common forms of hypertriglyceridemia are related to overweight and sedentary life style, which in turn lead to insulin resistance, metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Intensive lifestyle therapy is the main initial treatment of hypertriglyceridemia. Statins are a cornerstone of the modern lipids-modifying therapy. If the primary goal is to lower TG levels, fibrates (bezafibrate and fenofibrate for monotherapy, and in combination with statin; gemfibrozil only for monotherapy) could be the preferable drugs. Also ezetimibe has mild positive effects in lowering TG. Initial experience with en ezetimibe/fibrates combination seems promising. The recently released IMPROVE-IT Trial is the first to prove that adding a non-statin drug (ezetimibe) to a statin lowers the risk of future CV events. In conclusion, the classical clinical paradigm of lipids-modifying treatment should be changed and high TG should be recognized as an important target for therapy in their own right. Hypertriglyceridemia should be treated.
Topics: Animals; Cardiovascular Diseases; Cholesterol; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Insulin Resistance; Risk Factors
PubMed: 25471221
DOI: 10.1186/s12933-014-0159-y -
Clinical Cardiology Oct 1994Genetically determined and metabolically induced disturbances in lipid metabolism, as manifested in several types of dyslipidemia, have been shown to be causally related... (Review)
Review
Genetically determined and metabolically induced disturbances in lipid metabolism, as manifested in several types of dyslipidemia, have been shown to be causally related to the development of coronary artery disease (CAD). A diversity of clinical and angiographic studies has been made to evaluate the linkage between plasma lipid-control therapy in the development of initial and recurrent cardiovascular events. The plan of treatment invariably begins with a low-fat, low-cholesterol diet before initiation of drug therapy. However, many patients have difficulty in adhering to the low-fat diet. Fortunately, metabolic studies show that foods which contain fats rich in stearic (saturated) and oleic (monounsaturated) fatty acids may be given in limited amounts to boost patients' compliance to a low-fat diet and to prevent their blood lipids from rising to abnormal levels. A bile acid sequestrant (cholestyramine or colestipol) is the first-line drug for control of hypercholesterolemia. Either gemfibrozil or gemfibrozil plus niacin is prescribed to raise high-density lipoprotein (HDL) levels of CAD patients. Approval of two HMG CoA reductase inhibitors, pravastatin and simvastatin, by the FDA gives physicians the additional flexibility of employing a single or a combination drug therapy for optimal control of dyslipidemia. The association of low serum cholesterol level (< 160 mg/dl) with increase in noncardiac mortality has prompted health professionals to consider modifying the universal screening and treatment of serum cholesterol in children and young women and to use hypolipidemic drugs in patients judiciously.
Topics: Arteriosclerosis; Cholesterol; Coronary Disease; Drug Therapy, Combination; Exercise; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Niacin; Probucol
PubMed: 8001298
DOI: 10.1002/clc.4960171003 -
European Journal of Medical Research May 2023The aim of this study is to assess the impact of the duration of the integrated disease management (IDM) program on COPD-related outcomes in real-world setting.
BACKGROUND
The aim of this study is to assess the impact of the duration of the integrated disease management (IDM) program on COPD-related outcomes in real-world setting.
METHODS
A retrospective cohort study among 3771 patients with COPD who had regularly completed 4 visits of IDM program within 1 year between April 1, 2017 and December 31, 2018. CAT score as the primary outcome used to investigate the association between IDM intervention duration and improvement in CAT score. Change in CAT score from baseline to each follow-up visit determined by using least-squares means (LSMeans) approach. The cut-off value of IDM duration for improving the CAT score was determined by the Youden index. Logistic regression was used to analyze the relationship between IDM intervention duration and MCID (the minimal clinically important difference) improvement in CAT score and the factor associated CAT improvement. Risks of COPD exacerbation events (COPD-related ED visit and COPD-related hospitalization) were estimated by using the cumulative incidence curve and Cox proportional hazards models.
RESULT
Among 3771 enrolled COPD patients, the majority of the study cohort were males (91.51%) and 42.7% of patients had CAT score of ≥ 10 at baseline. The mean of age was 71.47 years and the mean CAT at baseline were 10.49. The mean change from baseline in CAT score was - 0.87, - 1.19, - 1.23 and - 1.40 at 3-, 6-, 9- and 12 month follow-up (p < 0.0001 for all visits), respectively. Statistically significantly lower likelihood of achieving MCID improvement in CAT were observed at 3- and 6 month compared to 9 month (at 3 month: OR: 0.720, 95% CI 0.655-0.791; at 6 month: OR: 0.905, 95% CI 0.825-0.922). And only a modest increase likelihood of achieving MCID improvement in CAT at 12 month (OR: 1.097, 95% CI 1.001-1.201) compared with 9-month follow-up. In logistic regression on the entire cohort, CAT MCID improvement was most associated with baseline CAT scores ≥ 10, followed by frequent exacerbation in previous year (> 2 episodes/year), wheezing, and GOLD B or D at baseline. In baseline CAT ≥ 10 group, patients were more likely to achieve CAT MCID improvement and had greater decreases from baseline in CAT score observed at 3-, 6-, 9-, and 12 month compared with baseline CAT score < 10 group (all p < 0.0001). Moreover, in CAT ≥ 10 groups, patients who achieved CAT MCID improvement had lower risk of subsequent COPD exacerbation events (COPD-related ED visit: aHR: 1.196, 95% CI 0.985-1.453, p = 0.0713; COPD-related hospitalization: aHR: 1.529, 95% CI 1.215-1.924, p = 0.0003) when compared to those without.
CONCLUSION
This is the first real-world study indicating the association between COPD IDM intervention duration and COPD-related outcomes. From 3 to 12 month follow-up results showed that continued improvement over time in COPD-specific health status, particularly in patients with baseline CAT score of ≥ 10. Furthermore, a reduction of the risk of subsequent COPD exacerbations were observed in patients with CAT MCID improvement.
Topics: Male; Humans; Female; Retrospective Studies; Gemfibrozil; Pulmonary Disease, Chronic Obstructive; Disease Management
PubMed: 37221574
DOI: 10.1186/s40001-023-01136-0 -
The Journal of Neuroscience : the... Mar 2023Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal inherited neurodegenerative disease of children that occurs because of defective function of the lysosomal...
Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal inherited neurodegenerative disease of children that occurs because of defective function of the lysosomal membrane glycoprotein CLN3. JNCL features glial activation and accumulation of autofluorescent storage material containing subunit c of mitochondrial ATP synthase (SCMAS), ultimately resulting into neuronal loss. Until now, no effective therapy is available for JNCL. This study underlines the possible therapeutic importance of gemfibrozil, an activator of peroxisome proliferator-activated receptor α (PPARα) and a lipid-lowering drug approved by the Food and Drug Administration in an animal model of JNCL. Oral gemfibrozil treatment reduced microglial and astroglial activation, attenuated neuroinflammation, restored the level of transcription factor EB (TFEB; the master regulator of lysosomal biogenesis), and decreased the accumulation of storage material SCMAS in somatosensory barrel field (SBF) cortex of Cln3 (Cln3ΔJNCL) mice of both sexes. Accordingly, gemfibrozil treatment also improved locomotor activities of Cln3ΔJNCL mice. While investigating the mechanism, we found marked loss of PPARα in the SBF cortex of Cln3ΔJNCL mice, which increased after gemfibrozil treatment. Oral gemfibrozil also stimulated the recruitment of PPARα to the gene promoter in the SBF cortex of Cln3ΔJNCL mice, indicating increased transcription of in the CNS by gemfibrozil treatment via PPARα. Moreover, disease pathologies aggravated in Cln3ΔJNCL mice lacking PPARα (Cln3ΔJNCL) and gemfibrozil remained unable to decrease SCMAS accumulation, reduce glial activation, and improve locomotor performance of Cln3ΔJNCL mice. These results suggest that activation of PPARα may be beneficial for JNCL and that gemfibrozil may be repurposed for the treatment of this incurable disease. Despite intense investigations, no effective therapy is available for JNCL, an incurable inherited lysosomal storage disorder. Here, we delineate that oral administration of gemfibrozil, a lipid-lowering drug, decreases glial inflammation, normalizes and/or upregulates TFEB, and reduces accumulation of autofluorescent storage material in SBF cortex to improve locomotor activities in Cln3 (Cln3ΔJNCL) mice. Aggravation of disease pathology in Cln3ΔJNCL mice lacking PPARα (Cln3ΔJNCL) and inability of gemfibrozil to decrease SCMAS accumulation, reduce glial activation, and improve locomotor performance of Cln3ΔJNCL mice delineates an important role of PPARα in this process. These studies highlight a new property of gemfibrozil and indicate its possible therapeutic use in JNCL patients.
Topics: Mice; Animals; PPAR alpha; Gemfibrozil; Neuronal Ceroid-Lipofuscinoses; Neuroglia; Microglia; Disease Models, Animal; Membrane Glycoproteins; Molecular Chaperones
PubMed: 36697260
DOI: 10.1523/JNEUROSCI.2447-21.2023 -
Pharmacology Research & Perspectives Dec 2022UDP-glucuronosyltransferases (UGTs) catalyze the conjugation of various substrates with sugars. Since the UGT2 family forms a large cluster spanning 1.5 Mb, transgenic...
UDP-glucuronosyltransferases (UGTs) catalyze the conjugation of various substrates with sugars. Since the UGT2 family forms a large cluster spanning 1.5 Mb, transgenic mouse lines carrying the entire human UGT2 family have not been constructed because of limitations in conventional cloning techniques. Therefore, we made a humanized mouse model for UGT2 by chromosome engineering technologies. The results showed that six UGT2 isoforms examined were expressed in the liver of adult humanized UGT2 (hUGT2) mice. Thus, the functions of human UGT2B7 in the liver of hUGT2 mice were evaluated. Glucuronide of azidothymidine (AZT, zidovudine), a typical UGT2B7 substrate, was formed in the liver microsomes of hUGT2 mice but not in the liver microsomes of wild-type and Ugt2-knockout mice. When AZT was intravenously administered, AZT glucuronide was detected in the bile and urine of hUGT2 mice, but it was not detected in the bile and urine of wild-type and Ugt2-knockout mice. These results indicated that the hUGT2 mice express functional human UGT2B7 in the liver. This finding was also confirmed by using gemfibrozil as an alternative UGT2B7 substrate. Gemfibrozil glucuronide was formed in the liver microsomes of hUGT2 mice and was mainly excreted in the bile of hUGT2 mice after intravenous dosing of gemfibrozil. This hUGT2 mouse model will enable improved predictions of pharmacokinetics, urinary and biliary excretion and drug-drug interactions mediated by human UGT2, at least UGT2B7, in drug development research and basic research.
Topics: Humans; Mice; Animals; Zidovudine; Glucuronides; Gemfibrozil; Mice, Knockout; Mice, Transgenic; Chromosomes
PubMed: 36424908
DOI: 10.1002/prp2.1030 -
European Journal of Medicinal Chemistry Nov 2021Previous studies demonstrated that anti-hyperlipidemic drug gemfibrozil acts as NO- and heme-independent activator of NO receptor soluble guanylyl cyclase. A series of...
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.
Topics: Animals; Gemfibrozil; Humans; Mice; Nitric Oxide; Soluble Guanylyl Cyclase; Structure-Activity Relationship
PubMed: 34365128
DOI: 10.1016/j.ejmech.2021.113729 -
BMJ Open May 2023This study aims to understand the adverse drug reactions (ADRs) for non-statin antihyperlipidaemic drugs included in the China Anti-hyperlipidemic Drug Database.
OBJECTIVE
This study aims to understand the adverse drug reactions (ADRs) for non-statin antihyperlipidaemic drugs included in the China Anti-hyperlipidemic Drug Database.
DESIGN
An approach of Chinese national database analysis was employed to screen clinical trials involving non-statin antihyperlipidaemic drugs from 1989 to 2019.
SETTING
The database was provided by the China National Medical Products Administration Information Centre.
PARTICIPANTS
In total, 117 clinical studies with 8800 patients were selected from 2650 clinical trials of the Anti-hyperlipidemic Drug Database.
INTERVENTIONS
The non-statin antihyperlipidaemic drugs were divided into three groups: (1) fibrates (fenofibrate, gemfibrozil, bezafibrate, etofylline clofibrate); (2) nicotinic acid and derivatives (niacin, acipimox) and (3) others (probucol, cholestyramine).
RESULTS
The results of this study show that first, gastrointestinal symptoms were the most common reactions (6.975%), which account for approximately 50% of the reported cases with ADRs. Second, cholestyramine (16.418%) and gemfibrozil (13.158%) were the most common gastrointestinal side effect-causing non-statin antihyperlipidaemic drugs, which account for one-third of the population. Third, niacin (7.879%) and gemfibrozil (5.000%) were the most likely cause of liver disease symptoms. Finally, niacin (10.909%) and acipimox (18.847%) were the major non-statin antihyperlipidaemic drugs with skin symptoms.
CONCLUSION
This study revealed that gastrointestinal symptoms were the most common ADRs of fibrates, probucol and cholestyramine in the Chinese population. For nicotinic acid and derivatives, the ADRs of skin symptoms were the most common in China.
Topics: Humans; Niacin; Gemfibrozil; Probucol; Cholestyramine Resin; Hypolipidemic Agents; Fibric Acids; Drug-Related Side Effects and Adverse Reactions
PubMed: 37253501
DOI: 10.1136/bmjopen-2022-068915 -
Annals of Hepatology 2002Treatment of patients with nonalcoholic fatty liver disease (NAFLD) has typically been focused on the management of associated conditions such as obesity, diabetes... (Review)
Review
Treatment of patients with nonalcoholic fatty liver disease (NAFLD) has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipidemia. NAFLD associated with obesity may resolve with weight reduction, although the benefits of weight loss have been inconsistent. Appropriate control of glucose and lipid levels is always recommended, but not always effective in reversing the liver condition. Results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, vitamin E (alpha-tocopherol), metformin and thiazolidinedione derivatives suggest that these medications may be of potential benefit for patients with NAFLD. These medications, however, need first to be tested in well-controlled trials with clinically relevant end-points and extended follow up. A better understanding of the pathogenesis and natural history of NAFLD will help to identify the subset of patients at risk of progressing to advanced liver disease, and hence, those patients who should derive the most benefit from medical therapy.
Topics: Diabetes Complications; Diabetes Mellitus; Fatty Liver; Humans; Hyperlipidemias; Obesity
PubMed: 15114291
DOI: No ID Found -
Therapeutic Advances in Cardiovascular... Feb 2009Cardiovascular disease remains a leading cause of mortality worldwide. As dyslipidemia increases cardiovascular disease risk, proper management of dyslipidemia is one... (Review)
Review
UNLABELLED
Cardiovascular disease remains a leading cause of mortality worldwide. As dyslipidemia increases cardiovascular disease risk, proper management of dyslipidemia is one means by which to decrease cardiovascular disease risk. This review focuses on dyslipidemia treatment utilizing fibrate therapy, which targets high trigylcerides, low HDL, and high small, dense LDL, while contrasting fibrate therapy with statin therapy and combined therapy. Studies were obtained using electronic search strategies, such as Medline and Cochrane Library. Sources selected were limited to those that discussed fibrates, statins, and combined therapy, with specific emphasis placed on sources that focused on fibrates. Selected studies were then assessed for quality via analysis of the study's methodology, results, and data.
RESULTS
of selected studies were then stratified using a rating system devised to determine the quality of results using the scientific evidence provided for them. Combination fibrate and statin therapy can be more effective in achieving optimal lipid levels than just fibrate or statin therapy alone without significant side effects as long as gemfibrozil is not used in therapy.
Topics: C-Reactive Protein; Cardiovascular Diseases; Clofibric Acid; Drug Therapy, Combination; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipoproteins, HDL; Lipoproteins, LDL; Risk Assessment; Treatment Outcome; Triglycerides
PubMed: 19144670
DOI: 10.1177/1753944708096281