BACKGROUND: A detailed understanding of alterations in olanzapine pharmacokinetics during acute inflammatory states, associated with infections, remains lacking. This study aimed to investigate the impact of endotoxemia on the pharmacokinetics of olanzapine and desmethylolanzapine (DMO) in mice. METHODS: C57BL/6N mice received an intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) or saline (controls), followed 24 hours later by single oral or intravenous doses of olanzapine or intravenous DMO. Concentrations and unbound fractions of olanzapine and DMO were measured in the plasma and brain homogenates. RESULTS: In LPS-injected mice, the area under the concentration-time curve (AUCs) for olanzapine increased 3.8-fold in the plasma and 5.2-fold in brain homogenates, in consequence of a higher absolute bioavailability of olanzapine (+200%), a lower plasma clearance (-34%), and a higher brain penetration ratio for the unbound drug relative to controls (Kp,uu,brain 6.2 vs. 4.1). LPS attenuated the hepatic mRNA expression of cytochrome P450 1A2 and the metabolism of olanzapine to DMO. However, the AUC of plasma DMO increased by 140% due to a 4.8-fold decrease in the plasma clearance of DMO. The brain penetration of DMO was minimal (Kp,uu,brain ≤ 0.051). The LPS-injected mice exhibited a downregulation of the hepatic and ileal mRNA expression of P-glycoprotein (Abcb1a), whereas the expression of Abcb1a and Abcb1b in the brain was upregulated. CONCLUSIONS: Endotoxemia notably increases olanzapine concentrations in the plasma and brain following oral administration in mice. Further studies should clarify whether altered pharmacokinetics results in adverse effects in acutely infected patients taking oral olanzapine.
- MeSH
- Antipsychotic Agents * pharmacokinetics blood administration & dosage MeSH
- Administration, Oral MeSH
- Benzodiazepines * pharmacokinetics blood administration & dosage MeSH
- Endotoxemia * metabolism chemically induced MeSH
- Lipopolysaccharides MeSH
- Brain * metabolism drug effects MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Olanzapine pharmacokinetics MeSH
- Inflammation * chemically induced metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. METHODS: Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. RESULTS: Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001). CONCLUSIONS: Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.
V poslednom období sa črevný mikrobióm stáva poprednou témou aj na poli metabolického syndrómu, ktorý v súčasnosti dosiahol rozmery pandémie. Na základe výskumu sa preukázala spojitosť medzi črevným mikrobiómom a metabolickým syndrómom, ktorá je podmienená najmä metabolizmom mastných kyselín s krátkym reťazcom, žlčových kyselín, narušenou črevnou permeabilitou a v neposlednom rade metabolickou endotoxémiou. Presnejšie pochopenie mechanizmu patogenézy cez črevný mikrobióm by mohlo viesť ku zlepšeniu prevencie vážneho zdravotného a socioekonomického problému, a zároveň ku vzniku nových personalizovaných liečebných modalít metabolického syndrómu.
In the last two decades, the intestinal microbiome has become a hot topic in the field of metabolic syndrome, which has reached the dimensions of a pandemic. Research has shown an association between the intestinal microbiome and the metabolic syndrome which is mainly due to the metabolism of short-chain fatty acids, bile acids, impaired intestinal permeability and metabolic endotoxemia. A more accurate understanding of the mechanism of pathogenesis through the intestinal microbiome could lead to improved prevention of a serious health and socio-economic problem, as well as the emergence of new personalized treatment modalities.
- MeSH
- Endotoxemia MeSH
- Humans MeSH
- Fatty Acids MeSH
- Metabolic Syndrome * MeSH
- Obesity MeSH
- Gastrointestinal Microbiome * MeSH
- Bile Acids and Salts MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
BACKGROUND AND OBJECTIVES: Renal elimination of amikacin and other aminoglycosides is slowed down in sepsis-induced acute kidney injury increasing the risk of adverse effects. Since neutrophil gelatinase-associated lipocalin (NGAL) and aminoglycosides share the mechanisms for renal excretion, the predictive power of NGAL was examined towards the changes in amikacin pharmacokinetics during early endotoxemia in anesthetized Wistar rats. METHODS: Endogenous biomarkers of inflammation and acute kidney injury were assessed including NGAL in saline-injected controls and two groups of rats challenged with an intravenous injection of bacterial lipopolysaccharide (5 mg/kg)-a fluid-resuscitated group (LPS) and a fluid-resuscitated group infused intravenously with 8 μg/kg/h terlipressin (LPS-T). Sinistrin and amikacin were infused to measure glomerular filtration rate (GFR) and amikacin clearance (CLam). The investigations included blood gas analysis, chemistry and hematology tests and assessment of urine output, creatinine clearance (CLcr) and sinistrin clearance (CLsini). RESULTS: Within 3 h of injection, systemic and renal inflammatory responses were induced by lipopolysaccharide. Gene and protein expression of NGAL was increased in the kidneys and the concentrations of NGAL in the plasma (pNGAL) and urine rose 4- to 38-fold (P < 0.01). The decreases in CLam and the GFR markers (CLcr, CLsini) were proportional, reflecting the extent to which endotoxemia impaired the major elimination mechanism for the drug. Terlipressin attenuated lipopolysaccharide-induced renal dysfunction (urine output, CLcr, CLsini) and accelerated CLam. The pNGAL showed a strong association with the CLsini (rs = - 0.77, P < 0.0005). Concerning prediction of CLam, pNGAL was comparable to CLcr (mean error - 24%) and inferior to CLsini (mean error - 6.4%), while the measurement of NGAL in urine gave unsatisfactory results. CONCLUSIONS: During early endotoxemia in the rat, pNGAL has a moderate predictive ability towards CLam. Clinical studies should verify whether pNGAL can support individualized dosing of aminoglycosides to septic patients.
- MeSH
- Acute Kidney Injury blood MeSH
- Amikacin blood metabolism pharmacokinetics MeSH
- Biomarkers blood MeSH
- Cytokines MeSH
- Endotoxemia chemically induced MeSH
- Glomerular Filtration Rate physiology MeSH
- Rats MeSH
- Kidney physiopathology MeSH
- Lipocalin-2 blood metabolism urine MeSH
- Lipopolysaccharides pharmacology MeSH
- Metabolic Clearance Rate MeSH
- Urine MeSH
- Models, Animal MeSH
- Oligosaccharides pharmacokinetics MeSH
- Rats, Wistar * MeSH
- Predictive Value of Tests MeSH
- Sepsis drug therapy metabolism MeSH
- Inflammation MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Autonomic Nervous System physiology metabolism MeSH
- Endotoxemia etiology complications metabolism physiopathology MeSH
- Ascorbic Acid * analysis administration & dosage pharmacology physiology metabolism MeSH
- Humans MeSH
- Lipopolysaccharides physiology MeSH
- Metabolic Syndrome * complications metabolism physiopathology MeSH
- Oxidative Stress physiology MeSH
- Vitamin E analysis physiology metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Circulating lipopolysaccharide-binding protein (LBP), a metabolic endotoxemia marker, was identified as an independent predictor of atherosclerosis. Although increases in carotid intima-media thickness (CIMT) were repeatedly reported in obstructive sleep apnea (OSA), neither the role of OSA in metabolic endotoxemia nor of LBP in early atherosclerosis were explored in patients with OSA. At a tertiary university hospital we investigated the relationships between OSA, LBP and CIMT in 117 men who underwent full polysomnography and CIMT assessment by B-mode ultrasound. Circulating LBP concentrations and average CIMT increased from patients without OSA to those with mild-moderate and severe OSA (from 32.1+/-10.3 to 32.3+/-10.9 to 38.1+/-10.3 microg.ml(-1), p=0.015; from 0.52+/-0.09 to 0.58+/-0.06 to 0.62+/-0.10 mm, p=0.004, respectively). Oxygen desaturation index (ODI) was a predictor of serum LBP levels independent of age, waist-to-hip ratio (WHR), smoking, hypertension, HDL cholesterol, triglycerides and fasting glucose [p (ANOVA)=0.002, r(2)=0.154], with no independent effect of the ODI*WHR interaction term on LBP. Furthermore, serum LBP predicted CIMT independently of known risk factors of atherosclerosis including obesity (p<0.001, r(2)=0.321). Our results suggest that OSA severity contributes to metabolic endotoxemia in patients with OSA independently of obesity, and that LBP might represent a contributing factor promoting early atherosclerosis in such patients.
- MeSH
- Biomarkers blood MeSH
- Adult MeSH
- Endotoxemia blood diagnosis physiopathology MeSH
- Carotid Intima-Media Thickness * trends MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Membrane Glycoproteins blood MeSH
- Sleep Apnea, Obstructive blood diagnosis physiopathology MeSH
- Polysomnography methods trends MeSH
- Acute-Phase Proteins MeSH
- Cross-Sectional Studies MeSH
- Risk Factors MeSH
- Carrier Proteins blood MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Clostridium perfringens pathogenicity MeSH
- Endotoxemia diagnosis etiology MeSH
- Fatal Outcome MeSH
- Hemolysis * MeSH
- Humans MeSH
- Foodborne Diseases * MeSH
- Autopsy MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Case Reports MeSH
In the literature, few studies have investigated the effects of melatonin on energy metabolism in skeletal muscle in endotoxemia. We investigated the effects of melatonin on tissue structure, energy metabolism in skeletal muscle, and antioxidant level of rats with endotoxemia. We divided rats into 4 groups, control, lipopolysaccharide (LPS) (20 mg/kg, i.p., single dose), melatonin (10 mg/kg, i.p., three times), and melatonin + LPS. Melatonin was injected i.p. 30 min before and after the 2nd and 4th hours of LPS injection. Antioxidant status was determined by glutathione (GSH) measurement in the blood. Muscle tissue was stained using modified Gomori trichrome (MGT), succinic dehydrogenase (SDH), and cytochrome oxidase (COX) and histological scored. Also the sections were then stained with hematoxylin and eosin. The stained sections were visualized and photographed. Creatine, creatine phosphate, adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) levels were investigated using high performance liquid chromatography (HPLC) in muscle tissue. In the Melatonin + LPS group, blood GSH levels were increased compared with the LPS group (P<0.01). Melatonin reduced myopathic changes in the LPS group according to the histopathologic findings. In addition, ATP values were increased compared with the LPS group (P<0.05). Our findings showed melatonin treatment prevented muscle damage by increasing ATP and GSH levels in rats with LPS induced endotoxemia.
- MeSH
- Antioxidants pharmacology therapeutic use MeSH
- Endotoxemia blood drug therapy pathology MeSH
- Energy Metabolism drug effects MeSH
- Glutathione blood MeSH
- Muscle, Skeletal drug effects metabolism pathology MeSH
- Lipopolysaccharides MeSH
- Melatonin pharmacology therapeutic use MeSH
- Random Allocation MeSH
- Rats, Wistar MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The aim of the study was to evaluate short-term heart rate variability (HRV) as an index of cardiac autonomic control in rats with lipopolysaccharide (LPS)-induced endotoxemia. Animals were injected intraperitoneally with LPS (100 microg/kg b.w.) and control group with an equivalent volume of saline. ECG recordings were done before (base) and 60, 120, 180, 240 and 300 min after LPS or saline administration. HRV magnitude was quantified by time and frequency-domain analysis (mean RR interval, SDRR, RMSSD, spectral powers in low (LF) and high frequency (HF) bands. Heart tissue homogenates and plasma were analyzed to determine interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and oxidative stress level (TBARS). Administration of lipopolysaccharide was followed by continuous rise in colonic body temperature compared to saline-treated controls. Endotoxemia in rats was accompanied by significant decrease in HRV spectral activity in high-frequency range at maximal body temperature (logHFpower: 1.2+/-0.5 vs. 1.9+/-0.6 ms(2), P<0.01). Increased IL-6 was found in heart tissue homogenates of LPS rats (8.0+/-0.6 vs. 26.4+/-4.8 pg/ml, (P<0.05). In conclusions, reduced HRV in HF band may indicate a decreased parasympathetic activity in LPS-induced endotoxemia as basic characteristics of altered cardiac control during response to endotoxemia.
- MeSH
- Autonomic Nervous System physiopathology MeSH
- Bradycardia chemically induced physiopathology MeSH
- Time Factors MeSH
- Endotoxemia blood chemically induced physiopathology MeSH
- Interleukin-6 blood MeSH
- Lipopolysaccharides * MeSH
- Malondialdehyde blood MeSH
- Inflammation Mediators blood MeSH
- Disease Models, Animal MeSH
- Myocardium metabolism MeSH
- Oxidative Stress MeSH
- Rats, Wistar MeSH
- Heart innervation MeSH
- Heart Rate * MeSH
- Body Temperature Regulation MeSH
- Tumor Necrosis Factor-alpha blood MeSH
- Inflammation blood chemically induced physiopathology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The aim of our study was to investigate whether two potent anti-inflammatory agents, dexamethasone and anakinra, an IL-1 receptor antagonist, may influence acute kidney injury (AKI) and associated drug excretory functions during endotoxemia (LPS) in rats. Ten hours after LPS administration, untreated endotoxemic rats developed typical symptoms of AKI, with reduced GFR, impaired tubular excretion of urea and sodium, and decreased urinary excretion of azithromycin, an anionic substrate for multidrug resistance-transporting proteins. Administration of both immunosuppressants attenuated the inflammatory response, liver damage, AKI, and increased renal clearance of azithromycin mainly by restoration of GFR, without significant influence on its tubular secretion. The lack of such an effect was related to the differential effect of both agents on the renal expression of individual drug transporters. Only dexamethasone increased the urinary clearance of bile acids, in accordance with the reduction of the apical transporter (Asbt) for their tubular reabsorption. In summary, our data demonstrated the potency of both agents used for the prevention of AKI, imposed by endotoxins, and for the restoration of renal drug elimination, mainly by the improvement of GFR. The influence of both drugs on altered tubular functions and the expression of drug transporters was differential, emphasizing the necessity of knowledge of transporting pathways for individual drugs applied during sepsis. The effect of anakinra suggests a significant contribution of IL-1 signaling to the pathogenesis of LPS-induced AKI.
- MeSH
- Acute Kidney Injury etiology prevention & control MeSH
- Interleukin 1 Receptor Antagonist Protein pharmacology therapeutic use MeSH
- Anti-Bacterial Agents pharmacokinetics MeSH
- Anti-Inflammatory Agents pharmacology therapeutic use MeSH
- Azithromycin pharmacokinetics MeSH
- Dexamethasone pharmacology therapeutic use MeSH
- Renal Elimination drug effects MeSH
- Endotoxemia complications drug therapy MeSH
- Endotoxins pharmacokinetics MeSH
- Glomerular Filtration Rate drug effects MeSH
- Immunosuppressive Agents pharmacology therapeutic use MeSH
- Lipopolysaccharides MeSH
- Rats, Wistar MeSH
- Xenobiotics pharmacokinetics MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
