scholarly journals 1394. A Translational Pharmacokinetic Rat Model of Cerebral Spinal Fluid (CSF) and Plasma Concentrations of Cefepime

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S429-S429
Author(s):  
Jiajun Liu ◽  
Sean Avedissian ◽  
Gwendolyn Pais ◽  
Medha Joshi ◽  
Nathaniel J Rhodes ◽  
...  
Keyword(s):  
Rat Model ◽  
Cerebral Spinal Fluid ◽  
Prediction Models ◽  
Plasma Concentrations ◽  
Spinal Fluid ◽  
Total Daily Dose ◽  
Peripheral Compartment ◽  
Sprague Dawley ◽  
Time Curve ◽  
Two Samples

Abstract Background For treatment of central nervous system infections caused by GNB, adequate cefepime concentrations are required in the cerebral spinal fluid (CSF) and brain. However, high plasma cefepime exposures have resulted in neurotoxicity. There is a need to understand the real-time pharmacokinetic (PK) relationship between plasma and CSF concentrations as serial CSF sampling is not regularly performed. Methods Male Sprague-Dawley rats received cefepime via an internal jugular vein catheter. A total daily dose of 150 mg/kg/day was administered as a single injection every 24 hours for 4 days. Plasma samples (mean n = 5 per rat) was obtained via a second dedicated catheter, with up to five samples obtained on a single concentration–time curve. CSF sampling occurred via an intracisternal catheter, with up to two samples taken every 24 hours. Cefepime in plasma and CSF were quantified via LC–MS/MS. PK analyses were conducted using Pmetrics for R. Multiple physiologic compartmental models were fit, with the ultimate model selected by Akaike score and rule of parsimony. Each rat’s concentrations were predicted from the final model, and predictive performance was evaluated with bias and imprecision of the population and Bayesian posterior prediction models. PK parameters were estimated, and PK exposures during the first 24 hours (i.e., AUC0–24, CMAX0–24, CMIN0–24) were calculated for each rat from Bayesian posteriors. Results Eleven rats contributed PK data. A three-compartment model fit the data well [Figure 1: Plasma, Population (a) and Bayesian (b); Figure 2: CSF, Population (a) and Bayesian (b)]. Population median parameter values (CV%) for rate constant (Ke), volume central compartment (V1), volume CSF compartment (V3), rate to/from central/peripheral compartment (KCP, KPC), rate to/from central/CSF compartment (K13, K31) were: 5.04 hour−1 (43.4%), 0.069 L (39.24%), 0.28 hour−1 (52.11%), 17.42 hour−1(34.83%), 0.32 hour−1 (165.3), 0.31 hour−1 (79.89), respectively. Noncompartmental analysis of the Bayesian posteriors revealed a plasma median half-life, AUC0–24, CMAX0–24, and CMIN0–24 of 2.6 hours, 158.1 mg hour/L, 189.3 mg/L, and 0.0003 mg/L from the first dose. Conclusion Cefepime transit to the CSF is rapid and highly predictable in the rat model. This model will be highly useful for understanding neurotoxicity outcomes for cefepime. Disclosures J. Liu, Merck: Grant fund from Merck, Research grant.

scholarly journals A Translational Pharmacokinetic Rat Model of Cerebral Spinal Fluid and Plasma Concentrations of Cefepime

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Sean N. Avedissian ◽  
Gwendolyn Pais ◽  
Medha D. Joshi ◽  
Nathaniel J. Rhodes ◽  
Marc H. Scheetz
Keyword(s):  
Rat Model ◽  
Cerebral Spinal Fluid ◽  
Plasma Concentrations ◽  
Spinal Fluid ◽  
Therapeutic Window ◽  
Plasma Samples ◽  
Sprague Dawley ◽  
Intravenous Catheter ◽  
Sprague Dawley Rats

This study defines the transit of cefepime between plasma and cerebral spinal fluid (CSF) in a rat model. Male Sprague-Dawley rats received cefepime intravenously. Plasma samples were obtained via a second dedicated intravenous catheter. CSF sampling occurred via an intracisternal catheter. Drug exposures and transfer from the plasma to the CSF during the first 24 h were calculated. The median CSF/blood percentage of penetration was 19%. Cefepime transit to the CSF is rapid and predictable in the rat model. This model will be highly useful for understanding the therapeutic window for cefepime and neurotoxicity.

scholarly journals Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Rosario Russo ◽  
Angelo Mancinelli ◽  
Michele Ciccone ◽  
Fabio Terruzzi ◽  
Claudio Pisano ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Time Curve ◽  
Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

Rivaroxaban for Thromboprophylaxis in Patients Undergoing Total Hip Replacement: Comparison of Pharmacokinetics and Pharmacodynamics with Once- and Twice-Daily Dosing.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 903-903 ◽  
Author(s):  
Wolfgang Mueck ◽  
Bengt I. Eriksson ◽  
Lars C. Borris ◽  
Ola E. Dahl ◽  
Sylvia Haas ◽  
...  
Keyword(s):  
Confidence Intervals ◽  
Total Hip Replacement ◽  
Hip Replacement ◽  
Plasma Concentrations ◽  
Dose Finding ◽  
Total Daily Dose ◽  
Time Curve ◽  
Mixed Effect ◽  
Total Hip ◽  
Daily Dose

Abstract Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Two phase IIb, dose-finding studies with rivaroxaban for the prevention of venous thromboembolism (VTE) after total hip replacement (THR) were conducted: one with twice-daily (bid), and one with once-daily (od) rivaroxaban dosing. In the bid study, rivaroxaban total daily doses of 5–20 mg had similar efficacy and safety to enoxaparin (40 mg od), and the od study identified a dose within this range (10 mg od) as the appropriate dose for further investigation. This analysis compared the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban when given od or bid, using non-linear, mixed-effect population modeling. The analysis was restricted to the rivaroxaban 5, 10, and 20 mg total daily dose groups from each study, and used samples from 758 patients. In both studies, rivaroxaban PK were well described by an oral, one-compartment model, and were affected by anticipated factors: age and renal function influenced clearance, and body weight influenced volume of distribution. These effects were moderate, within the variability of the patient population, and suggested that no dose adjustment would be necessary, in this population. In both studies, the maximum and minimum plasma concentrations (Cmax and Ctrough, respectively) of rivaroxaban increased dose dependently (Table). Cmax values were higher, and Ctrough values were lower, in the od study than in the bid study; however, the 90% confidence intervals for Cmax and Ctrough in the two studies overlapped. These findings are as expected, and suggest that od dosing with rivaroxaban should not expose patients to a greater risk of bleeding (at Cmax) or VTE (at Ctrough) than bid dosing. Estimates for area under the rivaroxaban plasma-concentration time curve (AUC) were 20–28% higher in the od study than the bid study. In the PD analysis, prolongation of prothrombin time correlated with rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, this analysis of rivaroxaban in patients undergoing THR suggested that the PK and PD of rivaroxaban are predictable after od or bid dosing, allowing selection of a convenient od dosing regimen. Median predicted rivaroxaban PK parameters in THR patients at steady state (with 90% confidence intervals) Rivaroxaban total daily dose Parameter 5 mg 10 mg 20 mg n (bid/od) 122/124 122/140 118/132 bid Cmax (μg/L) 39.7 (29.2–73.4) 65.2 (46.2–105) 141 (101–218) od Cmax (μg/L) 69.0 (49–112) 124 (88.1–194) 222 (160–360) bid Ctrough (μg/L) 8.61 (1.71–26.5) 15.4 (4.65–46.2) 34.9 (7.85–99.7) od Ctrough (μg/L) 4.50 (0.7–37.7) 9.12 (1.34–37.8) 22.4 (4.3–95.7) bid AUC (μg·h/L) 531 (304–1188) 915 (583–1637) 1982 (1139–3757) od AUC (μg·h/L) 670 (377–1283) 1170 (767–2077) 2374 (1366–4858)

Rivaroxaban Has Predictable Pharmacokinetics (PK) and Pharmacodynamics (PD) When Given Once or Twice Daily for the Treatment of Acute, Proximal Deep Vein Thrombosis (DVT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1880-1880 ◽  
Author(s):  
Wolfgang Mueck ◽  
Giancarlo Agnelli ◽  
Harry Buller
Keyword(s):  
Confidence Intervals ◽  
Plasma Concentrations ◽  
Demographic Factors ◽  
Dose Finding ◽  
Phase Iii ◽  
Total Daily Dose ◽  
Efficacy And Safety ◽  
Time Curve ◽  
Mixed Effect ◽  
Mean Values

Abstract Introduction: Rivaroxaban is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Two large, phase IIb, dose-finding studies investigating rivaroxaban for the treatment of acute, proximal DVT, showed that rivaroxaban once daily (od) and twice daily (bid) had similar efficacy and safety profiles to standard therapy. In order to characterize the population PK/PD of rivaroxaban for DVT treatment, a population model was developed based on data from healthy subjects. Methods: Sparse PK/PD samples from 870 patients across the two studies were analyzed using non-linear, mixed-effect population modeling (NONMEM), version V level 1.1. The program analyzed population data to give estimates of mean values and variability in the population. Prothrombin time (PT) was determined at a central laboratory and was used in the PD investigation. For the PK profile, data was pooled from both clinical trials and specific exposure parameters for rivaroxaban, such as area under the plasma concentration-time curve (AUC), maximum and minimum plasma concentrations (Cmax and Ctrough, respectively) were predicted for each patient according to the dosing regimen received. Results: The PK of rivaroxaban were well described by an oral, one-compartment model, with demographic factors influencing clearance (age, renal function) and volume of distribution (age, body weight, gender); variations due to these factors were moderate, suggesting fixed dosing may be possible. Co-medications (e.g. diuretics, NSAIDs, aspirin) had no relevant effects on the PK of rivaroxaban. Rivaroxaban Cmax and Ctrough concentrations increased dose dependently (Table). As expected, Cmax was higher and Ctrough was lower after od dosing compared with bid dosing, at equivalent total daily doses; however, 90% confidence intervals overlapped, suggesting that od dosing with rivaroxaban should not expose patients to a greater risk of bleeding (at Cmax) or VTE (at Ctrough) than bid dosing. Clinically relevant rivaroxaban plasma concentrations correlated linearly with PT, confirming that it would be suitable for measuring rivaroxaban exposure, if necessary. Conclusions: The PK and PD of rivaroxaban were predictable with od and bid dosing, and affected by expected demographic factors in patients receiving it for DVT treatment. Combined with efficacy and safety results, this analysis aided the selection of an initial, intensified bid regimen followed by convenient, long-term rivaroxaban 20 mg od, for investigation in phase III studies in this indication. Predicted rivaroxaban PK parameters Parameter Rivaroxaban total daily dose *Values are shown as means (90% confidence intervals) 20 mg 30 mg 40 mg 60 mg n (od/bid) 134/117 134/- 252/114 -/119 od Cmax (μg/L)* 270.6 (189.1–418.7) 324.6 (234.2–491.3) 406.5 (268.4–599.9) - bid Cmax (μg/L)* 211.5 (130.3–360.7) - 320.9 (209.9–517.9) 400.6 (244.2–749.5) od Ctrough (μg/L)* 25.5 (5.9–86.9) 33.8 (8.4–132.9) 42.3 (9.7–161.8) - bid Ctrough (μg/L)* 65.1 (17.2–193.6) - 104.2 (31.3–277.8) 143.1 (46.6–347.9)

scholarly journals Pharmacokinetics, urinary excretion and plasma protein binding of ofloxacin in water buffalo calves (Bubalus bubalis)

2013 ◽  
Vol 84 (1) ◽  
Author(s):  
Ajay K. Ola ◽  
Harpal S. Sandhu ◽  
Vinod K. Dumka ◽  
Bibhuti Ranjan
Keyword(s):  
Urinary Excretion ◽  
Half Life ◽  
High Performance ◽  
Water Buffalo ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Buffalo Calves ◽  
Time Curve

Pharmacokinetics and urinary excretion of an intravenous dose of 5 mg.kg–1 ofloxacin were investigated in water buffalo calves. Plasma concentrations of ofloxacin were determined by high-performance liquid chromatography. Ofloxacin was rapidly distributed from the central to the peripheral compartment as evidenced by a short distribution half-life (0.09 h ± 0.003 h) and high K12 (4.7 h–1 ± 0.1 h–1), and was detected in plasma for 8 h. The large volume of distribution (2.48 L.kg–1 ± 0.18 L.kg–1) obtained in this study indicated high distribution of ofloxacin in water buffalo calves. The elimination half-life, the area under the plasma drug concentration–time curve and total body clearance were 2.11 h ± 0.13 h, 6.20 µg.mL—1 ± 0.23 µg.mL—1.h and 0.81 mL.kg–1.h–1 ± 0.03 mL.kg–1.h–1, respectively. About 18.7% of administered drug was bound to plasma proteins and approximately 32.5% of the administered dose was recovered in urine within 48 h. The results of the study indicated a favourable pharmacokinetic profile of ofloxacin in water buffalo calves, which suggests that ofloxacin may be effective against urinary pathogens in this species.

scholarly journals Population Pharmacokinetics of Teicoplanin in Preterm and Term Neonates: Is It Time for a New Dosing Regimen?

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
A. Kontou ◽  
K. Sarafidis ◽  
O. Begou ◽  
H. G. Gika ◽  
A. Tsiligiannis ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Maintenance Dose ◽  
Plasma Concentrations ◽  
Central Compartment ◽  
Preterm Neonates ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Time Curve ◽  
Content Type

ABSTRACT Our objective was to develop a population pharmacokinetic (PK) model in order to evaluate the currently recommended dosing regimen in term and preterm neonates. By using an optimal design approach, a prospective PK study was designed and implemented in 60 neonates with postmenstrual ages (PMA) of 26 to 43 weeks. A loading dose of 16 mg/kg was administered at day 1, followed by a maintenance dose of 8 mg/kg daily. Plasma concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population PK (popPK) analysis was performed using NONMEM software. Monte-Carlo (MC) simulations were performed to evaluate currently recommended dosing based on a pharmacodynamic index of area under the concentration-time curve (AUC)/MIC ratio of ≥400. A two-compartment model with linear elimination best described the data by the following equations: clearance (CL) = 0.0227 × (weight [wt]/1,765)0.75 × (estimated creatinine clearance [eCRCL]/22)0.672, central compartment volume of distribution (V1) = 0.283 (wt/1,765), intercompartmental clearance (Q) = 0.151 (wt/1,765)0.75, and peripheral compartment volume (V2) = 0.541 (wt/1,765). The interindividual variability estimates for CL, V1, and V2 were 36.5%, 45.7%, and 51.4%, respectively. Current weight (wt) and estimated creatinine clearance (eCRCL) significantly explained the observed variability. MC simulation demonstrated that, with the current dosing regimen, an AUC/MIC ratio of ≥400 was reached by only 68.5% of neonates with wt of <1 kg when the MIC was equal to 1 mg/kg, versus 82.2%, 89.7%, and 92.7% of neonates with wt of 1 to <2, 2 to <3, or ≥3 kg, respectively. Augmentation of a maintenance dose up to 10 or 11 mg/kg for preterm neonates with wt of 1 to <2 or <1 kg, respectively, increases the probability of reaching the therapeutic target; the recommended doses seem to be adequate for neonates with wt of ≥2 kg. Teicoplanin PK are variable in neonates, with wt and eCRCL having the most significant impact. Neonates with wt of <2 kg need higher doses, especially for Staphylococcus spp. with an MIC value of ≥1 mg/liter.

scholarly journals Effect of Ethanol on Fluoroquinolone Efficacy in a Rat Model of Pneumococcal Pneumonia

2006 ◽  
Vol 50 (1) ◽  
pp. 210-219 ◽  
Author(s):  
Keith M. Olsen ◽  
Martha Gentry-Nielsen ◽  
Mei Yue ◽  
Mary U. Snitily ◽  
Laurel C. Preheim
Keyword(s):  
Rat Model ◽  
Pneumococcal Pneumonia ◽  
Lethal Dose ◽  
Free Fraction ◽  
Liquid Diet ◽  
High Dose ◽  
Sprague Dawley ◽  
Time Curve ◽  
Cell Counts ◽  
Concentration Time

ABSTRACT This investigation compared the effect of ethanol on fluoroquinolone antibiotic efficacy and pharmacodynamics in an ethanol-fed rat model of pneumococcal pneumonia. Male Sprague-Dawley rats received a liquid diet containing 36% of total calories as ethanol. Paired controls (pair-fed controls) were fed a liquid diet without ethanol or received rat chow. Diets began 7 days before and continued for 10 days after transtracheal infections with 10 times the 50% lethal dose of type 3 Streptococcus pneumoniae. Beginning 18 h after infection, the rats received once daily subcutaneous phosphate-buffered saline, levofloxacin, moxifloxacin, or trovafloxacin at 50 or 100 mg/kg of body weight. White blood cell counts were determined, blood samples were collected for culture, and mortality was recorded. Additional rats were killed on day 5 for pharmacodynamic studies and quantitative cultures of bronchoalveolar lavage fluid. Bacteremia occurred by day 3 in 20 of 22 untreated rats. All 22 untreated rats died by day 9. Moxifloxacin treatment was effective in all diet groups at both the 50- and 100-mg/kg doses. In contrast, 50-mg/kg doses of levofloxacin and trovafloxacin improved survival in ethanol-fed rats but were ineffective in chow-fed rats. High-dose trovafloxacin at 100 mg/kg was associated with increased mortality in pair-fed rats. The free-fraction area under the concentration-time curve/MIC ratio exceeded 50 with all antibiotics in the ethanol group but dropped below 30 with levofloxacin and trovafloxacin in the pair- and chow-fed rats, with higher mortality. Achievement of adequate antibiotic-free fraction area under the concentration-time curve/MIC ratios helps overcome ethanol-induced immune defects induced in experimental pneumococcal pneumonia.

scholarly journals 24-Hour Pharmacokinetic Relationships for Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
J. Nicholas O'Donnell ◽  
Nathaniel J. Rhodes ◽  
Thomas P. Lodise ◽  
Walter C. Prozialeck ◽  
Cristina M. Miglis ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
High Performance ◽  
Rat Kidney ◽  
Plasma Concentrations ◽  
Rank Correlation ◽  
Kidney Injury ◽  
Urinary Biomarkers ◽  
Sprague Dawley ◽  
Time Curve ◽  
Minimum Concentration

ABSTRACT Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration (C max), and the minimum concentration. Spearman's rank correlation coefficient (rs ) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage (rs = 0.348, P = 0.017) and proximal tubule damage (rs = 0.342, P = 0.019). The vancomycin AUC and C max were most predictive of increases in KIM-1 levels (rs = 0.438 and P = 0.002 for AUC and rs = 0.451 and P = 0.002 for C max). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or C max.

scholarly journals Plasma amino acid and metabolite signatures tracking diabetes progression in the UCD-T2DM rat model

2016 ◽  
Vol 310 (11) ◽  
pp. E958-E969 ◽  
Author(s):  
Brian D. Piccolo ◽  
James L. Graham ◽  
Kimber L. Stanhope ◽  
Oliver Fiehn ◽  
Peter J. Havel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Amino Acid ◽  
Rat Model ◽  
Plasma Concentrations ◽  
Elevated Plasma ◽  
Sprague Dawley ◽  
Muscle Weight ◽  
Onset Of Diabetes ◽  
Post Onset

Elevations of plasma concentrations of branched-chain amino acids (BCAAs) are observed in human insulin resistance and type 2 diabetes mellitus (T2DM); however, there has been some controversy with respect to the passive or causative nature of the BCAA phenotype. Using untargeted metabolomics, plasma BCAA and other metabolites were assessed in lean control Sprague-Dawley rats (LC) and temporally during diabetes development in the UCD-T2DM rat model, i.e., prediabetic (PD) and 2 wk (D2W), 3 mo (D3M), and 6 mo (D6M) post-onset of diabetes. Plasma leucine, isoleucine, and valine concentrations were elevated only in D6M rats compared with D2W rats (by 28, 29, and 30%, respectively). This was in contrast to decreased plasma concentrations of several other amino acids in D3M and/or D6M relative to LC rats (Ala, Arg, Glu, Gln, Met, Ser, Thr, and Trp). BCAAs were positively correlated with fasting glucose and negatively correlated with plasma insulin, total body weight, total adipose tissue weight, and gastrocnemius muscle weight in the D3M and D6M groups. Multivariate analysis revealed that D3M and D6M UCD-T2DM rats had lower concentrations of amino acids, amino acid derivatives, 1,5-anhydroglucitol, and conduritol-β-opoxide and higher concentrations of uronic acids, pantothenic acids, aconitate, benzoic acid, lactate, and monopalmitin-2-glyceride relative to PD and D2W UCD-T2DM rats. The UCD-T2DM rat does not display elevated plasma BCAA concentrations until 6 mo post-onset of diabetes. With the acknowledgement that this is a rodent model of T2DM, the results indicate that elevated plasma BCAA concentrations are not necessary or sufficient to elicit an insulin resistance or T2DM onset.

scholarly journals Ameliorative Effects of Bredemolic Acid on Markers Associated with Renal Dysfunction in a Diet-Induced Prediabetic Rat Model

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Akinjide Moses Akinnuga ◽  
Angezwa Siboto ◽  
Bongiwe Khumalo ◽  
Ntethelelo Hopewell Sibiya ◽  
Phikelelani Ngubane ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Renal Dysfunction ◽  
Rat Model ◽  
Plasma Concentrations ◽  
Normal Diet ◽  
Male Rats ◽  
Pharmacological Intervention ◽  
Sprague Dawley ◽  
Prediabetic State ◽  
Diet Modification

Recently, studies have shown that renal dysfunction is associated not only with overt diabetes but also with the preceding stage known as prediabetes. Diet and pharmacological interventions are the therapeutic approaches to managing prediabetes, but the compliance in combining the two interventions is low. Hence, the efficacy of pharmacological intervention is reduced without diet modification. In our previous study, we established that bredemolic acid (BA) ameliorated glucose homeostasis via increased GLUT 4 expression in the skeletal muscle of prediabetic rats in the absence of diet intervention. However, the effects of bredemolic acid on renal function in prediabetic condition are unknown. Therefore, this study was aimed at investigating the ameliorative effects of bredemolic acid on renal dysfunction in a diet-induced prediabetic rat model. Thirty-six Sprague-Dawley male rats (150–180 g) were divided into two groups: the nonprediabetic (n=6) and prediabetic (n=30) groups which were fed normal diet (ND) and high-fat high-carbohydrate (HFHC) diet, respectively, for 20 weeks. After the 20th week, the prediabetic groups were subdivided into prediabetic control (PD) and 4 other prediabetic groups which were treated with either BA (80 mg/kg) or metformin (MET, 500 mg/kg) for further 12 weeks (21st to 32nd). Plasma, urine, and kidney samples were collected for biochemical analysis. The untreated prediabetic (PD) rats presented increased fluid intake and urine output; increased creatinine, urea, and uric acid plasma concentrations; albuminuria; proteinuria; sodium retention; potassium loss; increased aldosterone and kidney injury molecule (KIM-1) concentration; and increased urinary podocin mRNA expression. However, BA administration attenuated the renal markers and oxidative stress and decreased the urinary podocin mRNA expression. In conclusion, BA administration, regardless of diet modification, attenuates renal dysfunction in an experimentally induced prediabetic state.

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