scholarly journals Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 359
Author(s):  
Dilip Roy ◽  
Amol Kulkarni ◽  
Manu Chaudhary ◽  
Saransh Chaudhary ◽  
Anurag Payasi ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Polymyxin B ◽  
Control Group ◽  
Tubular Damage ◽  
Sprague Dawley ◽  
Serum Samples ◽  
Drug Induced ◽  
Sprague Dawley Rats ◽  
Life Threatening ◽  
Injury Assessment

Despite the crucial role of Polymyxin-B in treating life-threatening gram-negative infections, its clinical utility is limited due to the risk of acute kidney injury. In response, a novel formulation of polymyxin-B is being developed to mitigate drug-induced kidney injury. In this study, we have assessed the toxicity of four variants of that novel formulation (VRP034_F21-F24) in comparison with standard polymyxin-B using kidney injury biomarkers in rats. Sprague-Dawley rats were subcutaneously administered either polymyxin-B (control) or one of the four polymyxin-B formulations at a dose of 25 mg/kg/day (HED: 4 mg/kg/day) in four divided doses for two days. Serum samples were collected at baseline and at the end of day 2 for the determination of serum biomarkers. Necropsy was done on day 2 and kidney was collected for histopathological evaluation. In the control group, statistically significant increase (p < 0.0001) in all biomarkers was observed on day 2 as compared to baseline values [urea: 311%; creatinine: 700%; KIM-1: 180%; cystatin-C: 66%] and 50% of the animals died (one after the 7th dose and two after the 8th dose) before scheduled necropsy. In contrast, animals treated with novel formulations did not show a significant increase across any of the biomarkers and no mortality was observed. Histopathology of the control group kidney confirmed necrotic changes in tissues with congestion and vacuolization, whereas only minor tubular damage was noted in two formulation groups (VRP034_F21, F24) and no appreciable damage was detected in the other two groups (VRP034_F22-23). The novel formulation of polymyxin-B tested in this study significantly reduced the risk of polymyxin-induced kidney injury in rats.

Effect of Lipid Emulsion on the Improvement of Renal Damage in Colistin-induced Nephrotoxicity

2020 ◽  
Vol 15 ◽  
Author(s):  
Naci Senkal ◽  
Ozum Atasoy ◽  
Emine Bilge Caparali ◽  
Mumin Alper Erdogan ◽  
Oytun Erbas
Keyword(s):  
Lipid Emulsion ◽  
Renal Damage ◽  
Cell Injury ◽  
Kidney Injury ◽  
Control Group ◽  
Tubular Damage ◽  
Sprague Dawley ◽  
Tissue Samples ◽  
Group 2 ◽  
Group 1

Background:: Colistin utilization has gradually increased worldwide with the arising of multidrug-resistant (MDR) gram-negative bacilli despite its nephrotoxicity. Lipid emulsion (LE) is widely used for the toxic overdose treatment of various drugs. Objective:: The aim of the present study is to evaluate the effect of lipid emulsion on improvement of renal damage in colistin-induced nephrotoxicity with experimental Sprague Dawley rat model. Methods:: Twenty-four male Sprague Dawley rats were initially assigned at random into 2 groups. Sixteen rats were given a single dose of 20 mg/kg colistin, eight rats received no medication (control group). Sixteen rats that were administered colistin sub-divided into 2 groups. Group 1/LE rats (n = 8) were given 20 ml/kg solution of lipid emulsion, and group 2/S rats (n = 8) were given 20 ml/kg/day (i.p.) of 0.9% NaCl saline; both were administered for 10 days. Then tubular injury was evaluated histopathologically. Serum levels of blood urea nitrogen (BUN), Kidney Injury Molecule-1 (KIM-1), and creatinine were measured. Besides, malondialdehyde (MDA) levels were determined in tissue samples for the assessment of lipid peroxidation. Results:: The mean percent of tubular epithelial cell injury and tubular dilatation was found significantly higher in group 2/S than control and group 1/LE (p < 0.0001 and < 0.001; respectively). KIM-1 and MDA levels were also statistically higher in group 2/S than control and group 1/LE. (p < 0.0001 and < 0.0001; respectively). Additionally, serum BUN and creatinine levels of group 2/S were significantly greater than control and group 1/LE (p < 0.0001 and < 0.0001; respectively). Conclusion:: In this present study, we determined that colistin-induced proximal tubular damage was decreased as histopathologically and serologically by the effect of lipid emulsion. Thus, our findings may guide to the future studies on the clinical use of colistin., particularly in MDR positive intensive care infections.

scholarly journals Effects of polaprezinc on gastric mucosal damage and neurotransmitters in a rat model of chemotherapy-induced vomiting

2018 ◽  
Vol 46 (6) ◽  
pp. 2436-2444
Author(s):  
Zhao Yang Liu ◽  
Wen Bo Xie ◽  
Ming Ru Li ◽  
Nan Teng ◽  
Xiao Liang ◽  
...  
Keyword(s):  
Rat Model ◽  
Mucosal Injury ◽  
Mucosal Damage ◽  
Gastric Mucosal Damage ◽  
Control Group ◽  
Sprague Dawley ◽  
Serum Samples ◽  
Sprague Dawley Rats ◽  
Hematoxylin And Eosin ◽  
Brain Tissues

Objective To investigate the effects of polaprezinc (PZ) on cyclophosphamide (CTX)- or cisplatin (DDP)-induced gastric mucosal injury and on a rat model of neurotransmitter-mediated vomiting. Methods Sprague–Dawley rats were divided at random into Control, CTX, DDP, PZ+CTX, and PZ+DDP groups. After 20 days, brain tissues and sera were analyzed for the levels of dopamine (DA), 5-hydroxytryptamine (5-HT), and nuclear factor kappa B (NF-κB). Hematoxylin and eosin-stained sections of stomach, intestine, and brain tissues were examined using light microscopy. Results The levels of DA, 5-HT, and NF-κB in brain and serum samples of rats treated with CTX or DDP were significantly increased compared with those of rats in the Control group. There was a significant decrease in these values in the PZ group. Moreover, PZ reduced damage to brain tissue caused by CTX or DDP. Conclusions PZ decreased the levels of DA, 5-HT, and NF-κB in blood and brain tissues caused by CTX or DDP and reduced the chemotherapy-induced damage to the small intestine, stomach, and brain. These findings can be translated to the clinic to enhance the efficacy and safety of chemotherapy.

Cytochrome C suppresses renal accumulation and nephrotoxicity of polymyxin B

2018 ◽  
Vol 38 (2) ◽  
pp. 193-200 ◽  
Author(s):  
Z-D Li ◽  
J Luo ◽  
L-H Jia ◽  
X-Y Wang ◽  
Z-K Xun ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Polymyxin B ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
C 30 ◽  
C 50

The receptor megalin plays an important role in the accumulation of polymyxin B (PMB) in renal cells in vitro. This study aimed to examine the effects of cytochrome c (cyto c), a typical megalin ligand, on renal accumulation and nephrotoxicity of PMB in vivo. Thirty Sprague-Dawley rats were randomly divided into the vehicle control group, PMB group, PMB + cyto c 50, 100, or 200 mg/kg group, respectively, and were treated with intravenous cyto c 30 min before the administration of PMB 4.0 mg/kg once a day for consecutive 5 days. On the 4th day after administration, 24 h urine was collected to determine N-acetyl-β-D-glucosaminidase excretion. Six hours after the last injection on the 5th day, kidneys were harvested to assay PMB concentration and observe pathological alterations, and blood samples were collected to assay serum creatinine (SCr), blood urea nitrogen (BUN), and blood β2-microglobulin (β2-MG) levels. Cyto c 50, 100, and 200 mg/kg decreased the accumulation of PMB in the kidney by 18.5%, 39.1% ( p < 0.01), and 36.8% ( p < 0.01), respectively, and reduced 24 h N-acetyl-β-D- glucosaminidase excretion by 22.5% ( p < 0.05), 40.4% ( p < 0.01), and 40.4% ( p < 0.01), respectively. Kidney pathological damage induced by PMB was markedly reduced by cyto c 100 mg/kg and 200 mg/kg. However, there were no significant differences in SCr, BUN, and blood β2-MG levels among the groups. These results indicated that cyto c may inhibit the renal accumulation and nephrotoxicity of PMB in a rat model, further proving the role of megalin in the accumulation of PMB.

scholarly journals In vivo model of Hirschsprung-associated enterocolitis using benzalkonium chloride

2021 ◽  
Author(s):  
Iskandar Rahardjo Budianto ◽  
Agus Firmansyah ◽  
Yefta Moenadjat ◽  
Ahmad Aulia Jusuf ◽  
Vivian Soetikno
Keyword(s):  
Sigmoid Colon ◽  
Topical Application ◽  
Benzalkonium Chloride ◽  
Hirschsprung's Disease ◽  
Hirschsprung’S Disease ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Life Threatening

BACKGROUND Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung’s disease. Studies using animal models on the pathogenesis of HAEC are limited. Thus, this study aimed to establish a rat model of HAEC using topical application of 0.1% benzalkonium chloride (BAC) in the sigmoid colon. METHODS 55 male Sprague Dawley rats aged 10−12 weeks old were separated into 11 groups. The control group (n = 5) was euthanized on day-7, and the other 10 groups (n = 5 in each group) treated with 0.1% BAC in the sigmoid colon for 15 min to induce Hirschsprung’s disease were euthanized on day-7, -10, -12, -14, -17, -19, -21, -23, -25, and -28. The sigmoid colon was excised, fixed in formalin, and sectioned for histological examinations with hematoxylin and eosin staining. The degree of HAEC was compared within all groups. RESULTS Rats that were sacrificed on day-7 to -12 showed the 1st degree or early HAEC, which was most likely caused by BAC application. The 2nd degree of HAEC occurred in rats that were sacrificed on day-14 that showed a macrophage infiltration in the sigmoid colon, thus fulfilled the initial criteria for HAEC (p = 0.0025 versus control). The degree of enterocolitis increased with time, and the highest degree was found in rats that were sacrificed on day-28 (p<0.001 versus control). CONCLUSIONS Topical application of 0.1% BAC for 15 min was successfully produced HAEC model in rats, which was occurred on day-14 after the application. This model provides a useful resource for further research on the pathogenesis of HAEC.

scholarly journals Hydrochloride pioglitazone protects diabetic rats against podocyte injury through preserving glomerular podocalyxin expression

2014 ◽  
Vol 58 (6) ◽  
pp. 630-639 ◽  
Author(s):  
Yan Xing ◽  
Shandong Ye ◽  
Yumi Chen ◽  
Wen Hu ◽  
Yan Chen
Keyword(s):  
Normal Control ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Control Group ◽  
Sprague Dawley ◽  
Urinary Sediment ◽  
Injury Index ◽  
Sprague Dawley Rats ◽  
Dose Dependent

Objective: We sought to test the effect of different dosages of pioglitazone (PIO) on the glomerular expression of podocalyxin and urinary sediment podocalyxin excretion and to explore the potential renoprotective mechanism. Materials and methods: Type 1 diabetes induced with streptozotocin (65 mg/kg) in 36 male Sprague-Dawley rats were randomly allocated to be treated with vehicle or 10, 20, 30 mg/kg/d PIO respectively for 8 weeks. Eight rats were enrolled in the normal control group. Results: At 8th week, rats were sacrificed for the observation of kidney injury through electron microscope. Glomerular podocalyxin production including mRNA and protein were determined by RT-PCR and immunohistochemistry respectively. Levels of urinary albumin excretion and urinary sediment podocalyxin, kidney injury index were all significantly increased, whereas expression of glomerular podocalyxin protein and mRNA were decreased significantly in diabetic rats compared to normal control. Dosages-dependent analysis revealed that protective effect of PIO ameliorated the physiopathological changes and reached a peak at dosage of 20 mg/kg/d. Conclusion: PIO could alleviate diabetic kidney injury in a dose-dependent pattern and the role may be associated with restraining urinary sediment podocalyxin excretion and preserving the glomerular podocalyxin expression.

scholarly journals Effect of aminophylline on the pharmacokinetics of amikacin in Sprague-Dawley rats

2019 ◽  
Vol 13 (03) ◽  
pp. 251-254
Author(s):  
Seth Kwabena Amponsah ◽  
Kwabena Frimpong-Manso Opuni ◽  
Kwabena Aboagye Antwi ◽  
Victor Pouzuing Kunkpeh
Keyword(s):  
Elimination Rate ◽  
Test Group ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Sprague Dawley ◽  
Serum Samples ◽  
Sprague Dawley Rats ◽  
Elimination Half ◽  
Apnea Of Prematurity

Introduction: In most resource-poor settings, amikacin is normally co-administered with aminophylline among preterm newborns with infection and apnea of prematurity. There is the likelihood of an interaction between concurrently administered amikacin that is excreted almost solely via kidneys, and aminophylline, which is known to increase filtration fraction. The aim of this study was to evaluate the effect of aminophylline on the pharmacokinetics of amikacin using an animal model. Methodology: Twelve male Sprague-Dawley rats (7 – 8 weeks old) were put into 2 equal groups. The test group received amikacin (10 mg/kg/day) with aminophylline (5 mg/kg/day) via the intraperitoneal route, and the control group received only amikacin (10 mg/kg/day) via the same route. On Day 4, after daily administration of drugs, tail vein blood samples were collected at different time points. Serum samples at each time point for each group were pooled and analyzed by fluorescence polarization immunoassay. Non-compartment pharmacokinetic analysis was used to estimate pharmacokinetic parameters. Area under the concentration-time curves (AUCs) were extrapolated from time 0 to infinity (AUC0→∞). Elimination rate constant (Ke) and elimination half-life (t1/2e) were also estimated. Results: Pharmacokinetic parameters of the control group (amikacin only) vis-a-vis the test group were as follows: Cmax; 42.4 μmol/L vs 19.0 μmol/L, AUC0→∞; 84.9 μmol/L/h vs 41.4 μmol/L/h, Ke; 0.12 hours-1 vs 0.24 hours-1, and t1/2; 5.87 hours vs 2.88 hours, respectively. Conclusion: This study suggests possible interaction between aminophylline and amikacin. However, further studies need to be conducted in humans to ascertain this finding.

Early Development of Drug-Induced Hepatic Necrosis

1971 ◽  
Vol 29 ◽  
pp. 576-577
Author(s):  
F. G. Zaki ◽  
E. Detzi ◽  
C. H. Keysser
Keyword(s):  
Early Development ◽  
Hepatic Necrosis ◽  
Screening Tests ◽  
Dense Matrix ◽  
Sprague Dawley ◽  
Electron Microscopic ◽  
Drug Induced ◽  
Hepatocellular Damage ◽  
Sprague Dawley Rats ◽  
Microscopic Studies

This study represents the first in a series of investigations carried out to elucidate the mechanism(s) of early hepatocellular damage induced by drugs and other related compounds. During screening tests of CNS-active compounds in rats, it has been found that daily oral administration of one of these compounds at a dose level of 40 mg. per kg. of body weight induced diffuse massive hepatic necrosis within 7 weeks in Charles River Sprague Dawley rats of both sexes. Partial hepatectomy enhanced the development of this peculiar type of necrosis (3 weeks instead of 7) while treatment with phenobarbital prior to the administration of the drug delayed the appearance of necrosis but did not reduce its severity.Electron microscopic studies revealed that early development of this liver injury (2 days after the administration of the drug) appeared in the form of small dark osmiophilic vesicles located around the bile canaliculi of all hepatocytes (Fig. 1). These structures differed from the regular microbodies or the pericanalicular multivesicular bodies. They first appeared regularly rounded with electron dense matrix bound with a single membrane. After one week on the drug, these vesicles appeared vacuolated and resembled autophagosomes which soon developed whorls of concentric lamellae or cisterns characteristic of lysosomes (Fig. 2). These lysosomes were found, later on, scattered all over the hepatocytes.

scholarly journals Skeletal Muscle Metabolomic Responses to Endurance and Resistance Training in Rats under Chronic Unpredictable Mild Stress

2021 ◽  
Vol 18 (4) ◽  
pp. 1645
Author(s):  
Xiangyu Liu ◽  
Xiong Xue ◽  
Junsheng Tian ◽  
Xuemei Qin ◽  
Shi Zhou ◽  
...  
Keyword(s):  
Resistance Exercise ◽  
Endurance Exercise ◽  
Field Tests ◽  
Treadmill Running ◽  
Control Group ◽  
Mild Stress ◽  
Chronic Unpredictable Mild Stress ◽  
Sprague Dawley ◽  
Exercise Interventions ◽  
Sprague Dawley Rats

The objectives of this study were to compare the antidepressant effects between endurance and resistance exercise for optimizing interventions and examine the metabolomic changes in different types of skeletal muscles in response to the exercise, using a rat model of chronic unpredictable mild stress (CUMS)-induced depression. There were 32 male Sprague-Dawley rats randomly divided into a control group (C) and 3 experimental groups: CUMS control (D), endurance exercise (E), and resistance exercise (R). Group E underwent 30 min treadmill running, and group R performed 8 rounds of ladder climbing, 5 sessions per week for 4 weeks. Body weight, sucrose preference, and open field tests were performed pre and post the intervention period for changes in depressant symptoms, and the gastrocnemius and soleus muscles were sampled after the intervention for metabolomic analysis using the 1H-NMR technique. The results showed that both types of exercise effectively improved the depression-like symptoms, and the endurance exercise appeared to have a better effect. The levels of 10 metabolites from the gastrocnemius and 13 metabolites from the soleus of group D were found to be significantly different from that of group C, and both types of exercise had a callback effect on these metabolites, indicating that a number of metabolic pathways were involved in the depression and responded to the exercise interventions.

Ranitidine as an alcohol dehydrogenase inhibitor in acute methanol toxicity in rats

2009 ◽  
Vol 29 (2) ◽  
pp. 93-101 ◽  
Author(s):  
Amal A El-Bakary ◽  
Sahar A El-Dakrory ◽  
Sohayla M Attalla ◽  
Nawal A Hasanein ◽  
Hala A Malek
Keyword(s):  
Alcohol Dehydrogenase ◽  
High Performance ◽  
Negative Control Group ◽  
Positive Control ◽  
Negative Control ◽  
Control Group ◽  
Sprague Dawley ◽  
Blood Samples ◽  
Methanol Poisoning ◽  
Sprague Dawley Rats

Methanol poisoning is a hazardous intoxication characterized by visual impairment and formic acidemia. The therapy for methanol poisoning is alcohol dehydrogenase (ADH) inhibitors to prevent formate accumulation. Ranitidine has been considered to be an inhibitor of both gastric alcohol and hepatic aldehyde dehydrogenase enzymes. This study aimed at testing ranitidine as an antidote for methanol acute toxicity and comparing it with ethanol and 4-methyl pyrazole (4-MP). This study was conducted on 48 Sprague-Dawley rats, divided into 6 groups, with 8 rats in each group (one negative control group [C1], two positive control groups [C2, C3] and three test groups [1, 2 and 3]). C2, C3 and all test groups were exposed to nitrous oxide by inhalation, then, C3 group was given methanol (3 g/kg orally). The three test groups 1, 2 and 3 were given ethanol (0.5 g/kg orally), 4-MP (15 mg/kg intraperitoneally) and ranitidine (30 mg/kg intraperitoneally), respectively, 4 hours after giving methanol. Rats were sacrificed and heparinized, cardiac blood samples were collected for blood pH and bicarbonate. Non-heparinized blood samples were collected for formate levels by high performance liquid chromatography. Eye balls were enucleated for histological examination of the retina. Ranitidine corrected metabolic acidosis (p = .025), decreased formate levels (p = .014) and improved the histological findings in the retina induced by acute methanol toxicity.

scholarly journals Drug Induced Pneumonitis Secondary to Treatment with Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir (VIEKIRA PAK®) for Chronic Hepatitis C: Case Report of an Unexpected Life-Threatening Adverse Reaction

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Shih Yea Sylvia Wu ◽  
Bridget Faire ◽  
Edward Gane
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Kidney Injury ◽  
Complete Recovery ◽  
Final Diagnosis ◽  
Community Acquired Pneumonia ◽  
Drug Induced ◽  
First Case ◽  
Life Threatening

VIEKIRA PAK (ritonavir-boosted paritaprevir/ombitasvir and dasabuvir) is an approved treatment for compensated patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection. This oral regimen has minimal adverse effects and is well tolerated. Cure rates are 97% in patients infected with HCV GT 1a and 99% in those with HCV GT 1b. We report the first case of life-threatening allergic pneumonitis associated with VIEKIRA PAK. This unexpected serious adverse event occurred in a 68-year-old Chinese female with genotype 1b chronic hepatitis C and Child-Pugh A cirrhosis. One week into treatment with VIEKIRA PAK without ribavirin, she was admitted to hospital with respiratory distress and acute kidney injury requiring intensive care input. She was initially diagnosed with community acquired pneumonia and improved promptly with intravenous antibiotics and supported care. No bacterial or viral pathogens were cultured. Following complete recovery, she recommenced VIEKIRA PAK but represented 5 days later with more rapidly progressive respiratory failure, requiring intubation and ventilation, inotropic support, and haemodialysis. The final diagnosis was drug induced pneumonitis.

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