High-dose ifosfamide in relapsed pediatric osteosarcoma: Therapeutic effects and renal toxicity

2005 ◽  
Vol 44 (3) ◽  
pp. 215-219 ◽  
Author(s):  
Su G�ls�n Berrak ◽  
Margaret Pearson ◽  
Semha Berbero?lu ◽  
?nci Erg�rhan ?lhan ◽  
Norman Jaffe
Keyword(s):  
Renal Toxicity ◽  
High Dose ◽  
Therapeutic Effects ◽  
Pediatric Osteosarcoma

Therapeutic Effects of Milk Thistle Extract against Renal Toxicity Induced By Diethylnitrosamine and Carbon Tetrachloride in Adult Rats

2017 ◽  
Vol 10 (1) ◽  
pp. 107-124
Author(s):  
Amal. Ahmed ◽  
Abeer Hassanin ◽  
Abeer Hassan ◽  
Saadia Ali ◽  
A. El-Anwar
Keyword(s):  
Carbon Tetrachloride ◽  
Renal Toxicity ◽  
Milk Thistle ◽  
Therapeutic Effects ◽  
Adult Rats

scholarly journals N-Acetyl Cysteine Overdose Inducing Hepatic Steatosis and Systemic Inflammation in Both Propacetamol-Induced Hepatotoxic and Normal Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 442
Author(s):  
Gunn-Guang Liou ◽  
Cheng-Chi Hsieh ◽  
Yi-Ju Lee ◽  
Pin-Hung Li ◽  
Ming-Shiun Tsai ◽  
...  
Keyword(s):  
Inbred Mouse ◽  
Serum Triglyceride ◽  
Mouse Strains ◽  
High Dose ◽  
Therapeutic Effects ◽  
Protein Nitration ◽  
Cholesterol Levels ◽  
Antioxidative Enzyme Activities ◽  
Acetyl Cysteine ◽  
Dose Dependent

Acetaminophen (APAP) overdose induces acute liver damage and even death. The standard therapeutic dose of N-acetyl cysteine (NAC) cannot be applied to every patient, especially those with high-dose APAP poisoning. There is insufficient evidence to prove that increasing NAC dose can treat patients who failed in standard treatment. This study explores the toxicity of NAC overdose in both APAP poisoning and normal mice. Two inbred mouse strains with different sensitivities to propacetamol-induced hepatotoxicity (PIH) were treated with different NAC doses. NAC therapy decreased PIH by reducing lipid oxidation, protein nitration and inflammation, and increasing glutathione (GSH) levels and antioxidative enzyme activities. However, the therapeutic effects of NAC on PIH were dose-dependent from 125 (N125) to 275 mg/kg (N275). Elevated doses of NAC (400 and 800 mg/kg, N400 and N800) caused additional deaths in both propacetamol-treated and normal mice. N800 treatments significantly decreased hepatic GSH levels and induced inflammatory cytokines and hepatic microvesicular steatosis in both propacetamol-treated and normal mice. Furthermore, both N275 and N400 treatments decreased serum triglyceride (TG) and induced hepatic TG, whereas N800 treatment significantly increased interleukin-6, hepatic TG, and total cholesterol levels. In conclusion, NAC overdose induces hepatic and systemic inflammations and interferes with fatty acid metabolism.

Early Recognition of Renal Toxicity of High-dose Methotrexate Therapy

2008 ◽  
Vol 30 (12) ◽  
pp. 950-952 ◽  
Author(s):  
Theodore Scott Nowicki ◽  
Kari Bjornard ◽  
David Kudlowitz ◽  
Claudio Sandoval ◽  
Somasundaram Jayabose
Keyword(s):  
Renal Toxicity ◽  
Early Recognition ◽  
Methotrexate Therapy ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate

Abstract 528: Dose- And Salt-dependency Of Angiogenesis Inhibition-induced Blood Pressure Rise And Renal Toxicity

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Stephanie Lankhorst ◽  
Mariëtte H Kappers ◽  
Stefan Sleijfer ◽  
A H Danser ◽  
Anton H van den Meiracker
Keyword(s):  
Low Dose ◽  
Renal Toxicity ◽  
Pressure Rise ◽  
High Salt ◽  
High Dose ◽  
Low Doses ◽  
High Salt Diet ◽  
Salt Diet ◽  
Angiogenesis Inhibition ◽  
Cystatine C

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy, inducing hypertension and nephrotoxicity. We explored the dose- and salt-dependency of these side effects. In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with a high (27.5 mg/kg.day, n=14), an intermediate (14 mg/kg.day, n=6) and low dose (7 mg/kg.day, n=6) of sunitinib or vehicle (n=8) after normal salt diet for 2 weeks. The low dose-model was also combined with a high salt diet (8% NaCl and saline water). Eight days after administration rats were sacrificed and blood and 24h urine samples collected for biochemical measurements. With the high dose of sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). The intermediate and low doses induced MAP rises of 24.3±2.7 mmHg (p<0.001) and 13.4±3.3 mmHg (p<0.001), respectively. The low dose of sunitinib with high salt, induced a MAP rise of 43.5±2.2 mmHg (p<0.001 compared to normal salt). With the high dose, circulating ET-1 increased from 0.6±0.1 pg/ml to 1.6±0.2 pg/ml (p<0.01) and serum cystatine-C from 4.5±0.1 mg/L to 6.6±0.3 mg/L (p<0.001). Comparable increases in circulating ET-1 were seen with the intermediate and low doses, whereas serum cystatine-C did increase with the intermediate dose (to 6.3±0.1 mg/L, p0.05). Serum cystatine-C levels with low and high salt were identical. With the high dose of sunitinib, proteinuria increased from 7.5±1.3 to 33.3±4.8 mg/day (p<0.05). The rise in proteinuria was attenuated with the intermediate (16.2±2.1 mg/day, p<0.01) and low dose (19.9±3.3 mg/day, p<0.01), but increased to 40.4±30.1 mg/day (p>0.05) with high salt. Angiogenesis inhibition-induced hypertension and nephrotoxicity are dose-dependent with a lower threshold for the rise in BP than for renal toxicity. The BP rise observed with the low dose of sunitinib observed in normotensive rats is comparable to the sunitinib-induced BP rise observed in patients and clearly is salt-sensitive. Since cystatine-C levels during normal and high salt diet were comparable, the BP rise during high salt seems independent of renal dysfunction.

scholarly journals Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

2018 ◽  
Vol 48 (3) ◽  
pp. 971-982 ◽  
Author(s):  
Yang  Cheng ◽  
Tianyang Chen ◽  
Jian Ping ◽  
Jianjie Chen
Keyword(s):  
Treatment Group ◽  
Palmitic Acid ◽  
Inflammatory Cytokines ◽  
Kupffer Cells ◽  
Nonalcoholic Steatohepatitis ◽  
Lipid Accumulation ◽  
Hepatic Injury ◽  
High Dose ◽  
Therapeutic Effects ◽  
Dependent Manner

Background/Aims: Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with hepatic injury, inflammation and early to moderate fibrosis. Kupffer cells play a crucial role in promoting hepatic inflammation, which further facilitates the development of NASH. Here we investigated the effects of Cangju Qinggan Jiangzhi decoction (CQJD) on high fat diet (HFD) and methionine-choline deficient (MCD) induced mouse NASH pathogenesis. Methods: Mouse NASH models were developed by HFD and MCD diet. The treated mice were divided into three groups: the control group (n = 10), the low-dose CQJD treatment group (n = 10) and the high-dose CQJD treatment group (n = 10). The hepatic injury, inflammation, and apoptotic molecules were evaluated by H&E staining, immunohistochemistry and real-time PCR. Kupffer cells were isolated from control mice and CQJD-treated mice after stimulation by lipopolysaccharide (LPS) and/or palmitic acid. The level of the inflammatory cytokines TNFα, IL1β, and CCL2 was measured by ELISA. Results: The HFD-fed mice displayed significant metabolic, inflammatory, and oxidative stress-related alterations due to hepatic lipid accumulation. CQJD treatment largely normalized the hepatic injury, lowered the ALT/AST level, and reduced the severity of liver inflammation, as revealed by the decreased inflammatory cytokines levels. In vitro, CQJD blocked the activation of LPS- or palmitic acid-primed Kupffer cells in a dose-dependent manner. In the MCD diet-induced NASH mice, similar therapeutic effects of CQJD were also observed. Conclusion: CQJD ameliorates mouse nonalcoholic steatohepatitis. The reduction in liver injury and inflammation induced by CQJD is associated with reduced activation of Kupffer cells. Our results suggest that CQJD is a promising therapeutic strategy in clinical steatohepatitis.

scholarly journals Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models

2020 ◽  
Vol 8 (1) ◽  
pp. e000400 ◽  
Author(s):  
Taiki Kurino ◽  
Reiko Matsuda ◽  
Ayu Terui ◽  
Hiroyuki Suzuki ◽  
Tomomi Kokubo ◽  
...  
Keyword(s):  
Mouse Models ◽  
Pharmacological Activity ◽  
Tumor Model ◽  
High Dose ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Poor Outcome ◽  
Liver And Kidney ◽  
High Doses

BackgroundRecently, antiprogrammed cell death protein 1 (aPD-1) and antiprogrammed death-ligand 1 (aPD-L1) monoclonal antibodies (mAbs) have been approved. Even though aPD-1 and aPD-L1 mAbs target the same PD-1/PD-L1 axis, it is still unclear whether both mAbs exert equivalent pharmacological activity in patients who are sensitive to PD-1/PD-L1 blockade therapy, as there is no direct comparison of their pharmacokinetics (PK) and antitumor effects. Therefore, we evaluated the differences between both mAbs in PK and therapeutic effects in PD-1/PD-L1 blockade-sensitive mouse models.MethodsHerein, murine breast MM48 and colon MC38 xenografts were used to analyze the pharmacological activity of aPD-1 and aPD-L1 mAbs. The PK of the mAbs in the tumor-bearing mice was investigated at low and high doses using two radioisotopes (Indium-111 and Iodine-125) to evaluate the accumulation and degradation of the mAbs.ResultsaPD-1 mAb showed antitumor effect in a dose-dependent manner, indicating that the tumor model was sensitive to PD-1/PD-L1 blockade therapy, whereas aPD-L1 mAb failed to suppress tumor growth. The PK study showed that aPD-L1 mAb was accumulated largely in normal organs such as the spleen, liver, and kidney, resulting in low blood concentration and low distributions to tumors at a low dose, even though the tumors expressed PD-L1. Sufficient accumulation of aPD-L1 mAb in tumors was achieved by administration at a high dose owing to the saturation of target-mediated binding in healthy organs. However, degradation of aPD-L1 mAb in tumors was greater than that of aPD-1 mAb, which resulted in poor outcome presumably due to less inhibition of PD-L1 by aPD-L1 mAb than that of PD-1 by aPD-1 mAb.ConclusionAccording to the PK studies, aPD-1 mAb showed linear PK, whereas aPD-L1 mAb showed non-linear PK between low and high doses. Collectively, the poor PK characteristics of aPD-L1 mAb caused lower antitumor activity than of aPD-1 mAb. These results clearly indicated that aPD-L1 mAb required higher doses than aPD-1 mAb in clinical setting. Thus, targeting of PD-1 would be more advantageous than PD-L1 in terms of PK.

A retrospective safety analysis of adult patients treated with high-dose methotrexate for osteosarcoma in Stockholm, Sweden.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10083-10083 ◽  
Author(s):  
Daniel Alm ◽  
Christina Linder Stragliotto ◽  
Annika Folin ◽  
Jonas Bergh ◽  
Theodoros Foukakis
Keyword(s):  
Oral Mucositis ◽  
Blood Concentration ◽  
Renal Toxicity ◽  
Adult Patients ◽  
Bleeding Complications ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Hepatic Toxicity ◽  
Dose Methotrexate ◽  
Grade 3

10083 Background: Patients with osteosarcoma are routinely treated with pre- and post-operative chemotherapy that includes high-dose methotrexate. The treatment is associated with a risk of severe renal and hepatic toxicity. Methods: All patients with osteosarcoma that had received at least one cycle of high-dose methotrexate at the adult oncology department, Karolinska University Hospital were retrospectively identified. Treatment toxicity, including hematologic, renal, hepatic toxicity, infections and oral mucositis were registered and graded according to CTCAE v 4.0. A possible relationship between methotrexate blood concentration and toxicity was investigated. Results: Sixteen eligible patients that had received a total of 103 cycles of high-dose methotrexate were identified. Ten patients experienced a severe hepatic toxicity, (Grade 3, n=5 and Grade 4, n=5). Grade 3 renal toxicity was seen in one patient and although reversible, it led to treatment interruption. Reversible, grade 2 elavation of serum creatinine occured in 5 cases. Four grade 3 infections were seen in 2 patients and 8 patients had at least one occurrence of Grade 3 oral mucositis. Thrombocytopenia was a common event (Grade 3, n=5 and Grade 4, n=2) but no severe bleeding complications were observed. One patient died as a result of multi-organ failure two days after methotrexate administration. Methotrexate blood concentration at 24 hours from administration could predict for renal toxicity (p<0.005, by chi-square test), but not for other toxicity. Conclusions: High-dose methotrexate in adult patients with osteosarcoma was frequently associated with severe, however reversible toxicity.

High dose Cis-platinum diammine dichloride.Amelioration of renal toxicity by mannitol diuresis

Cancer ◽  
1977 ◽  
Vol 39 (4) ◽  
pp. 1372-1381 ◽  
Author(s):  
Daniel M. Hayes ◽  
Esteban Cvitkovic ◽  
Robert B. Golbey ◽  
Ellen Scheiner ◽  
Lawrence Helson ◽  
...  
Keyword(s):  
Renal Toxicity ◽  
High Dose

scholarly journals Ambulatory high-dose methotrexate administration among pediatric osteosarcoma patients in an urban, underserved setting is feasible, safe, and cost-effective

2010 ◽  
Vol 55 (7) ◽  
pp. 1296-1299 ◽  
Author(s):  
Kris M. Mahadeo ◽  
Ruth Santizo ◽  
Lindsay Baker ◽  
Joan O'Hanlon Curry ◽  
Richard Gorlick ◽  
...  
Keyword(s):  
Cost Effective ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Pediatric Osteosarcoma

scholarly journals Comparative Outcome of Thai Pediatric Osteosarcoma Treated with Two Protocols: the Role of High-Dose Methotrexate (HDMTX) in a Single Institute Experience

2014 ◽  
Vol 15 (22) ◽  
pp. 9823-9829 ◽  
Author(s):  
Worawut Choeyprasert ◽  
Samart Pakakasama ◽  
Nongnuch Sirachainan ◽  
Duantida Songdej ◽  
Ampaiwan Chuansumrit ◽  
...  
Keyword(s):  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Pediatric Osteosarcoma
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