Toxicity Screening After Repeated Dose of a Newly Developed Oral Heparin Derivative in Male Cynomolgus Monkeys

Kim, Choong-Yong; Kim, JeeEun; Han, Kyung-Nam; Kim, Sang-Kyoon; Park, KuiLea; Byun, Youngro

doi:10.2131/jts.32.411

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…APTT, TT, and PT are routinely measured to assess blood coagulation in toxicity studies of anticoagulants. 24,25 The results of the coagulation tests conducted here showed no significant change between the coagulation function of the two groups. Although the APTT of the exosome group was significantly higher than that of the control group on day 7 and day 14, there was no significant difference between the two groups before and after each time point.…”

Section: Discussionmentioning

confidence: 52%

Non-Clinical Safety Evaluation of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys

Hu,

Wang,

Xiao

et al. 2024

IJN

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In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future. Methods: 3.85 × 10 12 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection. Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group. Conclusion:To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 10 12 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.

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Section: Discussionmentioning

confidence: 52%

Non-Clinical Safety Evaluation of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys

Hu,

Wang,

Xiao

et al. 2024

IJN

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“…Furthermore, in this acute toxicity study, no other anticoagulant-related toxic changes in hematology and clinical chemistry were detected apart from the slight local swelling, the increase of TT, PT and APTT and the decrease of Fib after EH administration whose alterations ascribed to the pharmacodynamics of EH and were described in our preclinical animal thrombosis models (Liu et al, 2022a(Liu et al, , 2022b. APTT, TT and PT are routinely measured to assess blood coagulation in toxicity studies for anticoagulants (Kim et al, 2007;Kurata and Horii, 2004). Slight local redness and swelling at the injection site after administration suggested that there was minor bleeding at the injection site and it should be paid close attention in future clinical practices.…”

Section: Discussionmentioning

confidence: 71%

The toxicity assessment of neorudin in cynomolgus monkeys

et al. 2023

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In this study, the toxicity effects on circulatory system and respiratory system, and the acute toxicity test of recombinant neorudin (EPR-hirudin, EH) in cynomolgus monkeys were evaluated to provide reference information for clinical studies. Eighteen cynomolgus monkeys were randomly divided into three groups for single intravenous administration of 3, 30 mg/kg EH and normal saline, respectively. The changes of respiratory frequency, respiratory intensity, blood pressure and electrocardiogram before and after administration were recorded. In acute toxicity test, six cynomolgus monkeys were intravenously received EH at a single dose of 171, 257, 385, 578, 867 and 1300 mg/kg respectively. The vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of the animals were determined before administration and on the 7th and 14th day after administration. As the results showed that there were no significant abnormal changes in respiratory frequency, respiratory intensity, blood pressure or electrocardiogram in cynomolgus monkeys after receiving EH at 3 mg/kg and 30 mg/kg, and there was no statistical difference between the treated groups and normal saline group. In the acute toxicity test, no significant abnormalities were observed in vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of six cynomolgus monkeys at day 7 and 14 after EH administration. Furthermore, autopsies of all cynomolgus monkeys showed no abnormalities. The results of toxicokinetics showed that AUClast of the drug increased in proportion to the EH dose in the range of 171-578 mg/kg, and increased in over proportion to the EH dose in the range of 578-1300 mg/kg. The variation of Cmax was basically consistent with AUClast. In a sum, A single intravenous injection of 3 and 30 mg/kg of EH did not affect the circulatory system and respiratory system in cynomolgus monkeys and the maximum tolerated dose of EH in cynomolgus monkey is over 1300 mg/kg (equivalent to 619-1300 times of the proposed clinical equivalent dose).

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“…Therefore, there is a huge obligation for the development of an oral LMWH formulation (Hoffart et al 2006). Various strategies have been explored by researchers including use of penetration enhancers (Hayes et al 2006), microparticles (Javot et al 2009), polymeric nanoparticles (Chen et al 2009), dendrimeric nanocarriers (Bai and Ahsan 2009), chemical conjugates (Kim et al 2007a), biomimetic solid lipid nanoparticles (Paliwal et al 2011), alginate coated chitosan core shell nanoparticles (Bagre et al 2013), nanoparticles in enterically coated tablets containing permeation enhancers (Goharzadeh et al), nanocapsules as nanocarriers (Ramadan et al 2011), etc. However, till date, no oral formulation of heparin exists in the market (Hwang et al 2012, Kim et al 2011.…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of polymer lipid hybrid nanoparticles for oral delivery of LMWH

Hallan

Kaur²,

Jain

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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The present study aimed to develop an improved oral delivery system for low-molecular-weight heparin (LMWH), novel polymer lipid hybrid nanoparticles were developed. LMWH loaded chitosan polymer lipid hybrid nanoparticles (LMWH-CS-PLNs) were developed using double emulsification and solvent evaporation method. The performance of developed formulations was evaluated by using in vitro and in vivo behavior, such as drug release studies, in vitro permeation study, in vivo venous thrombolytic study, in vitro uptake studies by using intestinal epithelium resembling Caco-2 cell lines. The new CS-PLNs might provide an effective strategy for oral delivery of LMWH with improved encapsulation efficiency as compared to CS-NPs and SA-LNPs.

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Toxicity Screening After Repeated Dose of a Newly Developed Oral Heparin Derivative in Male Cynomolgus Monkeys

Cited by 6 publications

References 30 publications

Non-Clinical Safety Evaluation of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys

Non-Clinical Safety Evaluation of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys

The toxicity assessment of neorudin in cynomolgus monkeys

Development and characterization of polymer lipid hybrid nanoparticles for oral delivery of LMWH

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