Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

Kojima, Sayuri; Yoshida, Toshinori; Sasaki, Junya; Takahashi, Naofumi; Kuwahara, Maki; Shutoh, Yasufumi; Saka, Machiko; Nakashima, Nobuaki; Kosaka, Toshio; Harada, Takanori

doi:10.2131/jts.37.957

Cited by 7 publications

(5 citation statements)

References 43 publications

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“…e. the effect was on the generated cells populations, but the bulk was mature and not cycled in blood. A similar finding was reported before, where the P/N ratio increased with a decrease in the hemoglobin concentration, hematocrit, and mature erythrocyte count were observed in both mice (El-Alfy et al, 2016) and rats (Kojima et al, 2012), following methotrexate oral dosing of methotrexate. However, this is not consistent with the finding of Suzuki et al (1989) regarding the gradual decrease in the P/N ratio with time after the administration of MMC into mice.…”

Section: Resultssupporting

confidence: 90%

In vivo cytogenotoxicity testing of isotretinoin by the micronucleus assay in the blood of male Sprague-Dawley rats Isotretinoin is cytotoxic and genotoxic

Kazemi

Siam

Daradkeh

et al. 2022

GenApp

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Isotretinoin (ISO), one of vitamin A-derived retinoids, is comparatively the most widely prescribed drug in acne vulgaris pathogenesis. Despite its excellent therapeutic success, the systemic use of this drug showed undesirable serious side effects such as teratogenesis, oxidative stress, and genotoxicity. The uses of retinoids in cancer therapy are limited due to severe adverse reactions. This has led the scientific community to ask for further studies qualifying ISO features and comparing their efficacy and safety. The purpose of this study was to evaluate the cytogenotoxicity of multiple oral doses (5, 10, 15, and 20 mg/kg, daily for seven consecutive days) of ISO in male Sprague-Dawley rats. The micronucleus assay was used to investigate genotoxicity biomarkers such as the percentage of micronucleated polychromatic erythrocytes (%MNPCEs) and the percentage of aberrant cells (%Abc). Another goal was to test the cytotoxicity of the drug by measuring the ratio between PCEs and normochromatic erythrocytes (NCEs) (PCEs/NCEs). In comparison with the control, the three cytogenetic endpoints: %MNPCEs, P/N, and %Abc significantly (P ≤ 0.0017) dose-dependent increase. This suggested genotoxicity and cytotoxicity of the tested ISO doses. Therefore, the therapeutic uses of ISO should be restricted to a very narrow range border. Further studies are needed to shed more light on the safety profile of ISO therapy.

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Section: Resultssupporting

confidence: 90%

In vivo cytogenotoxicity testing of isotretinoin by the micronucleus assay in the blood of male Sprague-Dawley rats Isotretinoin is cytotoxic and genotoxic

Kazemi

Siam

Daradkeh

et al. 2022

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“…Kojima and colleagues demonstrated the signi cant decrease in red serial cells in rats treated with MTX [49]. In our study, anemia due to disruption of hematopoiesis in the bone marrow in the Wistar albino rats treated with MTX was detected.…”

Section: Discussionsupporting

confidence: 60%

The Effects of Pomegranate and Carvacrol on Methotrexate-Induced Bone Marrow Toxicity in Rats

Şen¹,

Bozkurt²,

Söker³

et al. 2014

CIM

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Purpose: The aim of this study was to evaluate the effects of pomegranate (PMG) extract and carvacrol (CARV) on methotrexate (MTX)-induced oxidative stress and bone marrow toxicity. Methods: Wistar albino rats (32 rats) were divided into four groups (n=8): Group 1 was control; Group 2 was given a single intraperitoneal injection of methotrexate (20 mg/kg); Group 3 was treated with carvacrol (73 mg/kg i.p.) one day before MTX (20 mg/kg i.p.) injection; and, Group 4 received a single dose of MTX (20 mg/kg i.p) while PMG was administered orally for seven days at 225 mg/kg. After animals were euthanized, blood samples were taken to evaluate hematological parameters and oxidative stress. In addition, the femur was cropped and bone marrow was extracted for examination. Results: White blood cell count, hemoglobin, hematocrit and platelet count were found to be decreased in the MTX group, but these changes were prevented in the groups that received CARV and PMG. Furthermore, decreased bone marrow cellularity was found in the groups treated with MTX, whereas the PMG and CARV groups had cellularity similar to controls. Strikingly, oxidative stress increased in the MTX group, but was ultimately decreased in the rats that received the antioxidants PMG and CARV. Conclusion: Carvacrol and PMG were found to be protective against methotrexate-induced oxidative bone marrow damage. Use of these antioxidants, in combination with chemotherapeutics, may help to reduce some adverse effects of methotrexate.

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“…To the best of our knowledge, sudden severe pancytopenia has not been observed at low doses in animals other than rodents (Kojima et al, 2012). The etiology of MTX-induced renal dysfunction is believed to be mediated by the precipitation of MTX, especially its metabolite, in the renal tubules owing to its very low solubility in an acidic environment.…”

Section: Doses Of Chemotherapeutic Drugs Are Currently Calculated Onmentioning

confidence: 98%

Pharmacokinetics of low‐dose methotrexate in horses

Rostang

Desjardins

Espana

et al. 2020

Vet Pharm & Therapeutics

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This study aimed to investigate both the pharmacokinetic behavior and tolerance of methotrexate (MTX) in horses to design a specific dosing regimen as a new immunomodulatory drug for long‐term treatment. To determine the primary plasma pharmacokinetic variables after single intravenous, subcutaneous or oral administration, six horses were administered 0.3 mg/kg MTX in a crossover design study. After a 10‐week washout, MTX was administered subcutaneously to three of the six previously treated horses at a dose of 0.3 mg/kg once per week for 3 months. In both studies, MTX and metabolite concentrations were measured using LC‐MS/MS. The absolute bioavailability of MTX was 73% following subcutaneous administration but less than 1% following oral administration. The plasma clearance was 1.54 ml min−1 kg−1 (extraction ratio = 2%). After 24 hr, plasma concentrations were below the LOQ. No adverse effects were noted except for a moderate reversible elevation in liver enzymes (GLDH). With regards to the main metabolites of MTX, very low concentrations of 7‐hydroxy‐MTX were found, whereas polyglutamated forms (mainly short chains) were found in red blood cells. A subcutaneous dose of 0.2 mg kg−1 week−1 may be safe and relevant in horses, although this has yet to be clinically confirmed.

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Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

Cited by 7 publications

References 43 publications

In vivo cytogenotoxicity testing of isotretinoin by the micronucleus assay in the blood of male Sprague-Dawley rats Isotretinoin is cytotoxic and genotoxic

In vivo cytogenotoxicity testing of isotretinoin by the micronucleus assay in the blood of male Sprague-Dawley rats Isotretinoin is cytotoxic and genotoxic

The Effects of Pomegranate and Carvacrol on Methotrexate-Induced Bone Marrow Toxicity in Rats

Pharmacokinetics of low‐dose methotrexate in horses

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