From Treatment to Tragedy: Severe Methotrexate Toxicity With Mucocutaneous Ulcers, Myelosuppression, and Nephropathy.

Methotrexate (MTX) is a well-established drug for the use of various neoplastic disorders. Recently, it has been widely used as a disease-modifying antirheumatic drug (DMARD) in low doses, mainly for rheumatoid arthritis (RA) and psoriasis. The drug is known to cause renal damage as well as be excreted via the kidneys, thus causing a higher incidence of adverse effects in patients with impaired renal function. The side effects of MTX toxicity range from mucocutaneous ulcers to nephrotoxicity and bone marrow depression, all of which are seen in this case. Here, we report an elderly male in his late 60s who was prescribed MTX 15 mg once a week along with folic acid 5 mg for RA by a general practitioner. Despite being prescribed once weekly, he continued to take MTX daily without following up with a physician for a span of five months. Following this, he presented to the medicine outpatient department with odynophagia due to oral ulcers for 10 days. He was diagnosed with MTX toxicity, causing nephropathy, myelosuppression, and mucocutaneous ulcerations. He was treated with injectable leucovorin 100 mg thrice a day until the toxicity subsided, leading to his eventual recovery.

Investigating the protective effects of Astragalus polysaccharides on cyclophosphamide-induced bone marrow suppression in mice and bone mesenchymal stem cells.

BACKGROUND: This study determines the role and mechanism of APS in cyclophosphamide-induced myelosuppression in mice and bone mesenchymal stem cells (BMSCs) cell model. METHODS: Cy-induced myelosuppression mice and BMSCs cell model were established. Fifty C57BL/6 mice (weighing 20 ± 2 g) were randomly divided into five groups. Femur and tibia samples, bone marrow samples, and blood samples were collected 3 days after the last injection of Cy. Histopathology changes and cell apoptosis were detected. Cell viability, apoptosis, cycle distribution, reactive oxygen species activity, osteogenesis ability, and protein levels were detected. γ-H2AX and senescence-associated ß-galactosidase activity expression was detected by immunofluorescence. Cy-induced senescence and Wnt/ß-catenin related protein levels were detected using western blotting. RESULTS: The results showed that APS effectively induced Cy-induced histological injury and cell apoptosis rate. After treated with APS, ROS and ALP levels were significantly increased. In BMSCs, cell viability, apoptosis, and cell cycle distribution were also influenced by APS treatment. Compared with the control group, cell viability was significantly increased, the cell apoptosis rate was decreased while the number of cells remained in the G0-G1 phase was increased. Meanwhile, ROS levels were significantly increased in APS group. Cell senescence and Wnt/ß-catenin related protein (γ-H2AX, SA-ß-gal, p21, p16, p-ß-catenin/ ß-catenin, c-Myc, and AXIN2) levels were also altered both in vivo and in vitro. Interestingly, the effects of APS were reversed by BML-284. CONCLUSION: Our results indicate that APS protected Cy-induced myelosuppression through the Wnt/ß-catenin pathway and APS is a potential therapeutic drug for Cy-induced myelosuppression.

Toxicity of Chemotherapeutics Based on Viscera-state doctrine / 中国实验方剂学杂志

Malignant tumors are important diseases that threaten human health. Although targeting and immunotherapy have been gradually applied in the treatment of malignant tumors in recent years， which can alleviate the suffering of patients to a certain extent， there are still problems of large adverse reactions and easy drug resistance. At present， chemotherapy is still the main method for the treatment of malignant tumors. While killing tumor cells， chemotherapy also damages normal cells， which often leads to drug toxicity， such as bone marrow suppression， gastrointestinal adverse reactions， liver and kidney function damage， and oral mucosal reactions. Although modern medicines have a certain effect on the toxicity of chemotherapy drugs， there are still limitations. Traditional Chinese medicine（TCM） has a long history of treating malignant tumors， and considers that chemotherapy is a drug with toxin invading the body， exacerbating the "deficiency"， "toxin" and "stasis" of the body， causing damage to Qi， blood and organs， especially in spleen， stomach， liver and kidney， and leading to bone marrow suppression， liver and kidney function injury and other adverse reactions. Studies have confirmed that the use of TCM treatment has a better clinical efficacy. Therefore， new therapies shall be explored based on the basic theory of traditional Chinese medicine. As the core part of the theoretical system of TCM， Viscera-state doctrine is closely related to looking， listening， questioning and feeling the pulse of TCM， and has constantly developed and improved. It has important significance in guiding diagnosis and treatment of diseases. This study is guided by viscera-state doctrine of TCM and based on the etiology and pathogenesis of TCM. It starts with the clinical manifestations of common drug toxicity of chemotherapy drugs， such as bone marrow suppression， gastrointestinal adverse reactions， liver and kidney function damage， oral mucosal reactions， which are external signs of the toxicity of chemotherapeutic drugs， and associates pathological manifestations of viscera to physiological functions. From elephants and Tibetans， it systematically summarizes the viscera characteristics of various common chemotherapeutic drugs and provides new ideas and methods for clinical use of TCM in treating the toxicity of chemotherapeutic drugs， so as to promote the application of viscera-state doctrine in diagnosis and treatment of diseases.

Lurasidone Induced Thrombocytopenia: Is it a Signal of Drug Induced Myelosuppression?

The U.S. Food and Drug Administration (FDA) has approved a supplemental new drug application Lurasidone (Latuda, Sunovion Pharmaceuticals), an atypical antipsychotic, for the treatment of schizophrenia in adolescents 13-17 years of age. Lurasidone was previously indicated in the U.S. for the treatment of adults with schizophrenia and major depressive episodes with bipolar I disorder as monotherapy. We present a case of a 29-year-old male patient who was hospitalized with thrombocytopenia (WHO grade-3 toxicity) (unlabeled) along with extrapyramidal disorder, gastritis, and hyperprolactinemia within 2-3 months of initiation of tablet lurasidone 80 mg/day (Lurasid, Intas Pharmaceuticals) in bipolar depression. Dechallenge was found to be positive in three reactions except hyperprolactinemia (outcome unknown) during hospital stay. The terms anemia and leukopenia are well labeled/listed with the drug literatures of lurasidone. Thus, this case presents a strong probability of lurasidone to cause myelosuppression/bone marrow depression.

Effect of Zhen Qi Fu Zheng granules on the bone marrow depression model induced by Zidorf.

Zidorf is a commonly used drug for the treatment of AIDS, the most common side effects of AZT was bone marrow depression. Therefore, we investigated the effects of Zhen Qi Fu Zheng (AQFZ) granules on the model of bone marrow depression induced by AZT. We showed that the high, medium and low doses of AQFZ granules could increase the number of WBC in the mice model induced by AZT, and the difference was significant (P < 0.01) compared with the model group. Each dose of AQFZ granules can increase the thymus cortex thickness, the number of thymus lymphocytes, spleen nodule size, the number of lymphocytes in the spleen (P < 0.01). The medium dose of AQFZ granules can also significantly improve the number of BMC in the bone marrow depression model (P < 0.01). As well as, the low dose of AQFZ granules can clearly increase the number of nucleated cells in a bone marrow (P < 0.05) and IL-2blood serum. So, AQFZ granules can improve and regulate the hemogram, bone marrow and immune level of bone marrow depression model induced by AZT.

Clinical Study of Acupoint Catgut-embedding Therapy for Prevention and Treatment of Bone Marrow Depression in Breast Cancer Patients Induced by FEC Chemotherapy / 广州中医药大学学报

Objective To compare the clinical efficacy of acupoint catgut-embedding therapy plus fundamental treatment versus fundamental treatment alone for the prevention and treatment of bone marrow depression in breast cancer patients induced by FEC(fluorouracil, epirubicin and cyclophosphamide) chemotherapy. Methods A total of 46 post-operation breast cancer patients accepting the first cycle of FEC chemotherapy were randomly divided into treatment group and control group, 23 cases in each group. The control group was given fundamental treatment including oral use of Chinese medicine of modified Xiangsha Liujunzi Decoction for regulating stomach and arresting vomiting, modified Guipi Decoction and Gui Lu Erxian Decoction for nourishing blood and generating blood, and western medicine of Batilol Tablets and Vitamin B4 Tablets. The treatment group was given acupoint catgut-embedding therapy on bilateral Zusanli(ST36) and Shenshu(BL23) plus fundamental treatment. The effect on bone marrow depression in the two groups was observed after treatment. Results(1) On post-chemotherapy day 7 and 8, the count of white blood cells (WBC) and neutrophils (NE) in the treatment group was higher than that in the control group, the difference being significant(P < 0.05 or P < 0.01).(2) The utilization of granulocyte colony-stimulating factor(G-CSF) in the treatment group was less than that in the control group, the difference being significant (P < 0.05). (3) On post-chemotherapy day 10, the effect on improving bone marrow depression in the treatment group was superior to that in the control group, the difference being significant (P<0.01) . Conclusion The acupoint catgut-embedding therapy plus fundamental treatment is more effective and safe for the prevention and treatment of bone marrow depression in breast cancer patients induced by FEC chemotherapy than fundamental treatment alone.

Adverse events in a newborn on valproate therapy due to loss-of-function mutations in CYP2C9.

An increased risk of valproate-induced toxicity has been reported in children, particularly in those younger than 2 years of age. Significant variations in valproate pharmacokinetics and shifts in the metabolic pathways towards CYP2C9-dependent metabolism seem to play some role in the age-related differences in the incidence of adverse events. We present the case of a premature patient with moderate hemorrhage in the subependymal region (grade II - intraventricular hemorrhage without ventricular dilatation), several myoclonic episodes in her right upper arm (series of jerks lasting milliseconds), and epileptiform abnormalities on the EEG (localized spike-and-wave in the left frontal region with preserved background activity who was treated with valproate. Serious side effects, consisting of bone marrow depression, hyperammonemia, and serum alkaline phosphatase elevation, were observed seventeen days after the beginning of valproate therapy. The toxic symptoms were likely the consequence of a reduced ability to metabolize valproate. The patient was demonstrated to carry two loss-of-function mutations in CYP2C9 (CYP2C9*3/*3) resulting in exaggerated blood concentrations of valproate. The present case highlights the importance of assaying inborn errors in CYP2C9 gene in pediatric patients to avoid valproate-evoked serious side effects.

Effects of Salidroside on expression of substance P and neurokinin-1 receptor of bone marrow cells in bone marrow depressed anemia mice / 中国免疫学杂志

Objective:To observe the effects of salidroside on the expression of substance P (SP)and neurokinin-1 receptor (NK-1R)of bone marrow cells(BMCs)in bone marrow(BM)depressed anemia mice,and to explore its roles for hematopoietic regulation.Methods:Automatic blood cell analysator was used to detected the changes of peripheral blood cells in each group ,immuno-histochemistry and reverse transcription-polymerase chain reaction ( RT-PCR) were used to analyze the expressions of SP and its receptor NK-1R of BMCs in each group respectively.Results: Peripheral blood testing results showed that the number of white blood cells (WBC),red blood cells(RBC)and hemoglobin(HB)of model group were significantly decreased when compared with control group.Compared with model group ,low-dose,middle-dose and high-dose salidroside obviously elevated the number of white blood cells ,and middle-dose salidroside obviously elevated the number of platelets.Immunohistochemistry studies showed that the expression of SP and its receptor NK-1R of BMCs was found in each group.Compared with control group , the expression of SP of BMCs was decreased obviously in model group(P0.05),and the expression of SP and its receptor NK-1R of BMCs was increased significantly in low-dose,middle-dose and high-dose salidroside groups (P<0.05).RT-PCR data showed that the expression of SP mRNA of BMCs was increased obviously in model group ,low-dose,middle-dose and high-dose salidroside groups when compared with control group (P<0.05).The expression of NK-1R mRNA of BMCs was un-detected in control group and model group.The expression level of NK-1R mRNA of BMCs was elevated gradually with the increase of salidroside dosage in low-dose,middle-dose and high-dose salidroside groups.Conclusion: The mRNA and protein expressions of SP and its receptor NK-1R of BMCs were up-regulated significantly by salidroside in dose-dependent manner.These data suggest that salidroside could participate in the recovery of hematopoietic function of BM depressed anemia mice by increasing the expression of SP and its receptor NK-1R of BMCs.