Integrated Network Pharmacology and Metabolomics Analysis to Reveal the Potential Mechanism of Siwu Paste on Aplastic Anemia Induced by Chemotherapy Drugs.

Purpose: This study aimed to reveal the multicomponent synergy mechanisms of SWP based on network pharmacology and metabolomics for exploring the relationships of active ingredients, biological targets, and crucial metabolic pathways. Materials: Network pharmacology, including TRRUST, GO, and KEGG, enrichment was used to discover the active ingredients and potential regulation mechanisms of SWP. LC-MS and multivariate data analysis method were further applied to analyze serum metabolomics profiling for discovering the potential metabolic mechanisms of SWP on AA induced by Cyclophosphamide (CTX) and 1-Acetyl-2-phenylhydrazine (APH). Results: A total of 27 important bioactive ingredients meeting the ADME (absorption, distribution, metabolism, and excretion) screening criteria from SWP were selected. Interaction networks were constructed and validated based on the 10 associated ingredients with the relevant targets. A total of 125 biomarkers were found by Metabolomics approach, which associated with the development of AA, mainly involved in amino acid metabolism and lipid metabolism. While SWP can reverse the above 12 metabolites changed by AA. Network analysis revealed the synergistic effects of SWP through the 43 crucial pathways, including Sphingolipid signaling pathway, Sphingolipid metabolism, Arginine and proline metabolism, VEGF signaling pathway, Estrogen signaling pathway. Conclusion: The study suggested that SWP is a useful alternative for the treatment of AA induced by CTX + APH. Its potential mechanisms are to improve hematopoietic microenvironment and promote bone marrow hematopoiesis therapies.

Toxic hepatitis-associated aplastic anaemia after dual homeopathic remedies and Gymnema sylvestre use.

Hepatitis-associated aplastic anaemia (HAAA) is a rare condition characterised by onset of acute hepatitis which is followed by development of severe pancytopenia due to bone marrow failure within 6 months. This syndrome can be precipitated by acute viral infections, but the aetiology remains unknown in the majority. Drug-induced HAAA is extremely rare and has been reported with nutritional and dietary supplements in current literature. We report the first cases of ayurvedic herbal and homeopathic remedies-associated HAAA in two patients which proved fatal in both. Evaluation of patients with acute hepatitis and severe pancytopenia must include a detailed evaluation for complementary and alternative medicine use.

Occupational exposure to cytostatic fumes during hyperthermic intraperitoneal chemotherapy.

Hyperthermic intraperitoneal chemotherapy (HIPEC)-heated, intra-abdominal chemotherapy-has become the treatment of choice for treating peritoneal metastases from ovarian, stomach or colorectal cancers. HIPEC has several advantages and disadvantages. The major benefit is minimal systemic toxicity for the patient, but there is a risk of occupational exposure for operating room staff. We have not found any reports of workers with chronic aplastic anaemia as a result of exposure to cytostatic fumes during HIPEC. The aim of this case report is to raise the awareness of potential negative health effects of inhalation exposure to cytostatic drugs. We present a rare case of a 43-year-old woman, suffering from aplastic anaemia as a long-term consequence of exposure to cytostatics. During the HIPEC procedure, surgical revision of the peritoneal cavity was undertaken which resulted in release of cytostatic fumes. Despite awareness of the health effects of occupational exposure to cytostatic drugs and well-developed procedures for safely handling them, unexpected exposure may occur causing serious medical conditions. These may develop in sensitive subjects although accidental high-level exposure may lead to unexpected long-term consequences in all workers. Medical staff need to be informed of the risks of HIPEC and safety guidelines to reduce the risk of exposure.

Effect of nutritional supplement on bone marrow-derived mesenchymal stem cells from aplastic anaemia.

Aplastic anaemia (AA) is characterised by pancytopenia resulting from a marked reduction in haemopoietic stem cells (HSC). The regulation of haemopoiesis depends on the interaction between HSC and various cells of the bone marrow (BM) microenvironment, including BM-derived mesenchymal stromal cells (BMSC). The purpose of this study was to analyse the biological effect of nutritional supplement (NS), a dietary supplement consisting of thirty-six compounds: amino acids, nucleotides, vitamins and micronutrients on the BMSC of AA rats. The AA rat model was established by irradiating X-ray (2·5 Gy) and intraperitoneal injections of cyclophosphamide (35 mg/kg; Sigma) and chloramphenicol (35 mg/kg; Sigma). Then AA rats were fed with NS in a dose-dependent manner (2266·95, 1511·3, 1057·91 mg/kg d) by intragastric administration. The effect of NS on the BMSC of AA rats was analysed. As compared with AA rats, NS treatment significantly improved these peripheral blood parameters and stimulated the proliferation of total femoral nucleated cells. NS treatment affected proliferative behaviour of BMSC and suppressed BMSC differentiation to adipocytes. Furthermore, NS treatment of AA rats accelerated osteogenic differentiation of BMSC and enhanced bone mineral density. Co-incubation of HSC with mesenchymal stromal cells and serum from AA rats subjected to high-dose NS markedly improved the yield of CD34+cells. Protein microarray analysis revealed that there were eleven differentially expressed proteins in the NS group compared with the AA rat group. The identified specific NS might be implicated in rehabilitation of BMSC in AA rats, suggesting their potential of nutritional support in AA treatment.

Comparative metabolomics analysis on hematopoietic functions of herb pair Gui-Xiong by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry and pattern recognition approach.

The compatibility of Angelicae Sinensis Radix (Danggui, DG) and Chuanxiong Rhizoma (Chuanxiong, CX), a famous herb pair Gui-Xiong (GX), can produce synergistic and complementary hematopoiesis. In present study, global metabolic profiling with ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) combined with pattern recognition method was performed to discover the underlying hematopoietic regulation mechanisms of DG, CX and GX on hemolytic and aplastic anemia rats (HAA) induced by acetyl phenylhydrazine (APH) and cyclophosphamide (CP). Thirteen endogenous metabolites contributing to the separation of model group and control group were tentatively identified. The levels of LPCs including lysoPC (18:0), lysoPC (20:4), lysoPC (16:0) and lysoPC (18:2), sphinganine, nicotinic acid, thiamine pyrophosphate, phytosphingosine, and glycerophosphocholine increased significantly (p<0.05) in HAA, while the levels of oleic acid, 8,11,14-eicosatrienoic acid, ceramides (d18:1/14:0), and 17a-hydroxypregnenolone decreased significantly (p<0.05) in comparison with control rats. Those endogenous metabolites were chiefly involved in thiamine metabolism and sphingolipid metabolism. The metabolic deviations could be regulated closer to normal level after DG, CX and GX intervention. In term of hematopoietic function, GX was the most effective as shown by the relative distance in PLS-DA score plots and relative intensity of metabolomic strategy, reflecting the synergic action between DG and CX. The relative distance calculation was firstly used in metabolomics for semi-quantization.

Effects of Sheng-Mai injection on the PRPP synthetase activity in BFU-es and CFU-es from bone marrows of mice with benzene-induced aplastic anemia.

160 Kunming mice were divided at random into 3 groups. Group 1: normal control (40 mice). Group 2: aplastic anemia (AA) control (60 mice); benzene inhalation was carried out for 2.5 months and sterilized normal saline was injected i.p. for another 6 weeks. Group 3: treated AA (60 mice); benzene was administered by inhalation in a similar manner, Sheng-Mai Injection (SMI) was administered i.p. for 6 weeks after the AA models were established. SMI is a famous Chinese traditional prescription of Panax ginseng C.A. Meyer (0.1 g/ml), Ophiopogon japonicus (Thunb.) Ker-Gawl (0.312 g/ml) and Fructus Schisandrae (0.158 g/ml). Activities of phosphoribosylpyrophosphate (PRPP) synthetase in BFU-Es and CFU-Es were estimated by ion pair reversed phase HPLC (IPrHPLC). Accompanying the sharp drop in counts of erythroid progenitor cells, the PRPP synthetase activity in CFU-Es of AA mice was reduced significantly (P<0.01), whereas there were no remarkable changes of this enzyme activity in their BFU-Es compared with the control group. Both the counts of erythroid progenitor cells and PRPP synthetase activity in CFU-Es returned nearly to normal levels following treatment with SMI of mice in Group 3 (P<0.01). Our results suggest that the attenuation of PRPP synthetase activity in peripheral erythrocytes of AA patients may originate from the weakening of activity of this enzyme in CFU-Es from their bone marrow. The impairment of PRPP formation would explain ATP depletion and disorders of energy metabolism in AA erythrocytes. SMI can distinctly increase the reduced quantity of erythroid progenitor cells and promote rapid restoration of PRPP synthetase activity in CFU-Es of AA mice.

[Effect of Astragalus membranaceus injection on megakaryocyte hematopoiesis in anemic mice].

OBJECTIVE: To assess the effect of Astragalus membranaceus injection (AMI) on megakaryocyte hematopoiesis in anemic mice and explore its mechanism. METHODS: Anemic models of mice were randomly divided into two groups: treatment group and anemic control group. Intraperitoneal doses of AMI (20 mg/(ml.20 g) q.d x 6) were given to the treatment group, and equal doses of physiological saline were given to the anemic control group. On days 8, 11 and 14 after treatment, blood platelet and bone marrow cells were determined, and the numbers of CFU-Meg (colony forming unit-megakaryocyte) and Meg-CSA (megakaryocyte colony-stimulating activity) were determined by using technique of hematopoietic progenitor cells culture in vitro. RESULTS: Serum Meg-CSA of the treatment group was significantly higher than that of the anemic control group. The abovementioned indices of the treatment group recovered to normal by day 11, which was markedly earlier than the day of recovery observed in the anemic control group. CONCLUSION: AMI can increase serum Meg-CSA of anemic mice and accelerate the recovery of megekaryocyte hematopoiesis after bone marrow suppression.

Aplastic anemia in a petrochemical factory worker.

A petrochemical worker with aplastic anemia was referred to our hospital. He worked in a petroleum resin-producing factory and had been exposed to low-level benzene while packaging the powder resin and pouring lime into a deactivation tank. According to the yearly environmental survey of the working area, the airborne benzene level was approximately 0.28 ppm. Exposure to benzene, a common chemical used widely in industry, may progressively lead to pancytopenia, aplastic anemia, and leukemia. The hematotoxicity of benzene is related to the amount and duration of exposure. Most risk predictions for benzene exposures have been based on rubber workers who were exposed to high concentrations. In the petroleum industry, the concentration of benzene is relatively low, and there are disputes over the toxicity of low-level benzene because of a lack of evidence. In this paper we report the case of aplastic anemia induced by low-level benzene exposure.

[Experimental study on effect of yishen shengxue tablet in treating aplastic anemia].

OBJECTIVE: To study the mechanism of Yishen Shengxue Tablet (YSSXT) in treating aplastic anemia. METHODS: Observing the effect of YSSXT on hematopoietic, immunologic, anti-infection and body resistance of model mice of aplastic anemia. RESULTS: YSSXT had marked effect of promotion on recovering myleran injury induced reduction of colony forming unit-spleen (CFU-S), colony forming unit-culture (CFU-C), colony forming unit-erythrocyte (CFU-E), markedly promoting the peritoneal macrophage phagocytosis of normal mice, also markedly lower the mortality of Staphylococcus aureus inoculated mice, and elevate the anoxia resistant ability under normal pressure of anoxic mice, prolonging their survival time. CONCLUSION: Using YSSXT to treat aplastic anemia that the effectiveness might be realized through promoting the proliferation of hematopoietic stem cells of bone marrow, enhancing the non-specific immunity, and the anti-infection as well as body resistance.

[Severe 5-fluorouracil toxicity in a woman treated for breast cancer with concurrent osteogenesis imperfecta and dehydrogenase deficiency]. / Toxicité sévère au 5-fluorouracile chez une femme traitée pour un cancer du sein, présentant une ostéogenèse imparfaite et un déficit en dihydropyrimidine déhydrogénase.

Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme involved in the catabolism of 5 fluorouracil (5 FU). The clinical importance of DPD has recently been demonstrated wit the identification of rare cases presenting a severe toxicity to 5 FU related to proven DPD deficiency. We report a new case in a patient with concurrent congenital osteogenesis imperfecta. We were surprised to find another similar association reported by Lyss. It is tempting to speculate that DPD activity may be abnormally regulated in osteogenesis imperfecta patients.

Phase I and pharmacologic study of the alkylating agent modulator novobiocin in combination with high-dose chemotherapy for the treatment of metastatic breast cancer.

PURPOSE: Resistance to alkylators may potentially be overcome by drugs that inhibits DNA repair, thus improving the efficacy of high-dose chemotherapy. This trial was performed to determine if novobiocin, an agent that inhibits DNA repair, could be given with high-dose alkylators. Study aims were to define the toxicities and maximal-tolerated dose (MTD) of novobiocin and the pharmacokinetics of novobiocin and high-dose cyclophosphamide and thiotepa. PATIENTS AND METHODS: Thirty-eight women with responsive metastatic breast cancer received high-dose cyclophosphamide (3 to 6 g/m2 over 4 days), thiotepa (400 to 800 mg/m2), and novobiocin (0.5 to 5.0 g/d x 7, orally) with autologous marrow support. Toxicity was monitored. The pharmacology of novobiocin, cyclophosphamide, and thiotepa was evaluated. RESULTS: There were no toxic deaths. The MTD of novobiocin was 4 g/d. All seven patients treated at 5 g/d developed grade III/IV mucositis and vomiting. The severity of mucositis correlated with the plasma levels of novobiocin. Other severe toxicities were not observed. Plasma novobiocin levels > or = 100 micrograms/mL, which are associated with reversal of drug resistance in animal models, were consistently seen at dose levels greater than 2 g. The dispositions of cyclophosphamide and thiotepa were not altered by novobiocin. CONCLUSION: Novobiocin may be given with high-dose alkylators in doses that produce plasma levels that augment the activity of these cytotoxics in experimental models. The pharmacology of high-dose cyclophosphamide and thiotepa is unaffected. Novobiocin 4 g/d orally for 7 days is recommended for future study.

[A case of rheumatoid arthritis complicated with salazosulfapyridine-induced aplastic anemia].

A 64 year-old woman with rheumatoid arthritis was admitted to our hospital because of general fatigue. She noticed polyarthralgia 8 months prior to the admission and diagnosis of rheumatoid arthritis was made. Administration of salazosulfapyridine (1.0 g/day) was started 6 months before the admission. Complete remission of rheumatoid arthritis was obtained in 2 months and blood cell counts showed normal values at that time. The results of laboratory tests included hemoglobin; 8.6 g/dl, white blood cell count; 1,900/mm3 with a differential of 19% neutrophils, 77% lymphocytes, and 4% monocytes; platelets were 21,000/mm3. A bone marrow aspiration and biopsy were performed. There were reduced numbers of myelocytes, erythroblasts, and megakaryocytes indicating aplastic anemia. Salazosulfapyridine was discontinued. Prednisolone, anabolic steroid and granulocyte-colony stimulating factor (G-CSF) were administrated. In spite of these therapy, recovery of peripheral blood cell counts have not been observed and supporting therapy including red cell and platelets transfusion have been continued. To our knowledge, this is the first case report which describes occurrence of aplastic anemia in patients with rheumatoid arthritis treated by salazosulfapyridine.

Aplastic anemia induced by an adulterated herbal medication.

Herbal medication use is common in many cultural groups. Because these products are unregulated, the potential for significant toxicity exists. We report a case of aplastic anemia associated with the use of an herbal medication by a 12-year-old boy. On analysis, the herbal medication was found to contain phenylbutazone, which has been strongly associated with the production of similar hematologic abnormalities. The medication was not listed as an ingredient and no warning was present on the box.

Benzene toxicity.

The proper control of benzene in the workplace and the general environment has been a subject of relatively intense interest for at least the past decade. The author reviews the toxicology of benzene, its hematologic effects in the human, and methods of measurement of benzene exposure in the workplace.