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Evidence-based Practice Guideline of Medication Therapy of High-dose Methotrexate in China was published in the British Journal of Clinical Pharmacology in February 2022. The guideline followed the latest definition of clinical practice guideline and the methodology specification for the guideline development of WHO. The Grading of Recommendations Assessment ， Development，and Evaluation （GRADE）approach was applied to rate the quality of evidence and determine the strength of recommendations. Finally ，this guideline presents 28 recommendations covering the whole process of clinical medication of high-dose methotrexate ，involving evaluation prior to administration （liver and renal function ，pleural effusion and ascites ， comedication，genetic testing ），pre-treatment and routine dosing regimen （pretreatment of hydration and alkalization ，urine alkalization，routine dosing regimen ），therapeutic drug monitoring （necessity，method，timing，target concentration ），leucovorin rescue（rescue timing ，rescue regimen ，rescue dose optimization ），and management of toxicities （liver and kidney function monitoring，supportive treatment ，blood purification treatment ）. This article aims to summarize and interpret the recommendations of this guideline ，so as to promote the better promotion and implementation of this guideline and provide comprehensive technical support and suggestions for whole-course individualized administration of high-dose methotrexate in China.
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Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial-mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy.
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Glioblastoma multiforme (GBM) in the central nervous system is the most lethal advanced glioma and currently there is no effective treatment for it. Studies of sinomenine, an alkaloid from the Chinese medicinal plant,
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Glioblastoma is the most common and aggressive primary tumor in the central nervous system, accounting for 12%-15% of all brain tumors. 3--Acetyl-11-keto--boswellic acid (AKBA), one of the most active ingredients of gum resin from Birdw., was reported to inhibit the growth of glioblastoma cells and subcutaneous glioblastoma. However, whether AKBA has antitumor effects on orthotopic glioblastoma and the underlying mechanisms are still unclear. An orthotopic mouse model was used to evaluate the anti-glioblastoma effects of AKBA. The effects of AKBA on tumor growth were evaluated using MRI. The effects on the alteration of metabolic landscape were detected by MALDI-MSI. The underlying mechanisms of autophagy reducing by AKBA treatment were determined by immunoblotting and immunofluorescence, respectively. Transmission electron microscope was used to check morphology of cells treated by AKBA. Our results showed that AKBA (100 mg/kg) significantly inhibited the growth of orthotopic U87-MG gliomas. Results from MALDI-MSI showed that AKBA improved the metabolic profile of mice with glioblastoma, while immunoblot assays revealed that AKBA suppressed the expression of ATG5, p62, LC3B, p-ERK/ERK, and P53, and increased the ratio of p-mTOR/mTOR. Taken together, these results suggested that the antitumor effects of AKBA were related to the normalization of aberrant metabolism in the glioblastoma and the inhibition of autophagy. AKBA could be a promising chemotherapy drug for glioblastoma.
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Salvianolic acid A (SalA) is an effective compound extracted from traditional Chinese medicine Bunge. The Forkhead box O3a (FOXO3a) signaling pathway plays crucial roles in the modulation of ischemia-induced cell apoptosis. However, no information about the regulatory effect of SalA on FoxO3a is available. To explore the anti-cerebral ischemia effect and clarify the therapeutic mechanism of SalA, SH-SY5Y cells and Sprague-Dawley rats were applied, which were exposed to oxygen glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion/reperfusion (MCAO/R) injuries, respectively. The involved pathway was identified using the specific inhibitor LY294002. Results showed that SalA concentration-dependently inhibited OGD/R injury triggered cell viability loss. SalA reduced cerebral infarction, lowered brain edema, improved neurological function, and inhibited neuron apoptosis in MCAO/R rats, which were attenuated by the treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) specific inhibitor LY294002. SalA time- and concentration-dependently upregulated the phosphorylation levels of protein kinase B (AKT) and its downstream protein FOXO3a. Moreover, the nuclear translocation of FOXO3a was inhibited by SalA both and , which was also reversed by LY294002. The above results indicated that SalA fought against ischemia/reperfusion damage at least partially the AKT/FOXO3a/BIM pathway.
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Objective To study the mangiferin absorption process of mangiferin polymorphs in SD rats thus to find out the optimal crystal form and explore the factors that may affect the clinical effects of mangiferin. Methods Each rat was given one of three crystal forms of mangiferin. Plasma concentration of mangiferin were determined by HPLC-MS method. After liquidliquid extraction by ethyl acetate, the chromatographic separation was carried out on an Agilent ZORBAX SB-C18 (2.1 mm× 100 mm,3.5 μm) with a mobile phase consisting of methanol-0.1％ formic acid aqueous solution (30:70) . Mass spectrometry were performed in positive ion mode. Ion mass-to-charge ratio was set at 445 and 447 for mangiferin and, cefuroxime sodium (internal standard) respectivel for quantitive analysis. Results The main pharmacokinetic parameters of mangiferin form II, Ⅴ, Ⅵ were as follows: AUC(0-24 h) were (1323. 27 ± 218. 07) ,(1974. 34 ± 469. 24) ,(1737. 79 ± 623. 06) ng · mL-1 · h, respectively; Cmax were (321.92±85.18) ,(455.83±277.07) ,(319.92±86.07) μg·L-1, respectively; tmax were (0.70±0.45) , (0.50±0.32) ,(0.50± 0.34) h, respectively; t1/2z were (2.78± 1.72) ,(5.29± 2.67) ,(5.31± 2.82) h, respectively. Conclusion The main pharmacokinetic parameters of mangiferin polymorphs in plasma of rats are different, and mangiferin form Ⅴ has the hightest AUC(0-24 h) and Cmax.
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Dihydropyridine (DHP) calcium channel blockers drugs (dipine in drug names) are currently used in the treatment of hypertension clinically. In recent years, with the emergence of generic drugs, it has been found that the drug efficacy is quite different from that of the original drug, and the reason is closely related to the difference in the crystal forms of the oral preparations. This paper reviews the polymorphic phenomenon of some DHP calcium channel blockers in the domestic market, introduces the clinical application and research progress of the DHP drugs, analyzes the differences between different crystal forms of the same drugs. This work may provide references and ideas for the research and development of generic drugs or new crystalline drug of DHP drugs.
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Objective According to the clinical medicinal crystal form———form γ of levonorgestrel, to establish the quantitative analysis method for levonorgestrel form γ by powder X-ray diffraction (PXRD) . Methods Firstly, single crystal X-ray diffractometry and powder X-ray diffractometry were used to confirm that the prepared levonorgestrel form γ was 100％ polymorphic purity, which provided a standard sample for quantitative analysis by single peak method; then, the standard samples of different quality levonorgestrel form γ for powder X-ray diffraction were weighed, the peak intensity values of characteristic diffraction peaks d = 6.4 , d = 6. 1 and d = 5. 6 of form γ as quantitative parameters selected, a linear relationship between the peak intensity value and the quality of form γ was established; finally, the content of levonorgestrel form γ was quantitatively analyzed. Results The peak intensity values of characteristic diffraction peaks d = 6.4 , d = 6.1 and d = 5.6 of levonorgestrel form γ and the quality showed a good linear relationship.In the range of form γ masses of 5 mg to 50 mg, the regression linear equations wereY = 459.59X+5 536.5, R2 = 0.993 0, Y = 430.03X+6 867.6, R2 = 0.990 5,Y = 615.95X+ 6 209.5, R2 = 0.990 8,respectively. Conclusion The method is simple, rapid, accurate and reliable, it can be used as quality control method for levonorgestrel polymorphs.
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The pharmaceutical co-crystal has attracted a lot of attention in recent years as a new direction in the research of polymorphism drugs. The research on pharmaceutical co-crystal has scientific significance for improving the solubility, bioavailability and physical or chemical stability of drugs. In this paper, from the perspective of drugs for the treatment of cardiovascular diseases(including five major types: heart failure, hypertension, coronary heart disease and arrhythmia, stroke) , the latest research results of pharmaceutical co-crystal reported in recent years are reviewed, hope to provide reference for the follow-up research and promote the development of pharmaceutical co-crystal in China.
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Objective To study the gastrointestinal absorption process of three letrozole polymorphs in rats, and evaluate the different pharmacokinetics parameters of different polymorphs. Methods A total of 18 SD rats were given the different letrozole polymorphs. Then the high-performance liquid chromatographic method was used for the determination of plasma concentration of letrozole in these SD rats.Finally the pharmacokinetic parameters among the different polymorphs were calculated. Results Cmax of letrozole crystal form I, crystal form II and crystal form III were (9.247± 4.612) ,(23.387± 9.049) and (15.682±1.589) mg·L-1, respectively, and AUC0→t were(198.115±47.014) ,(476.641±125.467) and (271.817±41.068) mg·L-1·h,respectively. Conclusion The different crystal forms of letrozole result in different plasma concentration in SD rats. Crystal form II may be its preponderant polymorphs which deserves further research and development.
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Polymorphism of chemical drugs has become a hot topic in pharmaceutical research at home and abroad. In this review, the phenomena, causes and significance of polymorphism were introduced briefly. The international drug development process and characteristics of the polymorphic drug development in our country were analyzed. Finally, the present situation and development in China was summarized from four aspects including the basic theory, technical methods, intellectual property rights and supervision. This paper can provide a reference for correct understanding the research level of polymorphic drugs in China and clarifying the direction of polymorphic drug research.
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A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30 mg/kg), allopurinol (20 mg/kg) or benzbromarone (20 mg/kg) were orally administered to mice for 7 days. On the 7th day, uric acid and creatinine in serum and urine, blood urea nitrogen (BUN), malondialdehyde (MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin (H&E) staining. Hepatic XOD, renal urate transporter 1 (URAT1), glucose transporter type 9 (GLUT9), organic anion transporter 1 (OAT1) and ATP-binding cassette transporter G2 (ABCG2) were detected by Western blot and real time polymerase chain reaction (PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid (FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our results suggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.
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Gangliosides are a class of important glycosphingolipids containing sialic acid that are widely distributed on the outer surface of cells and are abundantly distributed in brain tissue. Disialoganglioside with three glycosyl groups (GD3) and disialoganglioside with two glycosyl groups (GD2) are markedly increased in pathological conditions such as cancers and neurodegenerative diseases. GD3 and GD2 were found to play important roles in cancers by mediating cell proliferation, migration, invasion, adhesion, angiogenesis and in preventing immunosuppression of tumors. GD3 synthase (GD3S) is the regulatory enzyme of GD3 and GD2 synthesis, and is important in tumorigenesis and the development of cancers. The study of GD3S as a drug target may be of great significance for the discovery of new drugs for cancer treatment. This review will describe the gangliosides and their roles in physiological and pathological conditions; the roles of GD3 and GD2 in cancers; the expression, functions and mechanisms of GD3S, and its potential as a drug target in cancers.
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Objective Two co-crystals of isonicotinic acid hydrazide(INH)-malonic acid and INH-glutaric acid were prepared.The formation mechanism and intermolecular interaction were studied. Methods Three-dimensional structure of 2 co-crystals were obtained though single crystal X-ray diffraction(SXRD), and intermolecular interaction was analyzed using Hirshfeld surface method. Results INH-malonic acid crystalized in stoichiometric ratio of 1:0.5,while INH-glutaric acid in 1:1.Two co-crystals maintain their stable arrangement in space by hydrogen bond and van der Waals force. Conclusion With the existence of pyridine ring and carbohydrazide group in INH,which mainter-molecular interaction in co-crystal can be directly and clearly revealed by Hirshfeld surface analysis.
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The purpose of this study was to investigate the effects of salvianolic acid A (SAA) in systemic lupus erythematosus (SLE) induced by pristane in BALB/c mice. Lupus mice were established by confirming elevated levels of autoantibodies and IL-6 after intraperitoneal injection of pristane. Mice were then treated with daily oral doses of SAA for 5 months in parallel with mice treated with prednisone and aspirin as positive controls. The levels of autoantibodies were monitored at monthly intervals and nephritic symptoms observed by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. Western blot analysis of renal tissue was also employed. SAA treatment caused a significant reduction in the levels of anti-Sm autoantibodies and reduced renal histopathological changes and pathological effects. SAA treatment also significantly inhibited the phosphorylation of IKK, IB and NFB in renal tissues of lupus mice. In conclusion, the results suggest that SAA alleviates renal injury in pristane-induced SLE in BALB/c mice through inhibition of phosphorylation of IKK, IB and NFB.
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Objective To evaluate the polymorphism of levonorgestrel by kinds of analysis technologies, and get the preponderant pharmaceutical polymorph by in vitro assessment including the stability and solubility. Methods Three polymorphs were obtained by quick solvent removal and precipitation methods. These polymorphs were characterized by X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), Raman spectroscopy and microscope. Furthermore,the stability was studied by X-ray powder diffraction analysis technology and using the curve of solubility to evaluate the dissolution rate of the three crystal forms. Results The levonorgestrel polymorphs α,β and γ were identified. The results of stability indicated that the levonorgestrel polymorphs α and β were metastable while the levonorgestrel polymorph γ was stable,and the dissolution rate of α, β, γ decrease in turn. Conclusion The levonorgestrel polymorph α is preponderant pharmaceutical polymorph. And the research on preponderant pharmaceutical polymorph of levonorgestrel provides scientific basic data for its clinical drug evaluation and establishing the quality standards.
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OBJECTIVE To investigate the dynamic changes in urine metabolic profiles in rats induced by D-galactose (D-Gal),and to study the correlations between the differential metabolites and behavior indicators using the proton nuclear magnetic resonance (1H-NMR)-based metabonomics.METHODS Subcutaneous injection of D-Gal 100 mg· kg-1 for 10 weeks was adopted in the model group.The sample of urine was collected at day 0 (dO),d14,d28,d42,d56 and d70.NMR metabonomics technique was used for acquisition of data,which was analyzed by multivariate statistical analysis.The ability of learning and memory were measured by Morris water maze test from d70.After the behavioral test,the rats were sacrificed and the hippocampus was observed by hematoxylin-eosin staining.RESULTS Principal component analysis (PCA) results revealed that there was considerable difference between the model group and the normal control group at d70.According to the varible importance plot (VIP) calculation and S-plot scores,a total of 12 metabolites were screened and identified as potential biomarkers at d70.The differences of metabolites and Morris water maze test were subjected to correlation analysis,and the results showed that the levels of choline,lactate and dimethylglycine in the model group were significantly increased and negatively correlated with the times of crossing the platform (r =-0.90,-0.50 and-0.52;n=10).Formate was significantly negatively correlated with the time spent in the target area (r =-0.51,n=10),but choline and formate were significantly positively correlated with the escape latency (r =0.72 and 0.53;n=10).However,the levels of creatine and taurine decreased in the model group,which was significantly positively correlated to the times of acrossing platforms (r =0.89 and 0.71;n=10),while alanine was significantly positively correlated to the time spent in the target area(r =0.74,n=10).Taurine,alanine and creatine were significantly negatively correlated with the escape latency (r =-0.66,-0.50 and-0.85;n=10).The correlations between the differential metabolites and the behavioral indicators were further proved.CONCLUSION The metabolic profile changes in urine from D-Gal induced aging model rats are significantly correlated with impairement of ability in learning and memory.1H-NMR metabonomics in urinary metabolic profile changes may be used as an evaluation index in the D-Gal induced aging rats model.
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This study discussed problems in consistency assessment of generic drugs and analyzed effect of polymorphs on drug quality and its influence on consistency of curative efficiency.Relationship between evaluation method of polymorphs and curative efficiency was investigated.It showed that establishment of curative efficiency related evaluation indicators was necessary and improvment of techniques was important.Drug quality criteria should be added with requirement of curative efficiency control.Related information based on polymorphs could be provided for technical research in consistency assessment.
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The research and development (R & D) of novel Chinese materia medica (CMM) have made a great progress in recent years.But problems still exist in druggability evaluation of novel CMM,such as uncertain evaluation content and lack of key technology.Druggability evaluation is the key to the success or failure for R & D of novel CMM.Observation on the effect and safety of novel CMM is the core of druggability evaluation.The important pharmacological problems include the choice of evaluation indicator,clinical indication,analysis of material basis,investigation of mechanism,research on pharmacokinetics and safety evaluation.Modem technologies should be used in druggability evaluation.We should have a correct understanding of the concept of novel CMM.The grasp of the meaning of novel drugs and the essence of CMM theory will be helpful for R & D of novel CMM.