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  1. Fulltext Treatment of tetanus neonatorum in a rural setting
    Yong YF
    Med J Malaysia, 1983 Mar;38(1):74-6.
    PMID: 6688850
    Tetanus, especially tetanus neonatorum (T.N.) continues to be a significant medical and social problem in the developing countries. The case mortality rate remains very high even in the 'developed' countries, varying from 60-80 percent in various reports, and even higher in the case of tetanus neonatorum. Sanders et al had introduced the method of intrathecal injection of antitetanus serum (ATS) in 1976 and have achieved very encouraging results. As the conventional treatment of tetanus neonatorum had achieved very poor result, even in the very sophisticated centres, a case of tetanus neonatorum admitted to Cottage Hospital Semporna in Sabah had been treated with intrathecal ATS since June 1982. This paper reviews the results of this new approach to tetanus neonatorum treatment as compared to cases treated conventionally.
  2. Inhibition of Cytochrome P450s by Strobilanthes crispus Sub-Fraction (F3): Implication for Herb-Drug Interaction
    Yong YF, Liew MWO, Yaacob NS
    Eur J Drug Metab Pharmacokinet, 2022 Feb 11.
    PMID: 35146636 DOI: 10.1007/s13318-022-00754-z
    BACKGROUND AND OBJECTIVE: Strobilanthes crispus Blume sub-fraction (F3) has been reported to be cytotoxic against cancer cells and to cause murine mammary tumor regression. Potential utilization of F3 as an adjuvant in breast cancer treatment to alleviate chemotherapeutic drug resistance is currently hampered by potential cytochrome P450 (CYP)-mediated herb-drug interactions (HDIs). The current study assessed the inhibitory potency of F3 towards five CYP enzymes involved in tamoxifen metabolism.

    METHODS: Potential CYP inhibition by F3 was first determined using fluorescence assays, using known CYP inhibitors as reference. To further ascertain the inhibitory potency and mode of inhibition, high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis of specific metabolites of a CYP probe substrate was conducted.

    RESULTS: The half-maximal inhibitory concentration (IC50) values indicate that F3 exhibited relatively weak inhibition on CYP2B6, CYP2C19, CYP2D6, and CYP3A4. Highest susceptibility to inhibition by F3 was observed for CYP2C9, where the IC50 value from fluorescence-based assay was 35-fold higher than control. Further analysis by HPLC-MS/MS revealed relatively weak mixed-type inhibition of F3 on CYP2C9, as indicated by IC50 and inhibition constant (KI) values. The risk of clinically significant CYP2C9 inhibition by F3 was then predicted based on the attained KI value and the presumed amount of F3 absorbed from S. crispus leaves following consumption. The calculated maximum plasma concentration to inhibition constant Cmax/KI) ratio suggests that F3 consumption could potentially result in clinically significant drug interactions with medications metabolized by CYP2C9.

    CONCLUSION: Taken together, the results revealed a low probability of inhibition by F3 on CYP enzymes involved in tamoxifen metabolism. However, further in vivo investigation is necessary for potential F3 interaction with CYP2C9. The utility of a preliminary in vitro approach in the assessment of potential HDI was demonstrated in this study.

  3. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development for screening of potential tamoxifen-drug/herb interaction via in vitro cytochrome P450 inhibition assay
    Yong YF, Tan SC, Liew MWO, Yaacob NS
    J Chromatogr B Analyt Technol Biomed Life Sci, 2020 May 08;1148:122148.
    PMID: 32416571 DOI: 10.1016/j.jchromb.2020.122148
    Screening for potential drug-drug interaction (DDI) or herb-drug interaction (HDI) using in vitro cytochrome P450 inhibition (IVCI) assays requires robust analytical methods with high sensitivity and reproducibility. Utilization of liquid chromatography-mass spectrometry (LC-MS) for analyte quantification is often hampered by the presence of non-volatile IVCI sample buffer constituents that often results in ion suppression. In this study, to enable screening of drug interactions involving tamoxifen (TAM) metabolism using IVCI-LC-MS/MS, a liquid-liquid extraction (LLE) method was developed and optimized for sample clean-up. Utilization of chloroform as extraction solvent and adjustment of sample pH to 11 was found to result in satisfactory recovery (>70%) and low ion suppression (<19%). A LC-MS/MS method was subsequently developed and validated for simultaneous quantification of major TAM metabolites, such as N-desmethyltamoxifen (NDT), endoxifen (EDF) and 4-hydroxytamoxifen (HTF) to enable IVCI sample analysis. Satisfactory separation of E-/Z-isomers of endoxifen with peak resolution (Rs) of 1.9 was achieved. Accuracy and precision of the method was verified within the linear range of 0-50 ng/mL for NDT, 0-25 ng/mL for HTF and 0-25 ng/mL for EDF (E/Z isomers). Inhibitory potency (IC50, Ki and mode of inhibition) of known CYP inhibitors and Strobilanthes crispus extract was then evaluated using the validated method. In summary, the results demonstrated applicability of the developed LLE and validated LC-MS/MS method for in vitro screening of DDI and HDI involving TAM metabolism.
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