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  1. Human health risk assessment of selected pharmaceuticals in the five major river basins, China
    Dai C, Li S, Duan Y, Leong KH, Tu Y, Zhou L
    Sci Total Environ, 2021 Dec 20;801:149730.
    PMID: 34467938 DOI: 10.1016/j.scitotenv.2021.149730
    Pharmaceuticals in aquatic environment have raised wide attention in recent years due to their potential adverse effects and bioaccumulation in biota. China has been a major producer and consumer of pharmaceuticals, however, the potential human health risk of these chemicals is yet to be determined in China. In this study, we evaluated available exposure data for twenty pharmaceuticals in surface waters from Chinese five major river basins (the Yangtze, Haihe, Pearl, Songliao, and Yellow River Basins), and human health risk assessment was performed. Based on the concentration data and risk data, we conducted research on the source, cause, and control measures of the pharmaceuticals. The twenty pharmaceuticals were found to be ubiquitous in China with median concentrations between 0.09 and 304 ng/L. The estimated daily intake of pharmaceuticals from drinking water and eating fish was calculated. The intake via drinking water was significantly lower than that via eating fish. The risk quotients via water intake and fish consumption ranged from 0 to 17.2, with estrogen and sulfapyridine highest among the twenty pharmaceuticals. High risks of exposure were mainly in North China, including the Haihe and Songliao River Basins. This is the first analysis in Chinese major river basins that has filled the gaps in the research on the human health risks of pharmaceuticals. The results of the study provide basic information of pharmaceutical intake from drinking water and eating fish in China and provide insights into the risk management guidance of pharmaceuticals, and will facilitate the optimization of health advisories and policy making.
  2. Review on the contamination and remediation of polycyclic aromatic hydrocarbons (PAHs) in coastal soil and sediments
    Dai C, Han Y, Duan Y, Lai X, Fu R, Liu S, et al.
    Environ Res, 2022 Apr 01;205:112423.
    PMID: 34838568 DOI: 10.1016/j.envres.2021.112423
    The rapid economic and population growth in coastal areas is causing increasingly serious polycyclic aromatic hydrocarbons (PAHs) pollution in these regions. This review compared the PAHs pollution characteristics of different coastal areas, including industrial zones, commercial ports, touristic cities, aquacultural & agricultural areas, oil & gas exploitation areas and megacities. Currently there are various treatment methods to remediate soils and sediments contaminated with PAHs. However, it is necessary to provide a comprehensive overview of all the available remediation technologies up to date, so appropriate technologies can be selected to remediate PAHs pollution. In view of that, we analyzed the characteristics of the remediation mechanism, summarized the remediation methods for soil or sediments in coastal areas, which were physical repair, chemical oxidation, bioremediation and integrated approaches. Besides, this review also reported the development of new multi-functional green and sustainable systems, namely, micro-nano bubble (MNB), biochar, reversible surfactants and peracetic acid. While physical repair, expensive but efficient, was regarded as a suitable method for the PAHs remediation in coastal areas because of land shortage, integrated approaches would produce better results. The ultimate aim of the review was to ensure the successful restructuring of PAHs contaminated soil and sediments in coastal areas. Due to the environment heterogeneity, PAHs pollution in coastal areas remains as a daunting challenge. Therefore, new and suitable technologies are still needed to address the environmental issue.
  3. A novel mycelial pellet applied to remove polycyclic aromatic hydrocarbons: High adsorption performance & its mechanisms
    Zou JJ, Dai C, Hu J, Tong WK, Gao MT, Zhang Y, et al.
    Sci Total Environ, 2024 Apr 20;922:171201.
    PMID: 38417506 DOI: 10.1016/j.scitotenv.2024.171201
    Mycelial pellets formed by Penicillium thomii ZJJ were applied as efficient biosorbents for the removal of polycyclic aromatic hydrocarbons (PAHs), which are a type of ubiquitous harmful hydrophobic pollutants. The live mycelial pellets were able to remove 93.48 % of pyrene at a concentration of 100 mg/L within 48 h, demonstrating a maximum adsorption capacity of 285.63 mg/g. Meanwhile, the heat-killed one also achieved a removal rate of 65.01 %. Among the six typical PAHs (pyrene, phenanthrene, fluorene, anthracene, fluoranthene, benzo[a]pyrene), the mycelial pellets preferentially adsorbed the high molecular weight PAHs, which also have higher toxicity, resulting in higher removal efficiency. The experimental results showed that the biosorption of mycelial pellets was mainly a spontaneous physical adsorption process that occurred as a monolayer on a homogeneous surface, with mass transfer being the key rate-limiting step. The main adsorption sites on the surface of mycelia were carboxyl and N-containing groups. Extracellular polymeric substances (EPS) produced by mycelial pellets could enhance adsorption, and its coupling with dead mycelia could achieve basically the same removal effect to that of living one. It can be concluded that biosorption by mycelial pellets occurred due to the influence of electrostatic and hydrophobic interactions, consisting of five steps. Furthermore, the potential applicability of mycelial pellets has been investigated considering diverse factors. The mycelia showed high environmental tolerance, which could effectively remove pyrene across a wide range of pH and salt concentration. And pellets diameters and humic acid concentration had a significant effect on microbial adsorption effect. Based on a cost-effectiveness analysis, mycelium pellets were found to be a low-cost adsorbent. The research outcomes facilitate a thorough comprehension of the adsorption process of pyrene by mycelial pellets and their relevant applications, proposing a cost-effective method without potential environmental issues (heat-killed mycelial pellets plus EPS) to removal PAHs.
  4. Induction of intrinsic apoptosis in leukaemia stem cells and in vivo zebrafish model by betulonic acid isolated from Walsura pinnata Hassk (Meliaceae)
    Leong KH, Mahdzir MA, Din MF, Awang K, Tanaka Y, Kulkeaw K, et al.
    Phytomedicine, 2017 Mar 15;26:11-21.
    PMID: 28257660 DOI: 10.1016/j.phymed.2016.12.018
    BACKGROUND: Leukaemia stem cells (LSC) have been associated with disease relapse and chemotherapy resistance. Betulonic acid (BA), a pentacyclic lupane-type triterpenoid, was reported to exhibit cytotoxicity toward various cancer cells and to be capable of inducing intrinsic apoptosis in solid tumours. However, the in vitro and in vivo apoptotic effects of BA against LSC remain unknown.

    HYPOTHESIS/PURPOSE: We aimed to determine whether BA isolated from bark of Walsura pinnata Hassk (Meliaceae) has pro-apoptotic effects on LSC in in vitro and in vivo models.

    STUDY DESIGN/METHODS: The population of high purity LSC was isolated from the Kasumi-1 cell line using magnetic sorting and characterised by flow cytometry. Cell viability was assessed using the MTS assay to examine dose- and time-dependent effects. The colony formation assay was performed in MethoCult® H4435 enriched media. Apoptosis was analysed using Annexin-V and propidium iodide staining, mitochondrial transmembrane potential was studied using JC-1 staining, and expression of apoptosis related genes (BAX, Bcl-2 and survivin) was evaluated by real time-polymerase chain reaction (RT-PCR). Caspase 3/7 and 9 activities were monitored through Promega Caspase-Glo® over a period of 24h. The in vivo antileukaemia activity was evaluated using LSC xenotransplanted zebrafish, observed for DNA fragmentation from apoptosis by TUNEL assay.

    RESULTS: BA maintained its potency against the LSC population in comparison to parental Kasumi-1 cells (fold differences ≤ 1.94) over various treatment time points and significantly inhibited the formation of colonies by LSC. Apoptosis was triggered by BA through the upregulation of BAX and suppression of Bcl-2 and survivin genes with the loss of mitochondrial transmembrane potential, leading to the activation of caspase 9 followed by downstream caspase 3/7. BA was able to suppressed leukaemia formation and induced apoptosis in LSC xenotransplanted zebrafish.

    CONCLUSIONS: The results demonstrate that BA inhibited the proliferative and colonogenic properties of LSC. BA induced apoptosis in LSC through the mitochondria pathway and was effective in the in vivo zebrafish model. Therefore, BA could be a lead compound for further development into a chemotherapy agent against LSC.

  5. Fulltext Palladium nanoparticles anchored to anatase TiO2 for enhanced surface plasmon resonance-stimulated, visible-light-driven photocatalytic activity
    Leong KH, Chu HY, Ibrahim S, Saravanan P
    Beilstein J Nanotechnol, 2015;6:428-37.
    PMID: 25821683 DOI: 10.3762/bjnano.6.43
    Freely assembled palladium nanoparticles (Pd NPs) on titania (TiO2) nano photocatalysts were successfully synthesized through a photodeposition method using natural sunlight. This synthesized heterogeneous photocatalyst (Pd/TiO2) was characterized through field emission scanning electron microscopy (FESEM), high resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), BET surface area, UV-vis diffuse reflectance spectra (UV-DRS), Raman and photoluminescence (PL) analyses. The simple and smart synthesis anchored well the deposition with controlled Pd NPs size ranging between 17 and 29 nm onto the surface of TiO2. Thus, it gives the characteristic for Pd NPs to absorb light in the visible region obtained through localized surface plasmon resonance (LSPRs). Apparently, the photocatalytic activity of the prepared photocatalysts was evaluated by degrading the endocrine disrupting compound (EDC) amoxicillin (AMX) excited under an artificial visible light source. In the preliminary run, almost complete degradation (97.5%) was achieved in 5 h with 0.5 wt % Pd loading and the degradation followed pseudo-first-order kinetics. The reusability trend proved the photostability of the prepared photocatalysts. Hence, the study provides a new insight about the modification of TiO2 with noble metals in order to enhance the absorption in the visible-light region for superior photocatalytic performance.
  6. M/g-C3N4 (M=Ag, Au, and Pd) composite: synthesis via sunlight photodeposition and application towards the degradation of bisphenol A
    Hak CH, Sim LC, Leong KH, Lim PF, Chin YH, Saravanan P
    Environ Sci Pollut Res Int, 2018 Sep;25(25):25401-25412.
    PMID: 29951757 DOI: 10.1007/s11356-018-2632-8
    In this work, natural sunlight successfully induced the deposition of gold (Au), silver (Ag), and palladium (Pd) nanoparticles (NPs) with 17.10, 9.07, and 12.70 wt% onto the surface of graphitic carbon nitride (g-C3N4). The photocatalytic evaluation was carried out by adopting Bisphenol A (BPA) as a pollutant under natural sunlight irradiation. The presence of noble metals was confirmed by EDX, HRTEM, and XPS analysis. The deposition of Ag NPs (7.9 nm) resulted in the degradation rate which was 2.15-fold higher than pure g-C3N4 due to its relatively small particle size, contributing to superior charge separation efficiency. Au/g-C3N4 unveiled inferior photoactivity because the LSPR phenomenon provided two pathways for electron transfer between Au NPs and g-C3N4 further diminished the performance. The improved degradation lies crucially on the particle size and Schottky barrier formation at the interface of M/g-C3N4 (M=Au, Ag, and Pd) but not the visible light harvesting properties. The mechanism insight revealed the holes (h+) and superoxide radical (•O2-) radical actively involved in photocatalytic reaction for all composites.
  7. Amalgamation of N-graphene quantum dots with nanocubic like TiO2: an insight study of sunlight sensitive photocatalysis
    Lim PF, Leong KH, Sim LC, Abd Aziz A, Saravanan P
    Environ Sci Pollut Res Int, 2019 Feb;26(4):3455-3464.
    PMID: 30515688 DOI: 10.1007/s11356-018-3821-1
    In this work, a sunlight-sensitive photocatalyst of nanocubic-like titanium dioxide (TiO2) and N-doped graphene quantum dots (N-GQDs) is developed through a simple hydrothermal and physical mixing method. The successful amalgamation composite photocatalyst characteristics were comprehensively scrutinized through various physical and chemical analyses. A complete removal of bisphenol A (BPA) is attained by a synthesized composite after 30 min of sunlight irradiation as compared to pure TiO2. This clearly proved the unique contribution of N-GQDs that enhanced the ability of light harvesting especially under visible light and near-infrared region. This superior characteristic enables it to maximize the absorbance in the entire solar spectrum. However, the increase of N-GQDs weight percentage has created massive oxygen vacancies that suppress the generation of active radicals. This resulted in a longer duration for a complete removal of BPA as compared to lower weight percentage of N-GQDs. Hence, this finding can offer a new insight in developing effective sunlight-sensitive photocatalysts for various complex organic pollutants degradation.
  8. Fulltext Sugarcane juice derived carbon dot-graphitic carbon nitride composites for bisphenol A degradation under sunlight irradiation
    Sim LC, Wong JL, Hak CH, Tai JY, Leong KH, Saravanan P
    Beilstein J Nanotechnol, 2018;9:353-363.
    PMID: 29515949 DOI: 10.3762/bjnano.9.35
    Carbon dots (CDs) and graphitic carbon nitride (g-C3N4) composites (CD/g-C3N4) were successfully synthesized by a hydrothermal method using urea and sugarcane juice as starting materials. The chemical composition, morphological structure and optical properties of the composites and CDs were characterized using various spectroscopic techniques as well as transmission electron microscopy. X-ray photoelectron spectroscopy (XPS) results revealed new signals for carbonyl and carboxyl groups originating from the CDs in CD/g-C3N4 composites while X-ray diffraction (XRD) results showed distortion of the host matrix after incorporating CDs into g-C3N4. Both analyses signified the interaction between g-C3N4 and CDs. The photoluminescence (PL) analysis indicated that the presence of too many CDs will create trap states at the CD/g-C3N4 interface, decelerating the electron (e-) transport. However, the CD/g-C3N4(0.5) composite with the highest coverage of CDs still achieved the best bisphenol A (BPA) degradation rate at 3.87 times higher than that of g-C3N4. Hence, the charge separation efficiency should not be one of the main factors responsible for the enhancement of the photocatalytic activity of CD/g-C3N4. Instead, the light absorption capability was the dominant factor since the photoreactivity correlated well with the ultraviolet-visible diffuse reflectance spectra (UV-vis DRS) results. Although the CDs did not display upconversion photoluminescence (UCPL) properties, the π-conjugated CDs served as a photosensitizer (like organic dyes) to sensitize g-C3N4 and injected electrons to the conduction band (CB) of g-C3N4, resulting in the extended absorption spectrum from the visible to the near-infrared (NIR) region. This extended spectral absorption allows for the generation of more electrons for the enhancement of BPA degradation. It was determined that the reactive radical species responsible for the photocatalytic activity were the superoxide anion radical (O2•-) and holes (h+) after performing multiple scavenging tests.
  9. Fulltext HIV/Human herpesvirus co-infections: Impact on tryptophan-kynurenine pathway and immune reconstitution
    Yap SH, Abdullah NK, McStea M, Takayama K, Chong ML, Crisci E, et al.
    PLoS One, 2017;12(10):e0186000.
    PMID: 29016635 DOI: 10.1371/journal.pone.0186000
    BACKGROUND: Co-infections with human herpesvirus (HHV) have been associated with residual chronic inflammation in antiretroviral (ART)-treated human immunodeficiency virus (HIV)-infected individuals. However, the role of HHV in modulating the tryptophan-kynurenine pathway and clinical outcomes in HIV-infected individuals is poorly understood. Thus, we investigated the seroprevalence of four common HHVs among treated HIV-infected participants and their impact on kynurenine/tryptophan (K/T) ratio and long-term CD4 T-cell recovery in HIV/HHV co-infected participants.

    METHOD: In this cross-sectional study, HIV-infected participants receiving suppressive ART for a minimum of 12 months were recruited from the University Malaya Medical Centre (UMMC), Malaysia. Stored plasma was analyzed for CMV, VZV, HSV-1 and HSV-2 IgG antibody levels, immune activation markers (interleukin-6, interferon-γ, neopterin and sCD14), kynurenine and tryptophan concentrations. The influence of the number of HHV co-infection and K/T ratio on CD4 T-cell recovery was assessed using multivariate Poisson regression.

    RESULTS: A total of 232 HIV-infected participants were recruited and all participants were seropositive for at least one HHV; 96.1% with CMV, 86.6% with VZV, 70.7% with HSV-1 and 53.9% with HSV-2. K/T ratio had a significant positive correlation with CMV (rho = 0.205, p = 0.002), VZV (rho = 0.173, p = 0.009) and a tendency with HSV-2 (rho = 0.120, p = 0.070), with CMV antibody titer demonstrating the strongest modulating effect on K/T ratio among the four HHVs assessed in SOM analysis. In multivariate analysis, higher K/T ratio (p = 0.03) and increasing number of HHV co-infections (p<0.001) were independently associated with poorer CD4 T-cell recovery following 12 months of ART initiation.

    CONCLUSION: Multiple HHV co-infections are common among ART-treated HIV-infected participants in the developing country setting and associated with persistent immune activation and poorer CD4 T-cell recovery.

  10. Fulltext A Precise Prediction Method for the Properties of API-Containing Tablets Based on Data from Placebo Tablets
    Hayashi Y, Shirotori K, Kosugi A, Kumada S, Leong KH, Okada K, et al.
    Pharmaceutics, 2020 Jun 28;12(7).
    PMID: 32605318 DOI: 10.3390/pharmaceutics12070601
    We previously reported a novel method for the precise prediction of tablet properties (e.g., tensile strength (TS)) using a small number of experimental data. The key technique of this method is to compensate for the lack of experimental data by using data of placebo tablets collected in a database. This study provides further technical knowledge to discuss the usefulness of this prediction method. Placebo tablets consisting of microcrystalline cellulose, lactose, and cornstarch were prepared using the design of an experimental method, and their TS and disintegration time (DT) were measured. The response surfaces representing the relationship between the formulation and the tablet properties were then created. This study investigated tablets containing four different active pharmaceutical ingredients (APIs) with a drug load ranging from 20-60%. Overall, the TS of API-containing tablets could be precisely predicted by this method, while the prediction accuracy of the DT was much lower than that of the TS. These results suggested that the mode of action of APIs on the DT was more complicated than that on the TS. Our prediction method could be valuable for the development of tablet formulations.
  11. Fulltext A Time-Domain NMR Study of the State of Water in Wet Granules with Different Fillers and Its Contribution to the Wet Granulation Process and to the Characteristics of Granules
    Ito T, Okada K, Leong KH, Hirai D, Hayashi Y, Kumada S, et al.
    Chem Pharm Bull (Tokyo), 2019;67(3):271-276.
    PMID: 30828004 DOI: 10.1248/cpb.c18-00888
    The different states of water incorporated in wet granules were studied by a low-field benchtop 1H-NMR time-domain NMR (TD-NMR) instrument. Wet granules consisting different fillers [cornstarch (CS), microcrystalline cellulose (MCC), and D-mannitol (MAN)] with different water contents were prepared using a high-speed granulator, and then their spin-spin relaxation time (T2) was measured using the NMR relaxation technique. The experimental T2 relaxation curves were analyzed by the two-component curve fitting, and then the individual T2 relaxation behaviors of solid and water in wet granules were identified. According to the observed T2 values, it was confirmed that the molecular mobility of water in CS and MCC granules was more restricted than that in the MAN granule. The state of water appeared to be associated with the drying efficiency and moisture absorption capacity of wet granules. Thus, it was confirmed that the state of water significantly affected the wet granulation process and the characteristics of the resultant granules. In the final phase of this study, the effects of binders on the molecular mobility of water in granulation fluids and wet granules were examined. The state of water in granulation fluids was substantially changed by changing the binders. The difference was still detected in wet granules prepared by addition of these fluids to the fillers. In conclusion, TD-NMR can offer valuable knowledge on wet granulation from the viewpoint of molecular mobility of water.
  12. Effect of the molecular mobility of water adsorbed by disintegrants on storage-induced hydrolytic degradation of acetylsalicylic acid incorporated into tablets under humid conditions
    Ougi K, Okada K, Leong KH, Hayashi Y, Kumada S, Onuki Y
    Eur J Pharm Sci, 2020 Nov 01;154:105502.
    PMID: 32750421 DOI: 10.1016/j.ejps.2020.105502
    The purpose of this study was to investigate the effect of molecular mobility of water adsorbed by disintegrants on the hydrolytic degradation of active pharmaceutical ingredients (APIs). Fourteen different disintegrants were tested. First, powdered disintegrants were stored at conditions of 40 °C/75% relative humidity ("humid conditions") and their T2 relaxation times were measured by time-domain nuclear magnetic resonance for examination of the molecular mobility of water adsorbed by the disintegrant. From the observed T2 values, the water molecular mobility was fully characterized. In particular, the molecular mobility of water adsorbed by crospovidones was much higher than the molecular mobility of water adsorbed by the other test disintegrants because of longer T2 values. The next study examined the hydrolytic degradation of acetylsalicylic acid (ASA), a model moisture-sensitive API, stored under humid conditions. Physical mixtures of ASA and disintegrants or their model tablets were used as test samples, and they were stored for 7 d. The disintegrants contained in the samples clearly affected the ASA degradation: the most significant ASA degradation was observed for the crospovidone-containing samples. Finally, we analyzed the effect of the molecular mobility of water adsorbed by disintegrants on the ASA degradation by the least absolute shrinkage and selection operator (Lasso) regression techniques. As in the T2 experiment, various properties of disintegrants (i.e., water content, pH, and water activity) were used in this experiment as the explanatory variables. From the Lasso analysis, we successfully showed that the higher molecular mobility of water adsorbed by disintegrants significantly enhanced ASA degradation. These findings provide profound insights into the chemical stability of moisture-sensitive APIs in tablets.
  13. Characterization of Powder- and Tablet Properties of Different Direct Compaction Grades of Mannitol Using a Kohonen Self-organizing Map and a Lasso Regression Model
    Kosugi A, Leong KH, Tsuji H, Hayashi Y, Kumada S, Okada K, et al.
    J Pharm Sci, 2020 Aug;109(8):2585-2593.
    PMID: 32473211 DOI: 10.1016/j.xphs.2020.05.010
    The purpose of this study was to accumulate enhanced technical knowledge about the powder properties of direct compaction grades of mannitol that could lead to new tablet formulations. Fifteen different commercial direct compaction grades of mannitol were tested. Ten different powder properties representing flowability, particle size, specific surface area and manufacturing properties were measured. In addition, model tablets of each mannitol grade were prepared, and their disintegration time, friability, and tensile strength were measured. The data were analyzed by principle component analysis and a Kohonen self-organizing map to find correlations between powder properties. Self-organizing map clustering successfully classified the test grades into 5 distinct clusters having different powder properties. Each cluster was well characterized by statistical profiling. Subsequently, the contribution of the powder properties to the tablet properties was investigated by a least absolute shrinkage- and selection operator (Lasso) regression model. Mannitol grades with a larger particle size (D90) were prone to produce tablets with longer disintegration time, while a larger specific surface area of the particles was positively associated with tablets with higher mechanical strength. Our findings provide valuable information for the design of tablet formulations.
  14. Fulltext Effects of Manufacturing Process Variables on the Tablet Weight Variation of Mini-tablets Clarified by a Definitive Screening Design
    Usuda S, Masukawa N, Leong KH, Okada K, Onuki Y
    Chem Pharm Bull (Tokyo), 2021;69(9):896-904.
    PMID: 34470954 DOI: 10.1248/cpb.c21-00427
    This study investigated the effect of manufacturing process variables of mini-tablets, in particular, the effect of process variables concerning fluidized bed granulation on tablet weight variation. Test granules were produced with different granulation conditions according to a definitive screening design (DSD). The five evaluated factors assigned to DSD were: the grinding speed of the sample mill at the grinding process of the active pharmaceutical ingredient (X1), microcrystalline cellulose content in granules (X2), inlet air temperature (X3), binder concentration (X4) and the spray speed of the binder solution (X5) at the granulation process. First, the relationships between the evaluated factors and the granule properties were investigated. As a result of the DSD analysis, the mode of action of granulation parameters on the granule properties was fully characterized. Subsequently, the variation in tablet weight was examined. In addition to mini-tablets (3 mm diameter), this experiment assessed regular tablets (8 mm diameter). From the results for regular tablets, the variation in tablet weight was affected by the flowability of granules. By contrast, regarding the mini-tablets, no significant effect on the variation of tablet weight was found from the evaluated factors. From this result, this study further focused on other important factors besides the granulation process, and then the effect of the die-hole position of the multiple-tip tooling on tablet weight variation was proven to be significant. Our findings provide a better understanding of manufacturing mini-tablets.
  15. Characterization of the Salt and Free Base of Active Pharmaceutical Ingredients Based on NMR Relaxometry Measured by Time Domain NMR
    Chiba Y, Okada K, Hayashi Y, Leong KH, Kumada S, Onuki Y
    Chem Pharm Bull (Tokyo), 2022;70(2):162-168.
    PMID: 35110437 DOI: 10.1248/cpb.c21-00975
    NMR relaxometry measurement by time domain NMR (TD-NMR) is a promising technique for characterizing the properties of active pharmaceutical ingredients (APIs). This study is dedicated to identifying the salt and free base of APIs by NMR relaxometry measured by the TD-NMR technique. Procaine (PC) and tetracaine (TC) were selected as model APIs to be tested. By using conventional methods including powder X-ray diffraction and differential scanning calorimetry, this study first confirmed that the salt and free base of the tested APIs differ from each other in their crystalline form. Subsequently, measurements of T1 and T2 relaxation were performed on the tested APIs using TD-NMR. The results demonstrated that these NMR relaxometry measurements have sufficient capacity to distinguish the difference between the free base and salt of the tested APIs. Furthermore, quantification of the composition of the binary powder blends consisting of salt and free bases was conducted by analyzing the acquired T1 and T2 relaxation curves. The analysis of the T1 relaxation curves provided a partly acceptable estimation: a good estimation of the composition was observed from PC powders, whereas for TC powders the estimation accuracy changed with the free base content in the binary blends. For the analysis on T2 relaxation curves, a precise estimation of the composition was observed from all the samples. From these findings, the NMR relaxometry measurement by TD-NMR, in particular the T2 relaxation measurement, is effective for evaluating the properties of APIs having different crystalline forms.
  16. Fulltext Continuous Monitoring of the Hydration Behavior of Hydrophilic Matrix Tablets Using Time-Domain NMR
    Tsuji T, Ono T, Taguchi H, Leong KH, Hayashi Y, Kumada S, et al.
    Chem Pharm Bull (Tokyo), 2023;71(7):576-583.
    PMID: 37394606 DOI: 10.1248/cpb.c23-00214
    Time-domain NMR (TD-NMR) was used for continuous monitoring of the hydration behavior of hydrophilic matrix tablets. The model matrix tablets comprised high molecular weight polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG). The model tablets were immersed in water. Their T2 relaxation curves were acquired by TD-NMR with solid-echo sequence. A curve-fitting analysis was conducted on the acquired T2 relaxation curves to identify the NMR signals corresponding to the nongelated core remaining in the samples. The amount of nongelated core was estimated from the NMR signal intensity. The estimated values were consistent with the experiment measurement values. Next, the model tablets immersed in water were monitored continuously using TD-NMR. The difference in hydration behaviors of the HPMC and PEO matrix tablets was then characterized fully. The nongelated core of the HPMC matrix tablets disappeared more slowly than that of the PEO matrix tablets. The behavior of HPMC was significantly affected by the PEG content in the tablets. It is suggested that the TD-NMR method has potential to be utilized to evaluate the gel layer properties, upon replacement of the immersion medium: purified (nondeuterated) water is replaced with heavy (deuterated) water. Finally, drug-containing matrix tablets were tested. Diltiazem hydrochloride (a highly water-soluble drug) was employed for this experiment. Reasonable in vitro drug dissolution profiles, which were in accordance with the results from TD-NMR experiments, were observed. We concluded that TD-NMR is a powerful tool to evaluate the hydration properties of hydrophilic matrix tablets.
  17. Hip fracture incidence rates in Singapore 1991-1998
    Koh LK, Saw SM, Lee JJ, Leong KH, Lee J, National Working Committee on Osteoporosis
    Osteoporos Int, 2001;12(4):311-8.
    PMID: 11420781
    In this population-based study, we determined the incidence rates of hip fracture among Singapore residents aged 50 years and above. Information was obtained from a centralized database system which captured admissions with the primary diagnosis of a closed hip fracture (ICD-9 codes 820, 820.0, 820.2 and 820.8, n = 12,927) from all health care establishments in the country from 1991 to 1998 inclusive. After removing duplicates, hospital transfers, readmissions and non-acute care admissions, the total number of hip fractures was 9406. Based on the national population census 1990 (n = 464,100) and yearly population estimates, the age-adjusted hip fracture rates for 1991-1998 (per 100,000) were 152 in men and 402 in women. This was 1.5 and over 5 times higher than corresponding rates in the 1960s. From 1991 to 1998, these hip fracture rates tended to increase by 0.7% annually in men and by 1.2% annually in women. Among the three major racial groups, in men, the Chinese had significantly higher age-adjusted hip fracture rates (per 100,000): 168 (95% confidence interval (CI) 158-178) compared with 128 (95% CI 105-152) for Indians and 71 (95% CI 54-88) for Malays. A similar pattern occurred in women: 410 (95% CI 395-425), for Chinese compared with 361 (95% CI 290-432) for Indians and 264 (95% CI 225-303) for Malays. Since the 1960s, the main increases in hip fracture rates have been seen in the Chinese and Malays, with the rates in Indians appearing to decrease. Hip fracture incidence rates in Singapore have risen rapidly over the past 30-40 years, particularly in women, and are now among the highest in Asia. Significant racial differences in hip fracture rates occur within the same community. Time trends in hip fracture rates differed between races.
  18. In vitro inhibitory mechanisms and molecular docking of 1'-S-1'-acetoxychavicol acetate on human cytochrome P450 enzymes
    Haque AKMM, Leong KH, Lo YL, Awang K, Nagoor NH
    Phytomedicine, 2017 Jul 15;31:1-9.
    PMID: 28606510 DOI: 10.1016/j.phymed.2017.05.002
    BACKGROUND: The compound, 1'-S-1'-acetoxychavicol acetate (ACA), isolated from the rhizomes of a Malaysian ethno-medicinal plant, Alpinia conchigera Griff. (Zingiberaceae), was previously shown to have potential in vivo antitumour activities. In the development of a new drug entity, potential interactions of the compound with the cytochrome P450 superfamily metabolizing enzymes need to be ascertain.

    PURPOSE: The concomitant use of therapeutic drugs may cause potential drug-drug interactions by decreasing or increasing plasma levels of the administered drugs, leading to a suboptimal clinical efficacy or a higher risk of toxicity. Thus, evaluating the inhibitory potential of a new chemical entity, and to clarify the mechanism of inhibition and kinetics in the various CYP enzymes is an important step to predict drug-drug interactions.

    STUDY DESIGN: This study was designed to assess the potential inhibitory effects of Alpinia conchigera Griff. rhizomes extract and its active constituent, ACA, on nine c-DNA expressed human cytochrome P450s (CYPs) enzymes using fluorescent CYP inhibition assay.

    METHODS/RESULTS: The half maximal inhibitory concentration (IC50) of Alpinia conchigera Griff. rhizomes extract and ACA was determined for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. A. conchigera extract only moderately inhibits on CYP3A4 (IC50 = 6.76 ± 1.88µg/ml) whereas ACA moderately inhibits the activities of CYP1A2 (IC50 = 4.50 ± 0.10µM), CYP2D6 (IC50 = 7.50 ± 0.17µM) and CYP3A4 (IC50 = 9.50 ± 0.57µM) while other isoenzymes are weakly inhibited. In addition, mechanism-based inhibition studies reveal that CYP1A2 and CYP3A4 exhibited non-mechanism based inhibition whereas CYP2D6 showed mechanism-based inhibition. Lineweaver-Burk plots depict that ACA competitively inhibited both CYP1A2 and CYP3A4, with a Ki values of 2.36 ± 0.03 µM and 5.55 ± 0.06µM, respectively, and mixed inhibition towards CYP2D6 with a Ki value of 4.50 ± 0.08µM. Further, molecular docking studies show that ACA is bound to a few key amino acid residues in the active sites of CYP1A2 and CYP3A4, while one amino residue of CYP2D6 through predominantly Pi-Pi interactions.

    CONCLUSION: Overall, ACA may demonstrate drug-drug interactions when co-administered with other therapeutic drugs that are metabolized by CYP1A2, CYP2D6 or CYP3A4 enzymes. Further in vivo studies, however, are needed to evaluate the clinical significance of these interactions.

  19. Fulltext Induction of apoptosis in melanoma A375 cells by a chloroform fraction of Centratherum anthelminticum (L.) seeds involves NF-kappaB, p53 and Bcl-2-controlled mitochondrial signaling pathways
    Looi CY, Moharram B, Paydar M, Wong YL, Leong KH, Mohamad K, et al.
    BMC Complement Altern Med, 2013;13:166.
    PMID: 23837445 DOI: 10.1186/1472-6882-13-166
    Centratherum anthelminticum (L.) Kuntze (scientific synonyms: Vernonia anthelmintica; black cumin) is one of the ingredients of an Ayurvedic preparation, called "Kayakalp", commonly applied to treat skin disorders in India and Southeast Asia. Despite its well known anti-inflammatory property on skin diseases, the anti-cancer effect of C. anthelminticum seeds on skin cancer is less documented. The present study aims to investigate the anti-cancer effect of Centratherum anthelminticum (L.) seeds chloroform fraction (CACF) on human melanoma cells and to elucidate the molecular mechanism involved.
  20. Fulltext Induction of apoptosis in human breast cancer cells via caspase pathway by vernodalin isolated from Centratherum anthelminticum (L.) seeds
    Looi CY, Arya A, Cheah FK, Muharram B, Leong KH, Mohamad K, et al.
    PLoS One, 2013;8(2):e56643.
    PMID: 23437193 DOI: 10.1371/journal.pone.0056643
    Centratherum anthelminticum (L.) seeds (CA) is a well known medicinal herb in Indian sub-continent. We recently reported anti-oxidant property of chloroform fraction of Centratherum anthelminticum (L.) seeds (CACF) by inhibiting tumor necrosis factor-α (TNF-α)-induced growth of human breast cancer cells. However, the active compounds in CACF have not been investigated previously.
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