Publications by authors named "Paul Chi-Lui Ho"

31 Publications

3D printing of four-in-one oral polypill with multiple release profiles for personalized delivery of caffeine and vitamin B analogues.

Int J Pharm 2021 Apr 4;598:120360. Epub 2021 Feb 4.

Craft Health Pte Ltd., 21 Bukit Batok Crescent, #10-75, WCEGA Tower, Singapore 658065, Singapore; Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address:

Personalized supplementation has found recent momentum with an estimated global market size of USD 1.6 billion in 2019 and an expected CAGR of 8.5% between 2020 and 2028. Alongside this rising trend, a simple, accurate, inexpensive and flexible method to produce personalized dosage forms of a wide variety of supplements would be beneficial to both the industry players and individual consumers. Here, we present a 3D printing method to fabricate a four-in-one oral polypill with multiple release profiles for personalized delivery of caffeine and vitamin B analogues. The 3D printable formulations were fabricated and optimized from existing FDA GRAS excipients based on their viscosity, shear thinning properties, recovery of paste and mechanical strength. In the polypill, vitamin B analogues and caffeine were used as the model dietary ingredients. We performed a standard 2 stage USP in vitro dissolution test of the polypill, and demonstrated that vitamin B1, B3 and B6 could be immediately released within 30 min, while caffeine could be slowly released over a period of 4 h. This demonstrated the ability dietary supplement containing different ingredients with varying release profiles, all within a single polypill. Throughout the formulation and 3D printing process, there were no detectable changes to the dietary ingredients nor any interactions with the excipients. This method serves as an intriguing complement to traditional manufacturing of oral tablets, especially when flexibility in design, dose, volume and release profiles of each dietary ingredient is required, as exemplified in personalized supplementation.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120360DOI Listing
April 2021

A 3D printed human upper respiratory tract model for particulate deposition profiling.

Int J Pharm 2021 Mar 1;597:120307. Epub 2021 Feb 1.

School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Pharmacy and Bank Building A15, NSW 2006, Australia. Electronic address:

Pulmonary route is the main route of drug delivery for patients with asthma and chronic obstructive pulmonary diseases, offering several advantages over the oral route. Determining the amount of drug deposited onto various parts of the respiratory tract allows for a good correlation to clinical efficacy of inhalation drug devices. However, current in vitro cascade impactors measure only the aerodynamic particle size distribution, which does not truly represent the in vivo deposition pattern in human respiratory tract. In this study, a human upper respiratory tract model was fabricated using a 3D printer and subsequently characterized for its dimensional accuracy, surface finishing and air leaking. The effects of using a spacer and/or various airflow rates were also investigated. To assess this in vitro model, the deposition pattern of a model drug, namely, salbutamol sulphate, was tested. The resultant deposition pattern of salbutamol sulphate from a metered dose inhaler at 15 L per minute with the spacer, showed no significant difference from that of a published radiological in vivo study performed in adult humans. In addition, it was also found that the deposition pattern of salbutamol at 35 L per minute was comparable to the results of another published study in human. This in vitro model, showing reasonable in vitro-in vivo correlation, may provide opportunities for personalized medicine in special populations or disease states.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120307DOI Listing
March 2021

Editorial: Advances in Drug Formulation.

Front Pharmacol 2020 27;11:608771. Epub 2020 Nov 27.

Department of Chemistry, University of Peradeniya, Peradeniya, Sri Lanka.

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http://dx.doi.org/10.3389/fphar.2020.608771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775671PMC
November 2020

Metabolic Profiling of Female Tg2576 Mouse Brains Provides Novel Evidence Supporting Intranasal Low-Dose Pioglitazone for Long-Term Treatment at an Early Stage of Alzheimer's Disease.

Biomedicines 2020 Dec 9;8(12). Epub 2020 Dec 9.

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.

Accumulating evidence suggests that disruptions in brain energy metabolism may be a key player in the pathogenesis of Alzheimer's disease (AD). Pioglitazone (PIO) has been found to exert beneficial effects on metabolic dysfunction in many AD preclinical studies. However, limited success in clinical trials remains an obstacle to its development for the treatment of AD. PIO's poor brain penetration was often cited as a contributing factor to the lack of clinical benefit. In this study, we prepared PIO-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles and administered them as suspended nanoparticles via nebulization. Preliminary investigation of drug distribution to the brain revealed comparatively reduced systemic exposure after administering PIO nanoparticles via the intranasal route. In vitro, extracellular flux analysis showed significantly raised spare respiratory capacity when cells were treated with low-dose PIO nanoparticles. Tg2576 transgenic mice treated with low-dose PIO nanoparticles over four months exhibited an overall trend of reduced hyperactivity in open field tests but did not show any visible effect on alternation rates in the Y-maze task. Subsequent H NMR-based metabolic profiling of their plasma and different brain regions revealed differences in metabolic profiles in the cerebellum, cortex, and hippocampus of Tg2576 mice after long-term PIO treatment, but not in their midbrain and plasma. In particular, the specificity of PIO's treatment effects on perturbed amino acid metabolism was observed in the cortex of transgenic mice with increases in alanine and N-acetylaspartate levels, supporting the notion that PIO treatment exerts beneficial effects on impaired energy metabolism associated with AD. In conclusion, inhalation exposure to PIO nanoparticles presents an exciting opportunity that this drug could be administered intranasally at a much lower dose while achieving a sufficient level in the brain to elicit metabolic benefits at an early stage of AD but with reduced systemic exposure.
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http://dx.doi.org/10.3390/biomedicines8120589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764407PMC
December 2020

and Comparison of Curcumin-Encapsulated Chitosan-Coated Poly(lactic--glycolic acid) Nanoparticles and Curcumin/Hydroxypropyl-β-Cyclodextrin Inclusion Complexes Administered Intranasally as Therapeutic Strategies for Alzheimer's Disease.

Mol Pharm 2020 11 21;17(11):4256-4269. Epub 2020 Oct 21.

NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore 117583, Singapore.

Curcumin (CUR) has antioxidant and anti-inflammatory effects that are beneficial to Alzheimer's disease (AD). However, the poor solubility and high instability of CUR compromise its application greatly. In this study, CUR-encapsulated chitosan-coated poly (lactic--glycolic acid) nanoparticles (CUR-CS-PLGA-NPs) and hydroxypropyl-β-cyclodextrin-encapsulated CUR complexes (CUR/HP-β-CD inclusion complexes) were developed and compared through intranasal administration. studies indicated that CUR in CUR/HP-β-CD inclusion complexes was stable under physiological conditions over 72 h with 95.41 ± 0.01% remaining, which was higher than 49.66 ± 3.91% remaining in CUR-CS-PLGA-NPs. Meanwhile, CUR/HP-β-CD inclusion complexes showed a higher cellular uptake level of CUR than CUR-CS-PLGA-NPs in SH-SY5Y cells. Both formulations could reduce CUR's cellular cytotoxicity and showed a comparable antioxidant effect. Both formulations displayed the anti-inflammatory effect at 20 μM CUR in BV-2 cells, which decreased TNF-α and IL-6 levels to approximately 70 and 40%, respectively, when compared to the positive control, respectively. pharmacokinetic studies indicated that after intranasal administration, the AUC values of CUR in the plasma and brain of the CUR/HP-β-CD inclusion complex group were 2.57-fold and 1.12-fold higher than those in the CUR-CS-PLGA-NP group at the same dose of 2 mg/kg, respectively. In conclusion, CUR/HP-β-CD inclusion complexes displayed better properties than CUR-CS-PLGA-NPs as a carrier for intranasal delivery of CUR for application in AD.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00675DOI Listing
November 2020

Poly (ethylene glycol)-block-poly (D, L-lactide) (PEG-PLA) micelles for brain delivery of baicalein through nasal route for potential treatment of neurodegenerative diseases due to oxidative stress and inflammation: An in vitro and in vivo study.

Int J Pharm 2020 Dec 15;591:119981. Epub 2020 Oct 15.

NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117583, Singapore; Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore. Electronic address:

The application of baicalein (BE) in central nervous system (CNS) neurodegenerative diseases is hampered by its poor solubility and low oral bioavailability despite its neuroprotective effects. In this study, BE was encapsulated into poly (ethylene glycol)-block-poly (D, L-lactide) micelles (BE-MC) and administrated through nasal inhalation to enhance its brain distribution. BE-MC showed comparable in-vitro antioxidant activity to BE solution. Cytotoxicity study illustrated BE-MC could reduce BE's toxicity in SH-SY5Y cells and BV-2 cells. BE solution at concentration higher than 5 µM caused significant BV-2 cells' death after stimulation of LPS while BE-MC were non-toxic to cells at concentrations up to 50 µM. BE solution at 5 µM had no anti-inflammatory effects in BV-2 cells while BE-MC could reduce the inflammatory factor TNF-α at 5 µM and IL-6 at 20 µM significantly. Pharmacokinetic studies in C57BL/6 mice showed the absolute AUC values of BE in plasma and brain of BE-MC through nasal inhalation group were 5.09-fold and 1.50-fold higher than that of BE coarse powder through oral administration group at the same dose. Thus, our study indicated BE-MC administered nasally could be useful for treatment of CNS neurodegenerative diseases due to oxidative stress and inflammation.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119981DOI Listing
December 2020

High resolution photopolymer for 3D printing of personalised microneedle for transdermal delivery of anti-wrinkle small peptide.

J Control Release 2021 Jan 15;329:907-918. Epub 2020 Oct 15.

School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Pharmacy and Bank Building A15, Science Road, NSW 2006, Australia. Electronic address:

Acetyl-hexapeptide 3 (AHP-3) has good efficacy and safety profile as an anti-wrinkle small peptide. However, its skin permeation is poor due to its hydrophilicity and large molecular weight. 3D printing of personalised microneedles (MN), that contour to the skin surface, offers an attractive alternative for delivery for AHP-3. However, commercially available photocurable resin for 3D printing are not suitable for fabrication of drug loaded delivery systems. In this study, two liquid monomers, namely, polyethylene glycol diacrylate (PEGDA) and vinyl pyrrolidone (VP), were investigated at various proportions, for critical parameters such as mechanical strength of final polymer, rate of polymerisation, rate of swelling of final polymer, 3D printing resolution and safety profile of final polymer. The optimal resin, based on the above parameters, was that of ratio 7 VP: 3 PEGDA in weight. Drug loading into the optimal resin demonstrated that AHP-3 remained stable throughout the fabrication process and there was no effect on the physical properties of final polymer. Using a 3D scanned face model, a personalised MN patch was designed using computer aided design (CAD) software and subsequently fabricated using a Digital Light Processing (DLP) 3D printer, with the optimal resin. In vitro characterisation of fabricated MN patch demonstrated the ability to penetrate human cadaver dermatomed skin and the MN remained intact after compression. The final polymer also had minimal cytotoxicity to human dermal fibroblast. Therefore, personalised MN patch fabricated using the photopolymer can potentially be a novel approach to augment transdermal delivery of AHP-3 for effective wrinkle management.
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http://dx.doi.org/10.1016/j.jconrel.2020.10.021DOI Listing
January 2021

Application for proteomics analysis technology in studying animal-derived traditional Chinese medicine: A review.

J Pharm Biomed Anal 2020 Nov 13;191:113609. Epub 2020 Sep 13.

Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address:

Different therapeutically active ingredients, from plants, animals, and mineral sources, are prescribed as traditional Chinese medicines (TCM). TCMs, from animal sources, are rich in proteins and peptides. Different advanced proteomics technologies, such as two-dimensional gel electrophoresis (2-DE), multi-dimensional liquid chromatography (MDLC), matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS), and isobaric tags for relative and absolute quantitation (iTRAQ), have been applied to analyze TCMs, from animal sources. This paper reviews the common proteomic techniques for analyzing animal - derived TCMs. Various scientific studies have reported the application of proteomics for locating drug targets, identifying active components, and elucidating the mechanisms of action of animal - derived TCMs. However, these researches are still at the preliminary stage. This review has also discussed the existing challenges and future directions in this field of research.
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http://dx.doi.org/10.1016/j.jpba.2020.113609DOI Listing
November 2020

Geometrical optimisation of a personalised microneedle eye patch for transdermal delivery of anti-wrinkle small peptide.

Biofabrication 2020 04 9;12(3):035003. Epub 2020 Apr 9.

Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.

Acetyl-hexapeptide-3 (AHP-3) is a small peptide with good anti-wrinkle efficacy and safety profile. However, due to its hydrophilicity and high molecular weight, its skin permeation is generally poor. An innovative microneedle (MN) patch such as the curved, flexible or personalised MN patch is a viable avenue to deliver AHP-3. However, the well-researched geometrical relationship of MN on a flat MN patch cannot be assumed for these novel MN patches due to a complex mix of axial and shear forces. In this study, 3D printing was used for the fabrication of various MN patches with different MN geometries and curvatures. Both mechanical strength and skin penetration efficiency were used to determine the optimal MN geometry. The optimal MN geometry was then applied to the fabrication of a personalized MN patch (PMNP) for anti-wrinkle therapy, via 3D printing. In all, the general principles of MN geometrical effects on mechanical strength and skin penetration efficiency for a curved and a flat MN patch were similar. A MN height of 800 μm, tip diameter of 100 μm, interspacing of 800 μm and base diameter of 400 μm was observed to be the optimal MN geometry across all curvatures. In vitro skin permeation study demonstrated enhanced transdermal delivery of AHP-3 using the fabricated PMNP. Therefore, PMNP with optimized MN geometry can potentially be a novel approach to augment transdermal delivery of AHP-3 for effective wrinkle management.
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http://dx.doi.org/10.1088/1758-5090/ab6d37DOI Listing
April 2020

Reverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1 Mice, a Model for Alzheimer's Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist.

Mol Neurobiol 2019 Nov 23;56(11):7267-7283. Epub 2019 Apr 23.

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Republic of Singapore.

Identification of molecular mechanisms underlying early-stage Alzheimer's disease (AD) is important for the development of new therapies against and diagnosis of AD. In this study, gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics approach was employed to investigate the metabolic profiles in plasma and brain tissues harvested from 5-month-old APP/PS1 transgenic mice and their wildtype counterparts. Since different brain regions were expected to have their own distinct metabolic signals, four different brain regions, namely cortex, hippocampus, midbrain and cerebellum tissues, were dissected and had their metabolic profiles studied separately. Biochemical assays were also performed on plasma and brain cortex tissue of transgenic mice and wildtype mice, with a focus on mitochondrial health. Amyloid precursor protein and amyloid-β levels in plasma, brain cortex tissue and mitochondria fractions isolated from brain cortex were measured to assess the amyloid pathology. Our findings include the observation of extensive metabolic alterations in cortex and cerebellum of APP/PS1 mice, but not in their hippocampus, midbrain and plasma. The major pathways affected in cortex and cerebellum of APP/PS1 mice were closely related to impaired energy metabolism and perturbation of amino acid metabolism in these mice. APP/PS1 mice also exhibited higher amyloid-β40 and amyloid-β42 in their cortex, accumulation of mitochondria APP in their cortex, and presented an altered oxidative state in their brain. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (PIO) successfully restored the energy metabolism, lowered amyloid-β levels and afforded the APP/PS1 mice a better antioxidative capacity in their cortex.
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http://dx.doi.org/10.1007/s12035-019-1586-2DOI Listing
November 2019

A Review on Liquid Chromatography-Tandem Mass Spectrometry Methods for Rapid Quantification of Oncology Drugs.

Pharmaceutics 2018 Nov 8;10(4). Epub 2018 Nov 8.

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.

In the last decade, the tremendous improvement in the sensitivity and also affordability of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has revolutionized its application in pharmaceutical analysis, resulting in widespread employment of LC-MS/MS in determining pharmaceutical compounds, including anticancer drugs in pharmaceutical research and also industries. Currently, LC-MS/MS has been widely used to quantify small molecule oncology drugs in various biological matrices to support preclinical and clinical pharmacokinetic studies in R&D of oncology drugs. This mini-review article will describe the state-of-the-art LC-MS/MS and its application in rapid quantification of small molecule anticancer drugs. In addition, efforts have also been made in this review to address several key aspects in the development of rapid LC-MS/MS methods, including sample preparation, chromatographic separation, and matrix effect evaluation.
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http://dx.doi.org/10.3390/pharmaceutics10040221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321130PMC
November 2018

A Sensitive Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Nimbolide in Mouse Serum: Application to a Preclinical Pharmacokinetics Study.

Pharmaceutics 2018 Aug 8;10(3). Epub 2018 Aug 8.

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.

A sensitive and robust liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of nimbolide in mouse serum. Exemestane was used as the internal standard (IS). Here, we employed acetonitrile-based protein precipitation (PPT) for serum sample preparation, and performed chromatographic separation using an ODS Hypersil C18 column (100 mm × 2.1 mm, 5 µm) with gradient elution (0.1% formic acid in water vs 100% acetonitrile). The run time was 6 min. Instrumental analysis was performed by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the multiple-reaction monitoring (MRM) under positive mode. A good linear calibration was achieved in the 5⁻1000 ng/mL range. The intra- and inter-day precisions for nimbolide were ≤12.6% and ≤13.9% respectively. Intra-day accuracy ranged from 96.9⁻109.3%, while inter-day accuracy ranged from 94.3⁻110.2%. The matrix effect of nimbolide, detected but consistent at low and high concentrations, do not affect linearity of standard curve. In conclusion, we have developed and validated a sensitive analytical method for determination of a novel natural compound nimbolide in mouse serum, and it has been successfully applied to our preclinical study in investigating the pharmacokinetic properties of nimbolide, which could greatly facilitate the preclinical development of the promising lead compound for anticancer therapy.
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http://dx.doi.org/10.3390/pharmaceutics10030123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161292PMC
August 2018

Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates.

Antimicrob Agents Chemother 2018 04 27;62(4). Epub 2018 Mar 27.

Department of Pharmacy, National University of Singapore, Singapore.

Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.
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http://dx.doi.org/10.1128/AAC.01647-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914004PMC
April 2018

Pan-HDAC inhibition by panobinostat mediates chemosensitization to carboplatin in non-small cell lung cancer via attenuation of EGFR signaling.

Cancer Lett 2018 03 4;417:152-160. Epub 2018 Jan 4.

Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore. Electronic address:

Accumulating evidence has implicated the aberrant regulation of histone deacetylases (HDACs) as a nexus for multiple cancer hallmarks and in mediating tumor adaptation and resistance to genotoxic chemotherapy, suggesting a rational pairing of HDAC inhibitors with DNA damaging chemotherapeutic agents in the treatment of human malignancies. Here we report that panobinostat (LBH589), a potent pan-HDAC inhibitor, effectively curbed the proliferation of non-small cell lung cancer (NSCLC) cell lines A549, Calu-1, H226, H460, H838 and SKMES-1 at IC concentrations between 4 and 31 nmol/L via pleiotropic mechanisms, including crosstalk with EGFR signal transduction cascades. Combination therapy with carboplatin elicited rapid tumor cell kill and effectively restrained anchorage-independent clonogenic survival to a considerably greater extent over either monotherapy. The administration of carboplatin and panobinostat at clinically relevant doses to NOD-SCID xenograft mice drastically stalled disease progression by 92% as compared with negative control (P = .0026), which was greater than the 28% and 54% achieved with either carboplatin (P = .220) or panobinostat (P = .017) alone. These data demonstrate that panobinostat has strong anti-NSCLC activity and chemosensitizes tumors to carboplatin, thus justifying further evaluation of this combination approach in clinical trials.
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http://dx.doi.org/10.1016/j.canlet.2017.12.030DOI Listing
March 2018

Combined use of irinotecan with histone deacetylase inhibitor belinostat could cause severe toxicity by inhibiting SN-38 glucuronidation via UGT1A1.

Oncotarget 2017 Jun;8(25):41572-41581

Cancer Science Institute of Singapore, National University of Singapore, Singapore.

SN-38, the active metabolite of irinotecan, and histone deacetylase inhibitors (HDACis) such as belinostat, vorinostat and panobinostat, have all been shown to be deactivated by glucuronidation via UGTs. Since they all compete for UGTs for deactivation, we aimed to investigate the inhibitory effect of various HDACis on the glucuronidation of SN-38. This inhibitory effect was determined by measuring the formation rate of SN-38 glucuronide after SN-38 incubation with human recombinant UGT1A isoforms (1A1, 1A6, 1A7 and 1A9) and pooled human liver microsomes (HLM, wild type, UGT1A1*1*28 and UGT1A1*28*28 allelic variants), with and without HDACis. The data showed that belinostat at 100 and 200 µmol/L inhibited SN-38 glucuronidation via UGT1A1 in a dose-dependent manner, causing significant decrease in Vmax and CLint (p < 0.05) from 12.60 to 1.95 pmol/min/mg and 21.59 to 4.20 μL/min/mg protein respectively. Similarly, in HLMs, Vmax dropped from 41.13 to 10.54, 24.96 to 3.77 and 6.23 to 3.30 pmol/min/mg, and CLint reduced from 81.25 to 26.11, 29.22 to 6.10 and 5.40 to 1.34 µL/min/mg protein for the respective wild type, heterozygous and homozygous variants. Interestingly, belinostat at 200 µmol/L that is roughly equivalent to the average Cmax, 183 µmol/L of belinostat at a dose of 1,400 mg/m2 given intravenously once per day on days 1 to 5 every 3 weeks, was able to inhibit both heterozygous and homozygous variants to same extents (~64%). This highlights the potential clinical significance, as a large proportion of patients could be at risk of developing severe toxicity if irinotecan is co-administered with belinostat.
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http://dx.doi.org/10.18632/oncotarget.15017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522258PMC
June 2017

UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes.

Nat Microbiol 2016 Sep 19;1:16166. Epub 2016 Sep 19.

Novartis Institute for Tropical Diseases, 138670 Singapore.

A molecular understanding of drug resistance mechanisms enables surveillance of the effectiveness of new antimicrobial therapies during development and deployment in the field. We used conventional drug resistance selection as well as a regime of limiting dilution at early stages of drug treatment to probe two antimalarial imidazolopiperazines, KAF156 and GNF179. The latter approach permits the isolation of low-fitness mutants that might otherwise be out-competed during selection. Whole-genome sequencing of 24 independently derived resistant Plasmodium falciparum clones revealed four parasites with mutations in the known cyclic amine resistance locus (pfcarl) and a further 20 with mutations in two previously unreported P. falciparum drug resistance genes, an acetyl-CoA transporter (pfact) and a UDP-galactose transporter (pfugt). Mutations were validated both in vitro by CRISPR editing in P. falciparum and in vivo by evolution of resistant Plasmodium berghei mutants. Both PfACT and PfUGT were localized to the endoplasmic reticulum by fluorescence microscopy. As mutations in pfact and pfugt conveyed resistance against additional unrelated chemical scaffolds, these genes are probably involved in broad mechanisms of antimalarial drug resistance.
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http://dx.doi.org/10.1038/nmicrobiol.2016.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575994PMC
September 2016

A novel combinatorial strategy using Seliciclib(®) and Belinostat(®) for eradication of non-small cell lung cancer via apoptosis induction and BID activation.

Cancer Lett 2016 10 25;381(1):49-57. Epub 2016 Jul 25.

Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, National University of Singapore, Singapore; Department of Hematology & Oncology, National University Health System, Singapore. Electronic address:

With conventional anticancer agents for non-small cell lung cancer (NSCLC) reaching therapeutic ceiling, the novel combination using histone deacetylase inhibitor, PXD101 (Belinostat(®)), and CDK inhibitor, CYC202 (Seliciclib(®)), was investigated as an alternative anticancer strategy. At clinically achievable concentration of CYC202 (15 µM), combination therapy resulted in significant reduction in cell proliferation (IC50 = 3.67 ± 0.80 µM, p < 0.05) compared with PXD101 alone (IC50 = 6.56 ± 0.42 µM) in p53 wild-type A549 cells. Significant increase in apoptosis that occurred independently of cell cycle arrest was observed after concurrent treatment. This result was corroborated by greater formation of cleaved caspase-8, caspase-3 and PARP. Up-regulation of p53 and truncated BID protein levels was seen while Mcl-1 and XIAP protein levels were down-regulated upon combined treatment. Further analysis of apoptotic pathways revealed that caspase inhibitors, but not p53 silencing, significantly abrogated the cytotoxic enhancement. Moreover, the enhanced efficacy of this combination was additionally confirmed in p53 null H2444 cells, suggesting the potential of this combination for treatment of NSCLC that are not amenable to effects of conventional p53-inducing agents.
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http://dx.doi.org/10.1016/j.canlet.2016.07.023DOI Listing
October 2016

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development.

Oncotarget 2016 Jul;7(28):44790-44802

Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Nimbolide is one of the main components in the leaf extract of Azadirachta indica (A. indica). Accumulating evidence from various in vitro and in vivo studies indicates that nimbolide possesses potent anticancer activity against several types of cancer and also shows potential chemopreventive activity in animal models. The main mechanisms of action of nimbolide include anti-proliferation, induction of apoptosis, inhibition of metastasis and angiogenesis, and modulation of carcinogen-metabolizing enzymes. Although multiple pharmacodynamic (PD) studies have been carried out, nimbolide is still at the infant stage in the drug development pipeline due to the lack of systematic pharmacokinetic (PK) studies and long-term toxicological studies. Preclinical PK and toxicological studies are vital in determining the dosage range to support the safety of nimbolide for first-in-human clinical trials. In this review, we will provide a comprehensive summary for the current status of nimbolide as an anticancer and chemopreventive lead compound, and highlight the importance of systematic preclinical PK and toxicological studies in accelerating the process of application of nimbolide as a therapeutic agent against various malignancies.
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http://dx.doi.org/10.18632/oncotarget.8316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190135PMC
July 2016

UGT1A1 Mediated Drug Interactions and its Clinical Relevance.

Curr Drug Metab 2016 ;17(2):100-6

Cancer Science Institute of Singapore, National University of Singapore, P.O. Box: 117599, Singapore, Singapore.

Background: The administration of multiple drugs for the treatment of diseases is an integral aspect of modern medicine. Though its purpose is to create the intended therapeutic effect, the unintended consequences of drug interactions can cause severe side effects and subsequent economic losses. Likewise, herbal extracts and supplements with pharmacologically active moieties also have the potential to interact with medications. There are many possible mechanisms on how these moieties could potentially interact, one of which is mediated by modulation of the activity of metabolizing enzymes. One such enzyme of high clinical significance is uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphism of UGT1A1 has been found to affect the plasma concentrations of many drugs, and may even be linked to treatment outcome.

Objective: This mini-review summarized the potential in vitro and in vivo interactions mediated by UGT1A1.

Method: Firstly, literature search was conducted using the Web of Knowledge database. No date limitation was applied to the search. Following which, the interactions were stratified into 3 main categories based on its clinical significance. Both herbal and pharmacological drug moieties are covered within the scope of this mini-review.

Results: Of 35 UGT1A1 induced drug interactions, likely and unlikely to be clinically significant interactions are 11 and 6 respectively. The rest of them are inconclusive.

Conclusion: We hope that this secondary literature can broaden and update the perspective of clinicians, pharmacists and academics on the interactions mediated by UGT1A1.
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http://dx.doi.org/10.2174/1389200216666151103121253DOI Listing
October 2016

Garcinol: Current status of its anti-oxidative, anti-inflammatory and anti-cancer effects.

Cancer Lett 2015 Jun 18;362(1):8-14. Epub 2015 Mar 18.

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599; Department of Pharmacology, National University Health System, Singapore 117597; Department of Haematology-Oncology, National University Health System, Singapore 119228. Electronic address:

Garcinol is the main medicinal component of the dried fruit rind of Garcinia indica (G. indica), which has traditionally been extensively used to treat gastric ailments and skin irritation. In vitro studies of garcinol revealed its potential therapeutic effects, such as its anti-oxidative, anti-inflammatory and anti-cancer properties. Similarly, in vivo studies in animal models also demonstrated the efficacy of garcinol for the treatment of various inflammatory and cancerous conditions. Despite being well tolerated in preclinical studies, the toxicological profile of garcinol remains elusive. More importantly, systematic pharmacokinetics (PK) studies of garcinol to establish an appropriate route of administration and its effective concentration range under physiological conditions have not yet been performed. PK studies play an essential role in translating the preclinical findings of garcinol from cell line models and animal species to humans, thereby facilitating dose selection, the characterization of the therapeutic index, identification of a metabolic pathway, and the determination of garcinol's potency and tolerability. This paper reviews the current studies of garcinol as a potential anti-oxidant, anti-inflammatory and anti-cancer agent and highlights the importance of performing preclinical PK and toxicological studies on garcinol for its development pipeline.
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http://dx.doi.org/10.1016/j.canlet.2015.03.019DOI Listing
June 2015

Development of an UPLC-MS/MS method for assaying the enzymatic activity of propionyl coenzyme-A carboxylase.

Bioanalysis 2014 Feb;6(3):335-48

Department of Pharmacy, National University of Singapore, Singapore.

Background: Propionyl coenzyme-A carboxylase (PCC) is a mitochondrial enzyme previously quantifiable only by radiometric assay. Herein, we report a UPLC-MS/MS method as a superior alternative method for assaying PCC's activity. METHODOLOGY & RESULTS: For the development of the UPLC-MS/MS method, the mass spectra of propionyl coenzyme-A and methyl malonyl coenzyme-A precursor ions, and their full scan product ions were determined. MRM was used for the quantification of the analytes. The method showed good linearity and selectivity for further bioanalytical study.

Conclusion: The developed UPLC-MS/MS method is capable of rapidly quantifying PCC's enzymatic activity and demonstrated suitability for assaying PCC's activity in complex biological samples. Thus, the method will be useful in validating recombinant expression of PCC, and potentially for routine quantification of mitochondrial PCC's activity level in patient cells.
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http://dx.doi.org/10.4155/bio.13.297DOI Listing
February 2014

Antiproliferative activity against MCF-7 breast cancer cells by diamino-triazaspirodiene antifolates.

Chem Biol Drug Des 2009 Sep;74(3):322-6

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore 117543.

Two triazaspirodienes, having similar phenoxy propyloxy side chain, were identified as potent mammalian dihydrofolate reductase inhibitors; one having a 6,5-spiro bicyclic ring system (IC(50) = 2.3 nm) and the other a 6,6-spiro bicyclic system (IC(50) = 6.9 nm). They also showed more than 50% antiproliferative activity against the MCF-7 breast cancer cells at 20 microm. This study demonstrated the potential lead of the diamino-triazaspirodienes in anticancer chemotherapeutical agents' discovery.
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http://dx.doi.org/10.1111/j.1747-0285.2009.00860.xDOI Listing
September 2009

Mesoporous-silica-coated up-conversion fluorescent nanoparticles for photodynamic therapy.

Small 2009 Oct;5(20):2285-90

Division of Bioengineering, Faculty of Engineering, National University of Singapore, Singapore 117574, Singapore.

Near-infrared (NIR)-to-visible up-conversion fluorescent nanoparticles have potential to be used for photodynamic therapy (PDT) in deep tissue because NIR light can penetrate thick tissue due to weak absorption in the optical window. Here a uniform layer of mesoporous silica is coated onto NaYF(4) up-converting nanocrystals, with a large surface area of approximately 770 m(2) g(-1) and an average pore size of 2 nm. A photosensitizer, zinc phthalocyanine, is incorporated into the mesoporous silica. Upon excitation by a NIR laser, the nanocrystals convert NIR light to visible light, which further activates the photosensitizer to release reactive singlet oxygen to kill cancer cells. The photosensitizer encapsulated in mesoporous silica is protected from degradation in the harsh biological environment. It is demonstrated that the photosensitizers loaded into the porous silica shell of the nanoparticles are not released out of the silica while they continuously produce singlet oxygen upon excitation by a NIR laser. The nanoparticles are reusable as the photosensitizers encapsulated in the silica are removed by soaking in ethanol.
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http://dx.doi.org/10.1002/smll.200900692DOI Listing
October 2009

Tracking transplanted cells in live animal using upconversion fluorescent nanoparticles.

Biomaterials 2009 Oct 17;30(28):5104-13. Epub 2009 Jun 17.

Division of Bioengineering, Faculty of Engineering, National University of Singapore, Singapore 117574, Singapore.

With the emergence of cell transplant as an attractive treatment modality for various diseases, there is a parallel need to track the fate of these cells to assess their therapeutic effectiveness. Here, we report the use of upconversion fluorescent nanoparticles, silica/NaYF(4):Yb,Er, to dynamically track live myoblast cells in vitro and in a living mouse model of cryoinjured hind limb. Nanoparticles loaded into cells were confirmed for its intracellular uptake by confocal imaging, spectrophotometry and inductively coupled plasma analysis. Loaded nanoparticles demonstrated absolute resistance to photobleaching and were applied for dynamic imaging to real time track in vitro cell migratory activity for a continuous 5 h duration using a time-lapse confocal microscope. Direct observation on the direction, speed and cell-cell interaction of migrating cells was clearly visualized. In vivo confocal imaging of nanoparticle-loaded cells intravenously injected into a mouse tail vein showed them flowing in the ear blood vessels. Nanoparticle-loaded cells were also unambiguously identified with superior contrast against a negligible background at least 1300 microm deep in a fully vascularized living tissue upon intramuscular injection. Spatiotemporal migratory activity of the transplanted cells within the three-dimensional living tissue was captured for at least 7 days post-delivery. Direct in vivo visualization of cell dynamics in the native tissue was unobtrusively followed over a 4 h time course and revealed subtle migratory activity of the transplanted cells. With these unique optical properties, we present silica/NaYF(4):Yb,Er nanoparticles as a new fluorescent live cell tracker probe for superior in vitro and in vivo dynamic imaging.
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http://dx.doi.org/10.1016/j.biomaterials.2009.05.062DOI Listing
October 2009

Comparison of the in vitro and in vivo effects of retinoids either alone or in combination with cisplatin and 5-fluorouracil on tumor development and metastasis of melanoma.

Cancer Chemother Pharmacol 2008 Dec 9;63(1):167-74. Epub 2008 May 9.

Department of Pharmacy, National University of Singapore, Singapore.

Purpose: Retinoids have previously been reported to inhibit proliferation of melanoma cell lines in vitro. However, the relative antimetastatic efficacy of various retinoids on melanoma in vivo is unknown. Therefore, we investigated the effects of different retinoids on the invasion and metastasis of murine melanoma B16-F10 cells in vitro and in vivo. Based on the findings, the antitumor effects of a selected retinoid either alone or in combination with cisplatin were also investigated in a preclinical mouse melanoma model.

Methods: Cell proliferation and invasion analyses of murine melanoma B16-F10 cells were assessed in the presence of different retinoids, either alone or in combination with cisplatin (CDDP) or 5-fluorouracil (5-FU). Experimental lung metastasis assay was performed in this study to investigate the antimetastatic efficacy of retinoids. Additionally, a mouse melanoma model was used to assess the antitumor efficacy of a selected retinoid in combination with cisplatin.

Results: Retinoids showed significant antiproliferation and anti-invasion effects on murine melanoma B16-F10 cells. Pretreatment with retinoids increased the sensitivity to CDDP but not to 5-FU in in-vitro. Moreover, the number of metastatic colonies formed in the lungs of mice injected intravenously with B16-F10 cells was significantly reduced by injecting the respective retinoid once a day for 10 days. Treatment with a combination of cisplatin and 13-cis-retinoic acid resulted in a significant reduction in primary tumor size and the number of lung metastatic nodules in melanoma-bearing mice.

Conclusion: These results suggest that retinoids not only exhibit antimetastatic effect, but also enhance the antitumor activity of cisplatin in vivo.
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http://dx.doi.org/10.1007/s00280-008-0763-1DOI Listing
December 2008

Physicochemical effects of terpenes on organogel for transdermal drug delivery.

Int J Pharm 2008 Jun 4;358(1-2):102-7. Epub 2008 Mar 4.

Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.

It is accepted that terpenes are effective penetration enhancers to promote the passage of drugs or chemicals through the human skin barrier. However the physical and chemical changes of a pharmaceutical vehicle induced by the incorporation of terpenes have not been explored. Thus, this study examines the effects of three terpenes (linalool, cineole, limonene) on the rheology and chemical stability of an organogel composed of dibutyllauroylglutamide (GP1) and propylene glycol (PG). At a given GP1 concentration, oxygen-containing linalool and cineole decreased gel moduli (elastic and viscous) and brittleness, and the reverse was obtained for hydrocarbon limonene. Probably, linalool and cineole interfered with hydrogen bonding between GP1 molecules while limonene could have initiated a phase separation-mediated gelation, changing the gel morphology. Microcalorimetry detected minute heat endotherms for gels (with and without terpenes) subjected to accelerated heat testing. These heat changes could arise from a small degree of structural disruption of the gel network. Heat endotherms normalized with respect to GP1 content were used to assess gel chemical stability. Although the terpenes altered rheology, they did not significantly affect the chemical stability of the gels. This is the first in the literature that reports the effect of penetration enhancers, such as terpenes, on the physical, rheological and chemical characteristics of a model pharmaceutical formulation for topical and transdermal drug delivery.
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http://dx.doi.org/10.1016/j.ijpharm.2008.02.021DOI Listing
June 2008

A preliminary ecotoxicity study of pharmaceuticals in the marine environment.

J Toxicol Environ Health A 2006 Nov;69(21):1959-70

Tropical Marine Science Institute, National University of Singapore, Singapore.

Environmental fates and effects of pharmaceuticals in the aquatic environment have been the focus of recent research in environmental ecotoxicology. Worldwide studies of common over-the-counter pharmaceuticals have reported detectable levels in the aquatic environment, but there are few studies examining impacts on marine habitats. These drugs can affect the functions of various vertebrates and invertebrates. The stability of two pharmaceuticals, cyclizine (CYC) and prochlorperazine (PCZ), in seawater was examined under light and dark conditions, as well as the toxicity of these compounds to larvae of the barnacle Balanus amphitrite, which is a cosmopolitan marine organism found in most of the world's oceans. CYC was very stable under all the tested conditions. On the other hand, PCZ degraded in light but not in the dark, and was more stable in seawater than fresh water. For the barnacle larvae, the LC50 of prochlorperazine was 0.93 microg/ml and the LC50 for CYC was approximately 0.04 microg/ml.
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http://dx.doi.org/10.1080/15287390600751371DOI Listing
November 2006

Limonene GP1/PG organogel as a vehicle in transdermal delivery of haloperidol.

Int J Pharm 2006 Mar 31;311(1-2):157-64. Epub 2006 Jan 31.

Department of Pharmacy, Faculty of Science, National University of Singapore, 18, Science Drive 4, Singapore 117543, Singapore.

Penetration enhancers are a classical means for improving transdermal drug delivery (TDD). Enhancers permeate into the skin and reversibly decrease the barrier resistance. Basically, our aim is to formulate a transdermal gel containing an appropriate enhancer for a controlled drug release. Terpenes, namely limonene, linalool and cineole, in propylene glycol (PG) were first investigated in vitro for their capacity to enhance the percutaneous release of an anti-psychotic drug, haloperidol (HP). Relative to oxygenated linalool and cineole, hydrocarbon limonene was more effective as a skin enhancer; it increased human skin permeability and decreased lag time. Limonene was thus incorporated in an organogel comprised of gelator GP1 and PG. This skin-friendly gel in a transdermal patch could act as a long-acting formulation that delivers HP at a sustained percutaneous rate. The microscopic framework of the organogel is a branched network of interlocking fibres. Varying the gelator content modulates the fibre density and gel stiffness, and presents different degrees of resistance to drug diffusion on the vehicle side. Rheological and permeation studies demonstrated that an increase in gelator concentration increased gel moduli and decreased drug flux simultaneously. The rheology of the gel matrix influenced drug release rate in a manner described by several experimentally-derived correlations.
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http://dx.doi.org/10.1016/j.ijpharm.2005.12.042DOI Listing
March 2006

Human multidrug resistance associated protein 4 confers resistance to camptothecins.

Pharm Res 2005 Nov;22(11):1837-53

Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, Singapore 117543, Singapore.

Purpose: The multidrug resistance associated protein (MRP) 4 is a member of the adenosine triphosphate (ATP)-binding cassette transporter family. Camptothecins (CPTs) have shown substantial anticancer activity against a broad spectrum of tumors by inhibiting DNA topoisomerase I, but tumor resistance is one of the major reasons for therapeutic failure. P-glycoprotein, breast cancer resistance protein, MRP1, and MRP2 have been implicated in resistance to various CPTs including CPT-11 (irinotecan), SN-38 (the active metabolite of CPT-11), and topotecan. In this study, we explored the resistance profiles and intracellular accumulation of a panel of CPTs including CPT, CPT-11, SN-38, rubitecan, and 10-hydroxy-CPT (10-OH-CPT) in HepG2 cells with stably overexpressed human MRP4. Other anticancer agents such as paclitaxel, cyclophosphamide, and carboplatin were also included.

Methods: HepG2 cells were transfected with an empty vehicle plasmid (V/HepG2) or human MRP4 (MRP4/HepG2). The resistance profiles of test drugs in exponentially growing V/HepG2 and MRP4/HepG2 cells were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay with 4 or 48 h exposure time of the test drug in the absence or presence of various MRP4 inhibitors. The accumulation of CPT-11, SN-38, and paclitaxel by V/HepG2 and MRP4/HepG2 cells was determined by validated high-performance liquid chromatography methods.

Results: Based on the resistance folds from the MTT assay with 48 h exposure time of the test drug, MRP4 conferred resistance to CPTs tested in the order 10-OH-CPT (14.21) > SN-38 carboxylate (9.70) > rubitecan (9.06) > SN-38 lactone (8.91) > CPT lactone (7.33) > CPT-11 lactone (5.64) > CPT carboxylate (4.30) > CPT-11 carboxylate (2.68). Overall, overexpression of MRP4 increased the IC50 values 1.78- to 14.21-fold for various CPTs in lactone or carboxylate form. The resistance of MRP4 to various CPTs tested was significantly reversed in the presence of dl-buthionine-(S,R)-sulfoximine (BSO, a gamma-glutamylcysteine synthetase inhibitor), MK571, celecoxib, or diclofenac (all MRP4 inhibitors). In addition, the accumulation of CPT-11 and SN-38 over 120 min in MRP4/HepG2 cells was significantly reduced compared to V/HepG2 cells, whereas the addition of celecoxib, MK571, or BSO significantly increased their accumulation in MRP4/HepG2 cells. There was no significant difference in the intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells, indicating that P-glycoprotein was not involved in the observed resistance to CPTs in this study. MRP4 also conferred resistance to cyclophosphamide and this was partially reversed by BSO. However, MRP4 did not increase resistance to paclitaxel, carboplatin, etoposide (VP-16), 5-fluorouracil, and cyclosporine.

Conclusions: Human MRP4 rendered significant resistance to cyclophosphamide, CPT, CPT-11, SN-38, rubitecan, and 10-OH-CPT. CPT-11 and SN-38 are substrates for MRP4. Further studies are needed to explore the role of MRP4 in resistance, toxicity, and pharmacokinetics of CPTs and cyclophosphamide.
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http://dx.doi.org/10.1007/s11095-005-7595-zDOI Listing
November 2005

Herb-drug interactions: a literature review.

Drugs 2005 ;65(9):1239-82

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations. Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine). In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.
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http://dx.doi.org/10.2165/00003495-200565090-00005DOI Listing
October 2005