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Nanoemulsion-based Parenteral Drug Delivery System of Carbamazepine: Preparation, Characterization, Stability Evaluation and Blood-Brain Pharmacokinetics

Tan SL, Stanslas J, Basri M, Abedi Karjiban RA, Kirby BP, Sani D, et al.

Curr Drug Deliv, 2015;12(6):795-804.
PMID: 26324229

Carbamzepine (CBZ) was encapsulated in a parenteral oil-in-water nanoemulsion, in an attempt to improve its bioavailability. The particle size, polydispersity index and zeta potential were measured using dynamic light scattering. Other parameters such as pH, osmolality, viscosity, drug loading efficiency and entrapment efficiency were also recorded. Transmission electron microscopy revealed that emulsion droplets were almost spherical in shape and in the nano-range. The in vitro release profile was best characterized by Higuchi's equation. The parenteral nanoemulsion of CBZ showed significantly higher AUC0→5, AUC0→∞, AUMC0→5, AUMC0→∞, Cmax and lower clearance than that of CBZ solution in plasma. Additionally, parenteral nanoemulsion of CBZ showed significantly higher AUC0→∞, AUMC0→∞ and Cmaxthan that of CBZ solution in brain. The parenteral nanoemulsion of CBZ could therefore use as a carrier, worth exploring further for brain targeting.
Investigation and Optimization of Hydrogel Microneedles for Transdermal Delivery of Caffeine

Chandran R, Mohd Tohit ER, Stanslas J, Salim N, Tuan Mahmood TM

Tissue Eng Part C Methods, 2022 10;28(10):545-556.
PMID: 35485888 DOI: 10.1089/ten.TEC.2022.0045

Caffeine is therapeutically effective for treating apnea, cellulite formation, and pain management. It also exhibits neuroprotective and antioxidant activities in different models of Parkinson's disease and Alzheimer's disease. However, caffeine administration in a minimally invasive and sustainable manner through the transdermal route is challenging owing to its hydrophilic nature. Therefore, this study demonstrated a transdermal delivery approach for caffeine by utilizing hydrogel microneedle (MN) as a permeation enhancer. The influence of formulation parameters such as molecular weight (MW) of PMVE/MA (polymethyl vinyl ether/maleic anhydride) copolymer and sodium bicarbonate (NaHCO3) concentration on the swelling kinetics and mechanical integrity of the hydrogel MNs was investigated. In addition, the effect of different MN application methods and needle densities of hydrogel MN on the skin insertion efficiency and penetration depth was also evaluated. The swelling degree at equilibrium percentage (% Seq) recorded for hydrogels fabricated with Gantrez S-97 (MW = 1,500,000 Da) was significantly higher than formulation with Gantrez AN-139 (MW = 1,080,000 Da). Increasing the concentration of NaHCO3 also significantly increased the % Seq. Moreover, a 100% penetration was recorded for both the applicator and combination of applicator and thumb pressure compared with only 11% for thumb pressure alone. The average diameter of micropores created by the applicator method was 62.94 μm, which was significantly lower than the combination of both applicator and thumb pressure MN application (100.53 μm). Based on histological imaging, the penetration depth of hydrogel MN increased as the MN density per array decreased. The hydrogel MN with the optimized formulation and skin insertion parameters was tested for caffeine delivery in an in vitro Franz diffusion cell setup. Approximately 2.9 mg of caffeine was delivered within 24 h, and the drug release profile was best fitted to the Korsmeyer-Peppas model, displaying Super Case II kinetics. In conclusion, a combination of thumb and impact application methods and reduced needle density improved the skin penetration efficiency of hydrogel MNs. The results also show that hydrogel MNs fabricated from 3% w/w NaHCO3 and high MW of copolymer exhibit optimum physical and swelling properties for enhanced transdermal delivery.
Adaptive therapy to circumvent drug resistance to tyrosine kinase inhibitors in cancer: is it clinically relevant?

Faisal Hamdi AI, How SH, Islam MK, Lim JCW, Stanslas J

Expert Rev Anticancer Ther, 2022 Dec;22(12):1309-1323.
PMID: 36376248 DOI: 10.1080/14737140.2022.2147671

INTRODUCTION: Cancer is highly adaptable and is constantly evolving against current targeted therapies such as tyrosine kinase inhibitors. Despite advances in recent decades, the emergence of drug resistance to tyrosine kinase inhibitors constantly hampers therapeutic efficacy of cancer treatment. Continuous therapy versus intermittent clinical regimen has been a debate in drug administration of cancer patients. An ecologically-inspired shift in cancer treatment known as 'adaptive therapy' intends to improve the drug administration of drugs to cancer patients that can delay emergence of drug resistance.
AREAS COVERED: We discuss improved understanding of the concept of drug resistance, the basis of continuous therapy, intermittent clinical regimens, and adaptive therapy will be reviewed. In addition, we discuss how adaptive therapy provides guidance for future cancer treatment.
EXPERT OPINION: The current understanding of drug resistance in cancer leads to poor prognosis and limited treatment options in patients. Fighting drug resistance mutants is constantly followed by new forms of resistance. In most reported cases, continuous therapy leads to drug resistance and an intermittent clinical regimen vaguely delays it. However, adaptive therapy, conceptually, exploits multiple parameters that can suppress the growth of drug resistance and provides safe treatment for cancer patients in the future.
Drug-Loaded Hydrogel Microneedles for Sustainable Transdermal Delivery of Macromolecular Proteins

Chandran R, Mohd Tohit ER, Stanslas J, Salim N, Tuan Mahmood TM

Curr Drug Deliv, 2025 Jan 15.
PMID: 39819406 DOI: 10.2174/0115672018346286241121052105

INTRODUCTION: Poly(methyl vinyl ether co-maleic acid) (PMVE/MA) hydrogel microneedles (HMN) are investigated for transdermal delivery of macromolecular drugs owing to their biocompatibility and super-swelling properties. However, the drug delivery efficacy reduces with increasing molecular weight due to the entrapment within the HMN matrices. Furthermore, integrating external drug reservoirs extends the drug diffusion path and reduces the efficiency of drug permeation.
METHODS: A direct drug loading approach in the HMN matrix was introduced in this work following a pH modification step. The effect of pH modification on the physicochemical properties of HMN was studied. Then, bovine serum albumin (BSA), a model protein, was loaded into the pH-modified HMN, and the morphological changes in HMN and protein stability were also assessed. Finally, the efficacy of BSA-loaded HMN in the transdermal delivery was evaluated ex vivo.
RESULTS: A significant increase in swelling was recorded following the pH modification of HMN (p < 0.001). The structure of pH-modified hydrogel was highly porous, and ATR-FTIR spectra indicated a shift in the carboxylic peak. The secondary structure of BSA loaded in the pH-modified HMN was also preserved. The BSA-loaded HMN mediated a sustained ex-vivo drug release with a cumulative release of 64.70% (3.88 mg) in 24 h.
CONCLUSION: Hence, the model drug-incorporated PMVE/MA HMN system shows potential for sustainable transdermal delivery of proteins.
The evaluation expression of non-coding RNAs in response to HSV-G47∆ oncolytic virus infection in glioblastoma multiforme cancer stem cells

Vazifehmand R, Ali DS, Othman Z, Chau DM, Stanslas J, Shafa M, et al.

J Neurovirol, 2022 Dec;28(4-6):566-582.
PMID: 35951174 DOI: 10.1007/s13365-022-01089-w

Glioblastoma multiforme is the most aggressive astrocytes brain tumor. Glioblastoma cancer stem cells and hypoxia conditions are well-known major obstacles in treatment. Studies have revealed that non-coding RNAs serve a critical role in glioblastoma progression, invasion, and resistance to chemo-radiotherapy. The present study examined the expression levels of microRNAs (in normoxic condition) and long non-coding RNAs (in normoxic and hypoxic conditions) in glioblastoma stem cells treated with the HSV-G47∆. The expression levels of 43 miRNAs and 8 lncRNAs isolated from U251-GBM-CSCs were analyzed using a miRCURY LNA custom PCR array and a quantitative PCR assay, respectively. The data revealed that out of 43 miRNAs that only were checked in normoxic condition, the only 8 miRNAs, including miR-7-1, miR-let-7b, miR-130a, miR-137, miR-200b, miR-221, miR-222, and miR-874, were markedly upregulated. The expression levels of lncRNAs, including LEF1 antisense RNA 1 (LEF1-AS1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), long intergenic non-protein coding RNA 470 (LINC00470), tumor suppressor candidate 7 (TUSC7), HOX transcript antisense RNA (HOTAIR), nuclear paraspeckle assembly transcript 1 (NEAT1), and X inactive specific transcript (XIST), were markedly downregulated in the hypoxic microenvironment, and H19-imprinted maternally expressed transcript (H19) was not observed to be dysregulated in this environment. Under normoxic conditions, LEF1-AS1, MALAT1, LINC00470, H19, HOTAIR, NEAT1, and XIST were downregulated and TUSC7 was not targeted by HSV-G47∆. Overall, the present data shows HSVG47Δ treatment deregulates non-coding RNA expression in GBM-CSC tumor microenvironments.
Beneficial effects of TQRF and TQ nano- and conventional emulsions on memory deficit, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble Aβ levels in high fat-cholesterol diet-induced rats

Ismail N, Ismail M, Azmi NH, Bakar MFA, Yida Z, Stanslas J, et al.

Chem Biol Interact, 2017 Sep 25;275:61-73.
PMID: 28734741 DOI: 10.1016/j.cbi.2017.07.014

The study determined the effect of thymoquinone rich fraction (TQRF) and thymoquinone (TQ) in the forms of nano- and conventional emulsions on learning and memory, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble β-amyloid (Aβ) levels in rats fed with a high fat-cholesterol diet (HFCD). The TQRF was extracted from Nigella sativa seeds using a supercritical fluid extraction system and prepared into nanoemulsion, which later named as TQRF nanoemulsion (TQRFNE). Meanwhile, TQ was acquired commercially and prepared into thymoquinone nanoemulsion (TQNE). The TQRF and TQ conventional emulsions (CE), named as TQRFCE and TQCE, respectively were studied for comparison. Statin (simvastatin) and non-statin (probucol) cholesterol-lowering agents, and a mild-to-severe Alzheimer's disease drug (donepezil) were served as control drugs. The Sprague Dawley rats were fed with HFCD for 6 months, and treated with the intervention groups via oral gavage daily for the last 3 months. As a result, HFCD-fed rats exhibited hypercholesterolaemia, accompanied by memory deficit, increment of lipid peroxidation and soluble Aβ levels, decrement of total antioxidant status and down-regulation of antioxidants genes expression levels. TQRFNE demonstrated comparable effects to the other intervention groups and control drugs in serum biomarkers as well as in the learning and memory test. Somehow, TQRFNE was more prominent than those intervention groups and control drugs in brain biomarkers concomitant to gene and protein expression levels. Supplementation of TQRFNE into an HFCD thus could ameliorate memory deficit, lipid peroxidation and soluble Aβ levels as well as improving the total antioxidant status and antioxidants genes expression levels.
A pilot study on the association between SLCO1B1 RS4363657 polymorphism and muscle adverse events in adults with newly diagnosed dyslipidaemia who were prescribed a statin: the Malaysian primary health care cohort

C Thambiah S, Meor Anuar Shuhaili MFR, Chew BH, Samsudin IN, Abdul Rahman H, Stanslas J, et al.

Biomarkers, 2019 Nov;24(7):659-665.
PMID: 31342800 DOI: 10.1080/1354750X.2019.1648554

Introduction: Statin, the first-line treatment for dyslipidaemia, may have suboptimal adherence due to its associated muscle adverse events. These data, however, remain limited. Aim: To determine the association of serum creatine kinase (CK) and SLCO1B1 rs4363657 polymorphism with statin-associated muscle adverse events (SAMAE) among dyslipidaemia participants.
Methods: This was a prospective cohort study at government health clinics involving newly diagnosed adults with dyslipidaemia. SAMAE were recorded based on the patient's complaint after a month on statin. CK was taken at baseline and follow-up. Genetic profiling was performed for SLCO1B1 rs4363657 polymorphism.
Results: Among 118 participants, majority were Malay (72%) males (61%) with a mean age of 49 ± 12.2 years old and prescribed lovastatin (61.9). There was a significant association between statin types (lovastatin and simvastatin) and SAMAE (p = 0.0327); no significant association noted between CK and SAMAE (p = 0.5637). The SLCO1B1 rs4363657 polymorphism was significantly associated SAMAE (p
BsmI-ApaI-TaqI TAC (BAt) Haplotype of Vitamin D Receptor Gene Is Associated with Increased Risk of Major Depressive Disorder

Lye MS, Tor YS, Tey YY, Shahabudin A, Loh SP, Ibrahim N, et al.

J Mol Neurosci, 2021 May;71(5):981-990.
PMID: 33034825 DOI: 10.1007/s12031-020-01719-0

Heritability of major depressive disorder (MDD) is between 36 and 44%, suggesting that up to nearly half of the phenotypic variability is attributable to genes. A number of genetic polymorphisms have been shown to predispose certain individuals to depression. Of particular interest are the polymorphisms of the vitamin D receptor (VDR) gene. Although the VDR gene has been well characterized and a vast number of polymorphisms have been identified, the association between BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) single-nucleotide polymorphisms (SNPs), together with their haplotypes, and MDD risk have yet to be established. We conducted a matched case-control study with a total of 600 participants comprising 300 major depressive disorder (MDD) cases and 300 controls matched by age, gender and ethnicity in a 1:1 ratio, in four public hospitals in Kuala Lumpur and Selangor. Three adjacent SNPs of the VDR gene-BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236)-were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Odds ratios and 95% confidence intervals (CIs) were obtained from conditional logistic regression using Stata 16. Linkage disequilibrium and haplotype association with MDD were analyzed using the online SNPStats program. None of the genotypes of the three SNPs was significantly associated with risk of developing MDD after adjusting for confounding factors. However, the TAC (BAt) haplotype was associated with increased odds of MDD (adjusted OR = 2.17, 95% CI = 1.30-3.61, p = 0.003) using CCT (baT) as reference haplotype. The findings suggest that the BsmI-ApaI-TaqI TAC (BAt) haplotype of the VDR gene increases susceptibility to MDD.
In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein

Quah SY, Tan MS, Ho KL, Manan NA, Gorfe AA, Deb PK, et al.

Future Med Chem, 2020 09;12(18):1611-1631.
PMID: 32892640 DOI: 10.4155/fmc-2020-0104

Background: Andrographolide and its benzylidene derivatives, SRJ09 and SRJ23, potentially bind oncogenic K-Ras to exert anticancer activity. Their molecular interactions with K-Ras oncoproteins that lead to effective biological activity are of major interest. Methods & results: In silico docking and molecular dynamics simulation were performed using Glide and Desmond, respectively; while saturation transfer difference NMR was performed using GDP-bound K-RasG12V. SRJ23 was found to bind strongly and selectively to K-RasG12V, by anchoring to a binding pocket (namely p2) principally via hydrogen bond and hydrophobic interactions. The saturation transfer difference NMR analysis revealed the proximity of protons of functional moieties in SRJ23 to K-RasG12V, suggesting positive binding. Conclusion: SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.
Fulltext Lignosus rhinocerotis Cooke Ryvarden ameliorates airway inflammation, mucus hypersecretion and airway hyperresponsiveness in a murine model of asthma

Johnathan M, Muhamad SA, Gan SH, Stanslas J, Mohd Fuad WE, Hussain FA, et al.

PLoS One, 2021;16(3):e0249091.
PMID: 33784348 DOI: 10.1371/journal.pone.0249091

Lignosus rhinocerotis Cooke. (L. rhinocerotis) is a medicinal mushroom traditionally used in the treatment of asthma and several other diseases by the indigenous communities in Malaysia. In this study, the effects of L. rhinocerotis on allergic airway inflammation and hyperresponsiveness were investigated. L. rhinocerotis extract (LRE) was prepared by hot water extraction using soxhlet. Airway hyperresponsiveness (AHR) study was performed in house dust mite (HDM)-induced asthma in Balb/c mice while airway inflammation study was performed in ovalbumin (OVA)-induced asthma in Sprague-Dawley rats. Treatment with different doses of LRE (125, 250 and 500 mg/kg) significantly inhibited AHR in HDM-induced mice. Treatment with LRE also significantly decreased the elevated IgE in serum, Th2 cytokines in bronchoalveolar lavage fluid and ameliorated OVA-induced histological changes in rats by attenuating leukocyte infiltration, mucus hypersecretion and goblet cell hyperplasia in the lungs. LRE also significantly reduced the number of eosinophils and neutrophils in BALF. Interestingly, a significant reduction of the FOXP3+ regulatory T lymphocytes was observed following OVA induction, but the cells were significantly elevated with LRE treatment. Subsequent analyses on gene expression revealed regulation of several important genes i.e. IL17A, ADAM33, CCL5, IL4, CCR3, CCR8, PMCH, CCL22, IFNG, CCL17, CCR4, PRG2, FCER1A, CLCA1, CHIA and Cma1 which were up-regulated following OVA induction but down-regulated following treatment with LRE. In conclusion, LRE alleviates allergy airway inflammation and hyperresponsiveness, thus suggesting its therapeutic potential as a new armamentarium against allergic asthma.
Microarray-based identification of differentially expressed genes associated with andrographolide derivatives-induced resistance in colon and prostate cancer cell lines

Quah SY, Wong CC, Wong HC, Ho KL, Abdul Manan N, Deb PK, et al.

Toxicol Appl Pharmacol, 2021 08 15;425:115605.
PMID: 34087331 DOI: 10.1016/j.taap.2021.115605

Chemoresistance poses a major hurdle to cancer treatments. Andrographolide-derived SRJ09 and SRJ23 were reported to exhibit potent, selective inhibitory activities against colon and prostate cancer cells, respectively. In this study, previously developed resistant colon (HCT-116rst09) and prostate (PC-3rst23) cancer cell lines were used to elucidate the molecular mechanisms contributing to chemoresistance. Cytotoxic effects of SRJ09 and SRJ23 on both parental and resistant cells were investigated. Cell cycle distributions in HCT-116rst09 cells following SRJ09 treatment were analysed using flow cytometry. Whole-genome microarray analysis was performed on both parental and resistant cells to obtain differential gene expression profiles. Microarray data were subjected to protein-protein interaction network, functional enrichment, and pathway analyses. Reverse transcription-polymerase chain reaction (RT-PCR) was used to validate the changes in expression levels of selected genes. Besides morphological changes, HCT-116rst09 cells showed 7.0-fold resistance to SRJ09 while PC-3rst23 cells displayed a 5.5-fold resistance to SRJ23, as compared with their respective parental cells. G0/G1-phase cell cycle arrest was observed in HCT-116rst09 cells upon SRJ09 treatment. Collectively, 77 and 21 genes were found differentially modulated in HCT-116rst09 and PC-3rst23 cells, respectively. Subsequent bioinformatics analysis revealed several genes associated with FGFR4 and PI3K pathways, and cancer stemness, were chemoresistance mediators in HCT-116rst09 cells. RT-PCR confirmed the HMOX1 upregulation and ATG12 downregulation protected the PC-3rst23 cells from SRJ23 cytotoxicity. In conclusion, acquired chemoresistance to SRJ09 and SRJ23 in colon and prostate cancer cells, respectively, could be attributed to the alterations in the expression of genes such as those related to PI3K and autophagy pathways.
Fulltext Hypoxia-Induced Neuroinflammation in Alzheimer's Disease: Potential Neuroprotective Effects of Centella asiatica

Hambali A, Kumar J, Hashim NFM, Maniam S, Mehat MZ, Cheema MS, et al.

Front Physiol, 2021;12:712317.
PMID: 34721056 DOI: 10.3389/fphys.2021.712317

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterised by the presence of extracellular beta-amyloid fibrillary plaques and intraneuronal neurofibrillary tau tangles in the brain. Recurring failures of drug candidates targeting these pathways have prompted research in AD multifactorial pathogenesis, including the role of neuroinflammation. Triggered by various factors, such as hypoxia, neuroinflammation is strongly linked to AD susceptibility and/or progression to dementia. Chronic hypoxia induces neuroinflammation by activating microglia, the resident immune cells in the brain, along with an increased in reactive oxygen species and pro-inflammatory cytokines, features that are common to many degenerative central nervous system (CNS) disorders. Hence, interests are emerging on therapeutic agents and plant derivatives for AD that target the hypoxia-neuroinflammation pathway. Centella asiatica is one of the natural products reported to show neuroprotective effects in various models of CNS diseases. Here, we review the complex hypoxia-induced neuroinflammation in the pathogenesis of AD and the potential application of Centella asiatica as a therapeutic agent in AD or dementia.
Alkenylresorcinols and cytotoxic activity of the constituents isolated from Labisia pumila

Al-Mekhlafi NA, Shaari K, Abas F, Kneer R, Jeyaraj EJ, Stanslas J, et al.

Phytochemistry, 2012 Aug;80:42-9.
PMID: 22633846 DOI: 10.1016/j.phytochem.2012.04.008

Phytochemical investigation on the leaves of Labisia pumila (Myrsinaceae), an important medicinal herb in Malaysia, has led to the isolation of 1-O-methyl-6-acetoxy-5-(pentadec-10Z-enyl)resorcinol (1), labisiaquinone A (2) and labisiaquinone B (3). Along with these, 16 known compounds including 1-O-methyl-6-acetoxy-5-pentadecylresorcinol (4), 5-(pentadec-10Z-enyl)resorcinol (5), 5-(pentadecyl)resorcinol (6), (-)-loliolide (7), stigmasterol (8), 4-hydroxyphenylethylamine (9), 3,4,5-trihydroxybenzoic acid (10), 3,4-dihydroxybenzoic acid (11), (+)-catechin (12), (-)-epicatechin (13), kaempferol-3-O-α-rhamnopyranosyl-7-O-β-glycopyranoside (14), kaempferol-4'-O-β-glycopyranoside (15), quercetin-3-O-α-rhamnopyranoside (16), kaempferol-3-O-α-rhamnopyranoside (17), (9Z,12Z)-octadeca-9,12-dienoic acid (18) and stigmasterol-3-O-β-glycopyranoside (19) were also isolated. The structures of these compounds were established on the basis of 1D and 2D NMR spectroscopy techniques (¹H, ¹³C, COSY, HSQC, NOESY and HMBC experiments), mass spectrometry and chemical derivatization. Among the constituents tested 1 and 4 exhibited strongest cytotoxic activity against the PC3, HCT116 and MCF-7 cell lines (IC₅₀ values ≤ 10 μM), and they showed selectivity towards the first two-cell lines relative to the last one.
In vitro 3D colon tumor penetrability of SRJ09, a new anti-cancer andrographolide analog

Wong CC, Periasamy N, Sagineedu SR, Sidik S, Sumon SH, Loadman P, et al.

Invest New Drugs, 2014 Oct;32(5):806-14.
PMID: 24875131 DOI: 10.1007/s10637-014-0105-6

Limited tumor penetrability of anti-cancer drugs is recognized as one of the major factors that lead to poor anti-tumor activity. SRJ09 (3,19-(2-bromobenzylidene) andrographolide) has been identified as a lead anti-cancer agent for colon cancer. Recently, this compound was shown by us to be a mutant K-Ras binder. In this present study, the penetrability of SRJ09 through the DLD-1 colon cancer multicell layer (MCL) was evaluated. The amount of SRJ09 that penetrated through the MCL was quantitated by utilizing high performance liquid chromatography (HPLC). Histopathological staining was used to visualize the morphology of MCL. A chemosensitivity assay was performed to assess the anti-cancer activity of SRJ09 in DLD-1 cells. SRJ09 was able to penetrate through DLD-1 MCL and is inversely proportional with the MCL thickness. The flow rates for SRJ09 through MCL were 0.90 ± 0.20 μM/min/cm(2) and 0.56 ± 0.06 μM/min/cm(2) for days 1 and 5, respectively, which are better than doxorubicin. Histopathological examination revealed that the integrity of the DLD-1 MCL was retained and no visible damage was inflicted on the cell membrane, confirming the penetration of SRJ09 was by diffusion. Short term exposure (1 h) in DLD-1 cells demonstrated SRJ09 had IC50 of 41 μM which was approximately 4-folds lower than andrographolide, the parent compound of SRJ09. In conclusion, SRJ09 successfully penetrated through DLD-1 MCL by diffusion and emerged as a potential candidate to be developed as a clinically viable anti-colon cancer drug.
Semisynthesis and in vitro anticancer activities of andrographolide analogues

Jada SR, Subur GS, Matthews C, Hamzah AS, Lajis NH, Saad MS, et al.

Phytochemistry, 2007 Mar;68(6):904-12.
PMID: 17234223

The plant Andrographis paniculata found throughout Southeast Asia contains Andrographolide 1, a diterpenoid lactone, which has antitumour activities against in vitro and in vivo breast cancer models. In the present study, we report on the synthesis of andrographolide derivatives, 3,19-isopropylideneandrographolide (2), 14-acetyl-3,19-isopropylideneandrographolide (3) and 14-acetylandrographolide (4), and their in vitro antitumour activities against a 2-cell line panel consisting of MCF-7 (breast cancer cell line) and HCT-116 (colon cancer cell line). Compounds 2 and 4 were also screened at the US National Cancer Institute (NCI) for their activities against a panel of 60 human cancer cell lines derived from nine cancer types. Compound 2 was found to be selective towards leukaemia and colon cancer cells, and compound 4 was selective towards leukaemia, ovarian and renal cancer cells at all the dose-response parameters. Compounds 2 and 4 showed non-specific phase of the cell cycle arrest in MCF-7 cells treated at different intervals with different concentrations. NCI's COMPARE and SOM mechanistic analyses indicated that the anticancer activities of these new class of compounds were not similar to that of standard anticancer agents, suggesting novel mechanism(s) of action.
Challenges and Strategies for Improving Access to Cancer Drugs in Malaysia: Summary of Opinions Expressed at the 2nd MACR International Scientific Conference 2022

Tan SC, Poh WT, Yong ACH, Chua EW, Ooi J, Mahmud R, et al.

Cancer Manag Res, 2023;15:851-862.
PMID: 37636030 DOI: 10.2147/CMAR.S420890

Considerable progress has been made in cancer drug development in recent decades. However, for people in low- and middle-income countries, including Malaysia, many of these drugs are not readily available. During the 2nd Malaysian Association for Cancer Research (MACR) International Scientific Conference, a forum discussion was held to address these challenges and explore strategies to improve access to cancer medicines in the country. This paper presents the results of the said forum discussion. A few challenges to cancer drug access were highlighted, including lengthy approval and regulatory practices, cost of medicines, and manufacturing barriers. Besides, a few strategies for mitigating some of these challenges were proposed, such as mechanisms for cost reduction, uptake of biosimilars and generics, local manufacturing, public-private partnerships, strengthening the role of insurance companies, funding and regulation, and advocacy for fair pricing, by drawing examples from cancer medicines access initiatives in Malaysia and initiatives for different disease groups. Overall, this paper provides a comprehensive overview of the challenges and strategies for improving access to cancer medicines in Malaysia and provides valuable insights for policymakers, healthcare providers, the pharmaceutical industry, cancer patients, cancer support groups, and other stakeholders working on this important issue.
The Standardized Extract of Centella asiatica and Its Fractions Exert Antioxidative and Anti-Neuroinflammatory Effects on Microglial Cells and Regulate the Nrf2/HO-1 Signaling Pathway

Hambali A, Jusril NA, Md Hashim NF, Abd Manan N, Adam SK, Mehat MZ, et al.

J Alzheimers Dis, 2024;99(s1):S119-S138.
PMID: 38250772 DOI: 10.3233/JAD-230875

BACKGROUND: Neuroinflammation and oxidative stress can aggravate the progression of Alzheimer's disease (AD). Centella asiatica has been traditionally consumed for memory and cognition. The triterpenes (asiaticoside, madecassoside, asiatic acid, madecassic acid) have been standardized in the ethanolic extract of Centella asiatica (SECA). The bioactivity of the triterpenes in different solvent polarities of SECA is still unknown.
OBJECTIVE: In this study, the antioxidative and anti-neuroinflammatory effects of SECA and its fractions were explored on lipopolysaccharides (LPS)-induced microglial cells.
METHODS: HPLC measured the four triterpenes in SECA and its fractions. SECA and its fractions were tested for cytotoxicity on microglial cells using MTT assay. NO, pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), ROS, and MDA (lipid peroxidation) produced by LPS-induced microglial cells were measured by colorimetric assays and ELISA. Nrf2 and HO-1 protein expressions were measured using western blotting.
RESULTS: The SECA and its fractions were non-toxic to BV2 microglial cells at tested concentrations. The levels of NO, TNF-α, IL-6, ROS, and lipid peroxidation in LPS-induced BV2 microglial cells were significantly reduced (p
Role of the IL8 rs4073 polymorphism in central nervous system toxicity in patients receiving multidrug-resistant tuberculosis treatment

Badamasi IM, Muhammad M, Umar AA, Madugu UM, Gadanya MA, Aliyu IA, et al.

J Bras Pneumol, 2024;50(1):e20230338.
PMID: 38359298 DOI: 10.36416/1806-3756/e20230338

OBJECTIVE: To determine the role of the IL8 rs4073 polymorphism in predicting the risk of central nervous system (CNS) toxicity in patients receiving standard pharmacological treatment for multidrug-resistant tuberculosis (MDR-TB).
METHODS: A cohort of 85 consenting MDR-TB patients receiving treatment with second-line antituberculosis drugs had their blood samples amplified for the IL8 (rs4073) gene and genotyped. All patients were clinically screened for evidence of treatment toxicity and categorized accordingly. Crude and adjusted associations were assessed.
RESULTS: The chief complaints fell into the following categories: CNS toxicity; gastrointestinal toxicity; skin toxicity; and eye and ear toxicities. Symptoms of gastrointestinal toxicity were reported by 59% of the patients, and symptoms of CNS toxicity were reported by 42.7%. With regard to the genotypes of IL8 (rs4073), the following were identified: AA, in 64 of the study participants; AT, in 7; and TT, in 11. A significant association was found between the dominant model of inheritance and CNS toxicity for the crude model (p = 0.024; OR = 3.57; 95% CI, 1.18-10.76) and the adjusted model (p = 0.031; OR = 3.92; 95% CI, 1.13-13.58). The AT+TT genotype of IL8 (rs4073) showed a 3.92 times increased risk of CNS toxicity when compared with the AA genotype.
CONCLUSIONS: The AT+TT genotype has a tendency to be associated with an increased risk of adverse clinical features during MDR-TB treatment.
The impact of cycleanine in cancer research: a computational study

Nwaefulu ON, Al-Shar'i NA, Owolabi JO, Sagineedu SR, Woei LC, Wai LK, et al.

J Mol Model, 2022 Oct 04;28(11):340.
PMID: 36194315 DOI: 10.1007/s00894-022-05326-1

Cancer is imposing a global health burden because of the steady increase in new cases. Moreover, current anticancer therapeutics are associated with many drawbacks, mainly the emergence of resistance and the severe adverse effects. Therefore, there is a continuous need for developing new anticancer agents with novel mechanisms of action and lower side effects. Natural products have been a rich source of anticancer medication. Cycleanine, a natural product, was reported to exert an antiproliferative effect on ovarian cancer cells by causing apoptosis through activation of caspases 3/7 and cleavage of poly (ADP-ribose) polymerase to form poly (ADP-ribose) polymerase-1 (PARP1). It is well-established that PARP1 is associated with carcinogenesis, and different PARP1 inhibitors are approved as anticancer drugs. In this study, the cytotoxic activity of cycleanine was computationally investigated to determine whether it is a PARP1 inhibitor or a caspase activator. Molecular docking and molecular dynamics (MD) simulations were utilized for this purpose. The results showed that cycleanine has a good binding affinity to PARP1; moreover, MD simulation showed that it forms a stable complex with the enzyme. Consequently, the results showed that cycleanine is a potential inhibitor of the PARP1 enzyme.
Whole blood hydroxychloroquine: Does genetic polymorphism of cytochrome P450 enzymes have a role?

Jatta N, Stanslas J, Yong ACH, Ho WC, Wan Ahmad Kammal WSL, Chua EW, et al.

Clin Exp Med, 2023 Dec;23(8):4141-4152.
PMID: 37480404 DOI: 10.1007/s10238-023-01142-w

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and multifactorial etiologies ranging from environmental to genetic. SLE is associated with dysregulated immunological reactions, with increased immune complex formation leading to end-organ damages such as lupus nephritis, cutaneous lupus, and musculoskeletal disorders. Lupus treatment aims to reduce disease activity, prevent organ damage, and improve long-term patient survival and quality of life. Antimalarial, hydroxychloroquine (HCQ) is used as a first-line systemic treatment for lupus. It has shown profound efficacy in lupus and its associated conditions. However, wide variation in terms of clinical response to this drug has been observed among this group of patients. This variability has limited the potential of HCQ to achieve absolute clinical benefits. Several factors, including genetic polymorphisms of cytochrome P450 enzymes, have been stipulated as key entities leading to this inter-individual variation. Thus, there is a need for more studies to understand the role of genetic polymorphisms in CYP450 enzymes in the clinical response to HCQ. Focusing on the role of genetic polymorphism on whole blood HCQ in lupus disorder, this review aims to highlight up-to-date pathophysiology of SLE, the mechanism of action of HCQ, and finally the role of genetic polymorphism of CYP450 enzymes on whole blood HCQ level as well as clinical response in lupus.

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