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Identification of Vibrio harveyi isolated from diseased Asian seabass Lates calcarifer by use of 16S ribosomal DNA sequencing

Ransangan J, Mustafa S

J Aquat Anim Health, 2009 Sep;21(3):150-5.
PMID: 20043399 DOI: 10.1577/H09-002.1

The grow out of Asian seabass Lates calcarifer in marine net-cages is a popular aquaculture activity in Malaysia. Production of this species is greatly affected by the occurrence of vibriosis, which causes heavy mortality. Generally, young fish are more susceptible; they exhibit anorexia and skin darkening, followed by heavy mortality. The acutely affected older fish may also exhibit bloody lesions around the anus and the base of the fins. Twenty-one bacterial isolates obtained from internal organs (kidney, heart, spleen and liver) of the affected specimens were subjected to phenotypic characterization, testing for antibiotic susceptibility, and 16S ribosomal DNA sequencing. The sequencing result showed that all of the bacterial isolates belonged to Vibrio harveyi. The phenotypic characterization, however, identified 4 of the bacterial isolates as V. harveyi, 16 as V. parahaemolyticus, and 1 as V. alginolyticus. These findings suggest that biochemical features alone cannot be reliably used to identify bacterial pathogens, including V. harveyi, in aquaculture. Antibiotic susceptibility assays showed that some antibiotics, including oxytetracycline, nitrofurantoin, furazolidone, streptomycin, sulfamethoxazole, chloramphenicol, nalidixic acid, and oxolinic acid were effective against V. harveyi. Considering the side effects of these antibiotics, however, their use is not recommended in the aquaculture of Asian seabass.
Monoclonal antibodies specific to heat-treated porcine blood

Raja Nhari RM, Hamid M, Rasli NM, Omar AR, El Sheikha AF, Mustafa S

J Sci Food Agric, 2016 May;96(7):2524-31.
PMID: 26611757 DOI: 10.1002/jsfa.7547

Porcine blood is potentially being utilized in food as a binder, gelling agent, emulsifier or colorant. However, for certain communities, the usage of animal blood in food is strictly prohibited owing to religious concerns and health reasons. This study reports the development of monoclonal antibodies (MAbs) against heat-treated soluble proteins (HSPs) of autoclaved porcine blood; characterization of MAbs against blood, non-blood and plasma from different animal species using qualitative indirect non-competitive enzyme-linked immunosorbent assay (ELISA); and immunoblotting of antigenic components in HSPs of porcine blood.
TaqMan probe real-time polymerase chain reaction assay for the quantification of canine DNA in chicken nugget

Rahman MM, Hamid SB, Basirun WJ, Bhassu S, Rashid NR, Mustafa S, et al.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess, 2016;33(1):10-8.
PMID: 26458055 DOI: 10.1080/19440049.2015.1104558

This paper describes a short-amplicon-based TaqMan probe quantitative real-time PCR (qPCR) assay for the quantitative detection of canine meat in chicken nuggets, which are very popular across the world, including Malaysia. The assay targeted a 100-bp fragment of canine cytb gene using a canine-specific primer and TaqMan probe. Specificity against 10 different animals and plants species demonstrated threshold cycles (Ct) of 16.13 ± 0.12 to 16.25 ± 0.23 for canine DNA and negative results for the others in a 40-cycle reaction. The assay was tested for the quantification of up to 0.01% canine meat in deliberately spiked chicken nuggets with 99.7% PCR efficiency and 0.995 correlation coefficient. The analysis of the actual and qPCR predicted values showed a high recovery rate (from 87% ± 28% to 112% ± 19%) with a linear regression close to unity (R(2) = 0.999). Finally, samples of three halal-branded commercial chicken nuggets collected from different Malaysian outlets were screened for canine meat, but no contamination was demonstrated.
Polymerase chain reaction assay targeting cytochrome b gene for the detection of dog meat adulteration in meatball formulation

Rahman MM, Ali ME, Hamid SB, Mustafa S, Hashim U, Hanapi UK

Meat Sci, 2014 Aug;97(4):404-9.
PMID: 24769096 DOI: 10.1016/j.meatsci.2014.03.011

A polymerase chain reaction (PCR) assay for the assessment of dog meat adulteration in meatballs was developed. The assay selectively amplified a 100-bp region of canine mitochondrial cytochrome b gene from pure, raw, processed and mixed backgrounds. The specificity of the assay was tested against 11 animals and 3 plants species, commonly available for meatball formulation. The stability of the assay was proven under extensively autoclaving conditions that breakdown target DNA. A blind test from ready to eat chicken and beef meatballs showed that the assay can repeatedly detect 0.2% canine meat tissues under complex matrices using 0.04 ng of dog DNA extracted from differentially treated meatballs. The simplicity, stability and sensitivity of the assay suggested that it could be used in halal food industry for the authentication of canine derivatives in processed foods.
Reduction of Mo(VI) by the bacterium Serratia sp. strain DRY5

Rahman MF, Shukor MY, Suhaili Z, Mustafa S, Shamaan NA, Syed MA

J Environ Biol, 2009 Jan;30(1):65-72.
PMID: 20112865

The need to isolate efficient heavy metal reducers for cost effective bioremediation strategy have resulted in the isolation of a potent molybdenum-reducing bacterium. The isolate was tentatively identified as Serratia sp. strain DRY5 based on the Biolog GN carbon utilization profiles and partial 16S rDNA molecular phylogeny. Strain DRY5 produced 2.3 times the amount of Mo-blue than S. marcescens strain Dr.Y6, 23 times more than E. coli K12 and 7 times more than E. cloacae strain 48. Strain DRY5 required 37 degrees C and pH 7.0 for optimum molybdenum reduction. Carbon sources such as sucrose, maltose, glucose and glycerol, supported cellular growth and molybdate reduction after 24 hr of static incubation. The most optimum carbon source that supported reduction was sucrose at 1.0% (w/v). Ammonium sulphate, ammonium chloride, glutamic acid, cysteine, and valine supported growth and molybdate reduction with ammonium sulphate as the optimum nitrogen source at 0. 2% (w/v). Molybdate reduction was optimally supported by 30 mM molybdate. The optimum concentration of phosphate for molybdate reduction was 5 mM when molybdate concentration was fixed at 30 mM and molybdate reduction was totally inhibited at 100 mM phosphate. Mo-blue produced by this strain shows a unique characteristic absorption profile with a maximum peak at 865 nm and a shoulder at 700 nm, Dialysis tubing experiment showed that 95.42% of Mo-blue was found in the dialysis tubing suggesting that the molybdate reduction seen in this bacterium was catalyzed by enzyme(s). The characteristics of isolate DRY5 suggest that it would be useful in the bioremediation ofmolybdenum-containing waste.
Diagnosis and classification of optic neuritis

Petzold A, Fraser CL, Abegg M, Alroughani R, Alshowaeir D, Alvarenga R, et al.

Lancet Neurol, 2022 Dec;21(12):1120-1134.
PMID: 36179757 DOI: 10.1016/S1474-4422(22)00200-9

There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.
Occurrence and level of emerging organic contaminant in fish and mollusk from Klang River estuary, Malaysia and assessment on human health risk

Omar TFT, Aris AZ, Yusoff FM, Mustafa S

Environ Pollut, 2019 May;248:763-773.
PMID: 30851586 DOI: 10.1016/j.envpol.2019.02.060

The occurrence, level, and distribution of multiclass emerging organic contaminants (EOCs) in fish and mollusks from the Klang River estuary were examined. The targeted EOCs for this assessment were phenolic endocrine disrupting compounds (bisphenol A, 4-OP, and 4-NP), organophosphorous pesticides (quinalphos, chlorpyrifos, and diazinon), estrogenic hormones (E2, E1, and EE2), and pharmaceutically active chemicals (primidone, sulfamethoxazole, dexamethasone, diclofenac, amoxicillin, progesterone, and testosterone). Results from this study showed that the prevalent contamination of the Klang River estuary by EOCs with diclofenac, bisphenol A, progesterone, and amoxicillin were predominantly detected in fish and mollusks. Among the EOCs, diclofenac and progesterone had the highest concentrations in fish and mollusk samples, respectively. The concentrations of diclofenac and progesterone in fish and mollusk samples range from 1.42 ng/g to 10.76 ng/g and from 0.73 ng/g to 9.57 ng/g, respectively. Bisphenol A should also be highlighted because of its significant presence in both fish and mollusks. The concentration of bisphenol A in both matrices range from 0.92 ng/g to 5.79 ng/g. The calculated hazard quotient (HQ) for diclofenac, bisphenol A, and progesterone without consideration to their degradation byproduct were less than one, thus suggesting that the consumption of fish and mollusks from the Klang River estuary will unlikely pose any health risk to consumers on the basis of the current assessment. Nonetheless, this preliminary result is an important finding for pollution studies in Malaysian tropical coastal ecosystems, particularly for organic micropollutant EOCs, and can serve as a baseline database for future reference.
An improved SPE-LC-MS/MS method for multiclass endocrine disrupting compound determination in tropical estuarine sediments

Omar TFT, Aris AZ, Yusoff FM, Mustafa S

Talanta, 2017 Oct 01;173:51-59.
PMID: 28602191 DOI: 10.1016/j.talanta.2017.05.064

Estuary sediments are one of the important components of coastal ecosystems and have been regarded as a sink for various types of organic pollutants. Organic pollutants such as endocrine disrupting compounds (EDCs) which have been associated with various environmental and human health effects were detected in the estuary sediment at trace level. Considering various interferences that may exist in the estuarine sediment, a sensitive and selective method, capable of detecting multiclass EDC pollutants at the trace levels, needs to be developed and optimized to be applied for environmental analysis. A combination of Soxhlet extraction followed by offline solid phase extraction (SPE) cleaned up with detection based on LC triple quadrupole MS was optimized and validated in this study. The targeted compounds consisted of ten multiclass EDCs, namely, diclofenac, primidone, bisphenol A, estrone (E1), 17β-estradiol (E2), 17α-ethynylestradiol (EE2), 4-octylphenol (4-OP), 4-nonylphenol (4-NP), progesterone, and testosterone. The method showed high extraction efficiency with percentage of recovery from 78% to 108% and excellent sensitivity with detection limit between 0.02ngg-1 and 0.81ngg-1. Excellent linearity from 0.991 to 0.999 was achieved for the developed compounds and the relative standard deviation was less than 18%, an indication of good precision analysis. Evaluation of the matrix effects showed ionization suppression for all the developed compounds. Verification of the method was carried out by analyzing the estuarine sediment collected from Langat River. The analyzed estuarine sediments showed a trace concentration of diclofenac, bisphenol A, progesterone, testosterone, primidone, and E1. However, E2, EE2, 4-OP, and 4-NP were below the method's detection limit. Diclofenac exhibited the highest concentration at 2.67ngg-1 followed by bisphenol A (1.78ngg-1) while E1 showed the lowest concentration at 0.07ngg-1.
Risk assessment of pharmaceutically active compounds (PhACs) in the Klang River estuary, Malaysia

Omar TFT, Aris AZ, Yusoff FM, Mustafa S

Environ Geochem Health, 2019 Feb;41(1):211-223.
PMID: 30051257 DOI: 10.1007/s10653-018-0157-1

The concentration profile, distribution and risk assessment of pharmaceutically active compounds (PhACs) in the coastal surface water from the Klang River estuary were measured. Surface coastal water samples were extracted using offline solid phase, applying polymeric C18 cartridges as extraction sorbent and measuring with liquid chromatography mass spectrometry-mass spectrometry (LC MS-MS) technique. Extraction method was optimized for its recovery, sensitivity and linearity. Excellent recoveries were obtained from the optimized method with percentage of recoveries ranging from 73 to 126%. The optimized analytical method achieved good sensitivity with limit of detection ranging from 0.05 to 0.15 ng L-1, while linearity of targeted compounds in the LC MS-MS system was more than 0.990. The results showed that amoxicillin has the highest concentration (102.31 ng L-1) followed by diclofenac (10.80 ng L-1) and primidone (7.74 ng L-1). The percentage of contribution (% of total concentration) for the targeted PhACs is in the following order; amoxicillin (92.90%) > diclofenac (3.95%) > primidone (1.23%) > dexamethasone (0.75%) > testosterone (0.70%) > sulfamethoxazole (0.33%) > progesterone (0.14%). Environmental risk assessment calculated based on deterministic approach (the RQ method), showed no present risk from the presence of PhACs in the coastal water of Klang River estuary. Nonetheless, this baseline assessment can be used for better understanding on PhACs pollution profile and distribution in the tropical coastal and estuarine ecosystem as well as for future comparative studies.
Occurrence, distribution, and sources of emerging organic contaminants in tropical coastal sediments of anthropogenically impacted Klang River estuary, Malaysia

Omar TFT, Aris AZ, Yusoff FM, Mustafa S

Mar Pollut Bull, 2018 Jun;131(Pt A):284-293.
PMID: 29886949 DOI: 10.1016/j.marpolbul.2018.04.019

This baseline assessment reports on the occurrence, distribution, and sources of emerging organic contaminants (EOCs) in tropical coastal sediments of anthropogenically impacted Klang River estuary, Malaysia. Bisphenol A was the highest concentration detected at 16.84 ng g-1 dry weight, followed by diclofenac (13.88 ng g-1 dry weight) and E1 (12.47 ng g-1 dry weight). Five compounds, namely, amoxicillin, progesterone, diazinon, bisphenol A, and E1, were found in all sampling stations assessed, and other compounds such as primidone, diclofenac, testosterone, E2, and EE2 were ubiquitously present in sediment samples, with percentage of detection range from 89.04% to 98.38%. Organic carbon content and pH were the important factors controlling the fate of targeted compounds in the tropical estuarine sediment. On the basis of the literature from other studies, the sources of EOCs are thought to be from wastewater treatment plants, domestic/medical waste discharge, livestock activities, industrial waste discharge, and agricultural activities.
Fulltext Detection of Entamoeba histolytica in experimentally induced amoebic liver abscess: comparison of three staining methods

Ning TZ, Kin WW, Mustafa S, Ahmed A, Noordin R, Cheong TG, et al.

Asian Pac J Trop Biomed, 2012 Jan;2(1):61-5.
PMID: 23569836 DOI: 10.1016/S2221-1691(11)60191-3

To compare the efficacy of three different tissue stains, namely haematoxylin and eosin (H&E), periodic-acid Schiff (PAS) and immunohistochemical (IHC) stains for detection of Entamoeba histolytica (E. histolytica) trophozoites in abscessed liver tissues of hamster.
A survey on smartphone dependence and psychological effects among undergraduate students in a Malaysian University

Nasser NS, Loh JL, Rashid AA, Sharifat H, Ahmad U, Ibrahim B, et al.

Med J Malaysia, 2020 07;75(4):356-362.
PMID: 32723994

OBJECTIVE: Problematic smartphone use (PSU) is the development of pathological dependence at the expense of performing activities of daily living, thus having negative health and psychological impact on the users. Previous PSU studies focused on medical students and little is known regarding its effect on students undergoing other courses. The objective of this study is to identify the pattern of smartphone usage and determine the psychological factors affecting PSU among undergraduate students in Malaysia and compare the pattern among students from different fields of study.
METHOD: A prospective cross-sectional study was conducted using the validated Smartphone Addiction Scale-Malay version (SAS-M) questionnaire. One-way ANOVA was used to determine the correlation between the PSU among the students categorised by their ethnicity, hand dominance and by their field of study. MLR analysis was applied to predict PSU based on socio-demographic data, usage patterns, psychological factors and fields of study.
RESULTS: A total of 1060 students completed the questionnaire. Most students had some degree of problematic usage of the smartphone. Students used smartphones predominantly to access SNAs, namely Instagram. Longer duration on the smartphone per day, younger age at first using a smartphone and underlying depression carried higher risk of developing PSU, whereas the field of study (science vs. humanities based) did not contribute to an increased risk of developing PSU.
CONCLUSION: Findings from this study can help better inform university administrators about at- risk groups of undergraduate students who may benefit from targeted intervention designed to reduce their addictive behaviour patterns.
Fulltext Impact of prebiotics on equol production from soymilk isoflavones by two Bifidobacterium species

Mustafa SE, Mustafa S, Ismail A, Abas F, Abd Manap MY, Ahmed Hamdi OA, et al.

Heliyon, 2020 Oct;6(10):e05298.
PMID: 33134584 DOI: 10.1016/j.heliyon.2020.e05298

The influence of commercial prebiotics (fructo-oligosaccharides and inulin) and sugars (glucose and sucrose) on enhancing equol production from soymilk isoflavones by Bifidobacterium longum BB536 and Bifidobacterium breve ATCC 15700 was evaluated in vitro. Sterilized soymilk was inoculated with each bacterial species at 37 °C for 48 h. The growth and β-glucosidase enzyme activity for the two Bifidobacterium species in soymilk throughout fermentation were assessed. The highest viable count for B. breve (8.75 log CFU/ml) was reached at 36 h and for B. longum (8.55 log CFU/ml) at 24 h. Both bacterial species displayed β-glucosidase activity. B. breve showed increased enzyme activity (4.126 U) at 36 h, while B. longum exhibited maximum activity (3.935 U) at 24 h of fermentation. Among the prebiotics screened for their effect in isoflavones transformation to equol, inulin delivered the highest effect on equol production. The co-culture of B. longum BB536 and B. breve ATCC15700 in soymilk supplemented with inulin produced the highest level (11.49 mmol/l) of equol at 48 h of fermentation process. Level of daidzin declined whereas that of daidzein increased, and then gradually decreased due to formation of equol when soymilk was fermented using bifidobacterial. This suggests that the nutritional value of soymilk may be increased by increasing bioavailability of the bioactive ingredients. Collectively these data identify probiotics and prebiotic combinations suitable for inclusion in soymilk to enhance equol production.
Optimization of culture conditions of soymilk for equol production by Bifidobacterium breve 15700 and Bifidobacterium longum BB536

Mustafa SE, Mustafa S, Abas F, Manap MYABD, Ismail A, Amid M, et al.

Food Chem, 2019 Apr 25;278:767-772.
PMID: 30583440 DOI: 10.1016/j.foodchem.2018.11.107

This study analyzed the effect of pH (X1), temperature (X2) and inulin amount (X3) on transformation of isoflavones (daidzin and daidzein) to equol in soymilk fermented with Bifidobacterium spp. All responses significantly (p  0.05) difference between the experimental and predicted values, suggested the suitability of established models in explaining the daidzin and daidzein transformation to equol as a function of pH, temperature and inulin.
Modelling contaminant transport for pumping wells in riverbank filtration systems

Mustafa S, Bahar A, Aziz ZA, Suratman S

J Environ Manage, 2016 Jan 01;165:159-166.
PMID: 26433356 DOI: 10.1016/j.jenvman.2015.09.026

Analytical study of the influence of both the pumping well discharge rate and pumping time on contaminant transport and attenuation is significant for hydrological and environmental science applications. This article provides an analytical solution for investigating the influence of both pumping time and travelling time together for one-dimensional contaminant transport in riverbank filtration systems by using the Green's function approach. The basic aim of the model is to understand how the pumping time and pumping rate, which control the travelling time, can affect the contaminant concentration in riverbank filtration systems. Results of analytical solutions are compared with the results obtained using a MODFLOW numerical model. Graphically, it is found that both analytical and numerical solutions have almost the same behaviour. Additionally, the graphs indicate that any increase in the pumping rate or simulation pumping time should increase the contamination in groundwater. The results from the proposed analytical model are well matched with the data collected from a riverbank filtration site in France. After this validation, the model is then applied to the first pilot project of a riverbank filtration system conducted in Malaysia. Sensitivity analysis results highlight the importance of degradation rates of contaminants on groundwater quality, for which higher utilization rates lead to the faster consumption of pollutants.
Solute transport modelling to manage groundwater pollution from surface water resources

Mustafa S, Bahar A, Aziz ZA, Darwish M

J Contam Hydrol, 2020 Aug;233:103662.
PMID: 32569923 DOI: 10.1016/j.jconhyd.2020.103662

This article provides an analytical solute transport model to investigate the potential of groundwater contamination by polluted surface water in a two dimensional domain. The clogging of streambed which makes the aquifer partially penetrated by the stream, is considered in the model. The impacts of pumping process, hydraulic conductivity and clogging layer on the quality of water produced from nearby drinking water wells are evaluated. It is found that results are consistent with numerical simulation conducted by MODFLOW software. Moreover, the model is applied using data of contamination occurrence in Malaysia, where high contaminants concentrations are found close to streams. Results show that the pumping activities (rate and time period) are crucial factors when evaluating the risk of groundwater contamination from surface water. Additionally, this study illustrates that the increase in either hydraulic conductivity or leakance coefficient parameters due to the clogging layer will enlarge the area of contamination. The model is able to determine the suitable pumping rate and location of the well so that the contamination plume never reaches the extraction well, which is useful in constructing riverbank filtration sites.
Recombinant Enterovirus 71 Viral Protein 1 Fused to a Truncated Newcastle Disease Virus NP (NPt) Carrier Protein

Mustafa S, Abd-Aziz N, Saw WT, Liew SY, Yusoff K, Shafee N

Vaccines (Basel), 2020 Dec 07;8(4).
PMID: 33297428 DOI: 10.3390/vaccines8040742

Enterovirus 71 (EV71) is the major causative agent in hand, foot, and mouth disease (HFMD), and it mainly infects children worldwide. Despite the risk, there is no effective vaccine available for this disease. Hence, a recombinant protein construct of truncated nucleocapsid protein viral protein 1 (NPt-VP1198-297), which is capable of inducing neutralizing antibody against EV71, was evaluated in a mouse model. Truncated nucleocapsid protein Newcastle disease virus that was used as immunological carrier fused to VP1 of EV71 as antigen. The recombinant plasmid carrying corresponding genes was constructed by recombinant DNA technology and the corresponding protein was produced in Escherichia coli expression system. The recombinant NPt-VP1198-297 protein had elicited neutralizing antibodies against EV71 with the titer of 1:16, and this result is higher than the titer that is elicited by VP1 protein alone (1:8). It was shown that NPt containing immunogenic epitope(s) of VP1 was capable of inducing a greater functional immune response when compared to full-length VP1 protein alone. It was capable to carry larger polypeptide compared to full-length NP protein. The current study also proved that NPt-VP1198-297 protein can be abundantly produced in recombinant protein form by E. coli expression system. The findings from this study support the importance of neutralizing antibodies in EV71 infection and highlight the potential of the recombinant NPt-VP1198-297 protein as EV71 vaccine.
Analytical Modeling of Well Design in Riverbank Filtration Systems

Mustafa S, Darwish M, Bahar A, Aziz ZA

Ground Water, 2019 09;57(5):756-763.
PMID: 30740693 DOI: 10.1111/gwat.12868

Analytical studies for well design adjacent to river banks are the most significant practical task in cases involving the efficiency of riverbank filtration systems. In times when high pollution of river water is joined with increasing water demand, it is necessary to design pumping wells near the river that provide acceptable amounts of river water with minimum contaminant concentrations. This will guarantee the quality and safety of drinking water supplies. This article develops an analytical solution based on the Green's function approach to solve an inverse problem: based on the required level of contaminant concentration and planned pumping time period, the shortest distance to the riverbank that has the maximum percentage of river water is determined. This model is developed in a confined and homogenous aquifer that is partially penetrated by the stream due to the existence of clogging layers. Initially, the analytical results obtained at different pumping times, rates and with different values of initial concentration are checked numerically using the MODFLOW software. Generally, the distance results obtained from the proposed model are acceptable. Then, the model is validated by data related to two pumping wells located at the first riverbank filtration pilot project conducted in Malaysia.
Population pharmacokinetics of nevirapine in Malaysian HIV patients: a non-parametric approach

Mustafa S, Yusuf WN, Woillard JB, Choon TS, Hassan NB

Eur J Clin Pharmacol, 2016 Jul;72(7):831-8.
PMID: 27025609 DOI: 10.1007/s00228-016-2049-6

AIMS: Nevirapine is the first non-nucleoside reverse-transcriptase inhibitor approved and is widely used in combination therapy to treat HIV-1 infection. The pharmacokinetics of nevirapine was extensively studied in various populations with a parametric approach. Hence, this study was aimed to determine population pharmacokinetic parameters in Malaysian HIV-infected patients with a non-parametric approach which allows detection of outliers or non-normal distribution contrary to the parametric approach.
METHODS: Nevirapine population pharmacokinetics was modelled with Pmetrics. A total of 708 observations from 112 patients were included in the model building and validation analysis. Evaluation of the model was based on a visual inspection of observed versus predicted (population and individual) concentrations and plots weighted residual error versus concentrations. Accuracy and robustness of the model were evaluated by visual predictive check (VPC). The median parameters' estimates obtained from the final model were used to predict individual nevirapine plasma area-under-curve (AUC) in the validation dataset. The Bland-Altman plot was used to compare the AUC predicted with trapezoidal AUC.
RESULTS: The median nevirapine clearance was of 2.92 L/h, the median rate of absorption was 2.55/h and the volume of distribution was 78.23 L. Nevirapine pharmacokinetics were best described by one-compartmental with first-order absorption model and a lag-time. Weighted residuals for the model selected were homogenously distributed over the concentration and time range. The developed model adequately estimated AUC.
CONCLUSIONS: In conclusion, a model to describe the pharmacokinetics of nevirapine was developed. The developed model adequately describes nevirapine population pharmacokinetics in HIV-infected patients in Malaysia.
Exploring CYP2B6 activity by measuring the presence ofnevirapine hydroxy metabolites in plasma

Mustafa S, Hassan NB, Tan SC, Ab Rahman AK, Low LL, Wan Yusuf WN

Turk J Med Sci, 2016 Dec 20;46(6):1875-1881.
PMID: 28081342 DOI: 10.3906/sag-1503-116

BACKGROUND/AIM: Nevirapine is a reverse-transcriptase inhibitor widely used in combination therapy to treat HIV infection. Nevirapine is extensively metabolized in the liver and CYP2B6 is mainly responsible for oxidation of 3-hydroxynevirapine (3-OH NVP). This study aims to explore CYP2B6 activity by measuring 2-hydroxynevirapine (2-OH NVP) and 3-OH NVP in plasma and to identify factors associated with nevirapine pharmacokinetic parameters.
MATERIALS AND METHODS: A total of 112 patients were recruited and treated with nevirapine-based antiretroviral therapy. Plasma nevirapine and metabolite concentrations were assayed using high-performance liquid chromatography via liquid-liquid extraction.
RESULTS: Thirty-nine (34.8%) of the patients had no 3-OH NVP detected in their plasma while 2-OH NVP was detected in all patients. Metabolite concentrations were low compared to nevirapine. Positive correlations were observed between nevirapine and its metabolites, 2-OH NVP (P < 0.01) and 3-OH NVP (P = 0.012). Nevirapine concentration was decreased when concomitantly administered with methadone. Univariate analysis showed that ALT level, AST level, and detection of 3-OH NVP were associated with nevirapine pharmacokinetic parameters.
CONCLUSION: The variability of nevirapine pharmacokinetic parameters was caused by liver enzymes and the presence of 3-OH NVP metabolites. The presence of 3-OH NVP can probably be used to distinguished CYP2B6 activity and efficacy of nevirapine in patients with HIV infection.

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