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Human health risk assessment and bioaccumulation of trace metals in fish species collected from the Miri coast, Sarawak, Borneo

A A, R N, K P, Bing CH, R R

Mar Pollut Bull, 2018 Aug;133:655-663.
PMID: 30041362 DOI: 10.1016/j.marpolbul.2018.06.033

The concentrations of nine trace metals (Cr, Mn, Co, Ni, Cu, Zn, Rb, Cd, and Pb) were measured in different tissues of two pelagic and five demersal fish species collected from the Miri coast, Sarawak. The sequence of accumulation of trace metals in different tissues were: liver > gill > gonad > muscle. Zn (301.00 μg g-1) and Cd (0.10 μg g-1) was the maximum and minimum accumulated elements. According to the Hazard Index calculation, none of the elements will pose any adverse health effects to humans for both ingestion rates (normal and habitual fish consumers) proposed by USEPA, except for Pb and Cd in certain fish species. On the basis of the results, the level of elements in the edible muscle tissues of all the analyzed fish species from the Miri coast are below the maximum permissible limits of Malaysian and International seafood guideline values and safe for consumers.

Matched MeSH terms: Metals/pharmacokinetics*; Water Pollutants, Chemical/pharmacokinetics*
Estimating drug-free period using a graphical method: an alternative way to monitor extended-interval dosing of gentamicin therapy

Ab Rahman AF, Md Sahak N, Ali AM

Int J Pharm Pract, 2017 Feb;25(1):75-80.
PMID: 28097717 DOI: 10.1111/ijpp.12336

OBJECTIVES: Published nomograms to monitor extended-interval dosing (EID) gentamicin therapy were based on a fixed dose of 5 or 7 mg/kg. However, the average dose used for EID gentamicin regimen in our setting was about 3 mg/kg per day. We developed a new method of monitoring based on the duration of drug-free period (DFP) in a 24-h dosing interval.
METHODS: Hospitalised adult patients on EID gentamicin were selected. We considered a DFP of between 2 and 8 h as appropriate. Data from two blood samples (2 and 6 h postdose) from each patient were used to estimate the duration of DFP (i.e. DFP method 1). DFP was also calculated for the same patient using an empirically estimated elimination rate constant (Ke ) and the same 6 h postdose concentration value (DFP method 2). Correlation between the two methods was made. An alternative graphical method to estimate DFP was attempted.
KEY FINDINGS: Correlation between Ke and age was favourable (r = -0.453; P = 0.001). Ke derived from this empirical relationship was used to estimate DFP method 2. DFP method 1 correlated well with DFP method 2 (r = 0.742; P

Matched MeSH terms: Gentamicins/pharmacokinetics*
Designing novel bioconjugates of hydroxyethyl cellulose and salicylates for potential pharmaceutical and pharmacological applications

Abbas K, Amin M, Hussain MA, Sher M, Bukhari SNA, Jantan I, et al.

Int J Biol Macromol, 2017 Oct;103:441-450.
PMID: 28526350 DOI: 10.1016/j.ijbiomac.2017.05.061

This deals with fabrication of macromolecular prodrugs (MPDs) of salicylic acid (SA) and aspirin (ASP) based on a hydrophilic cellulose ether, hydroxyethyl cellulose (HEC). Degrees of substitution (DS) of SA and ASP per HEC repeating unit (HEC-RU) were achieved ranging from 0.60 to 2.18 and 0.53 to1.50, respectively. The amphiphilic HEC-SA conjugate 2 assembled into nanowire-like structures, while HEC-ASP conjugate 6 formed nanoparticles (diameter 300-00nm) at a water/DMSO interface. After oral administration in rabbit models, conjugates 2 and 6 showed plasma half-life of 6.96 and 7.01h with maximum plasma concentration (Cmax) of 15.27 and 23.01μg L-1, respectively, and each reached peak plasma concentration (tmax) at 4.0h. Immunomodulatory assays (interleukin 6 and tumor necrosis factor-α values) revealed that anti-inflammatory properties of SA and ASP were unaltered in conjugates. Swelling inhibition of 61 and 71% was observed for conjugates 2 and 6, respectively, in a carrageenan induced paw edema test. Cytotoxic profiling (MTT assay) showed that conjugates were safe for administration in the concentration range of 2-10mM up to 24h. Thermal analyses revealed that Tdm values of SA and ASP conjugates were increased by 99 and 154̊C, respectively, indicating extraordinary thermal stability imparted to drugs after MPD formation.

Matched MeSH terms: Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics; Salicylates/pharmacokinetics
Comparative analysis of antioxidant and antiproliferative activities of Rhodomyrtus tomentosa extracts prepared with various solvents

Abd Hamid H, Mutazah R, Yusoff MM, Abd Karim NA, Abdull Razis AF

Food Chem Toxicol, 2017 Oct;108(Pt B):451-457.
PMID: 27725206 DOI: 10.1016/j.fct.2016.10.004

Rhodomyrtus tomentosa (Aiton) Hassk. has a wide spectrum of pharmacological effects and has been used to treat wounds, colic diarrhoea, heartburns, abscesses and gynaecopathy. The potential antiproliferative activities of R. tomentosa extracts from different solvents were evaluated in vitro on HepG2, MCF-7 and HT 29 cell lines while antioxidant activity was monitored by radical scavenging assay (DPPH), copper reducing antioxidant capacity (CUPRAC) and β-carotene bleaching assay. Extracts from R. tomentosa show the viability of the cells in concentration-dependent manner. According to the IC50 obtained, the ethyl acetate extracts showed significant antiproliferative activity on HepG2 (IC50 11.47 ± 0.280 μg/mL), MCF-7 (IC50 2.68 ± 0.529 μg/mL) and HT 29 (IC50 16.18 ± 0.538 μg/mL) after 72 h of treatment. Bioassay guided fractionation of the ethyl acetate extract led to the isolation of lupeol. Methanol extracts show significant antioxidant activities in DPPH (EC50 110.25 ± 0.005 μg/ml), CUPRAC (EC50 53.84 ± 0.004) and β-carotene bleaching (EC50 58.62 ± 0.001) due to the presence of high total flavonoid and total phenolic content which were 110.822 ± 0.017 mg butylated hydroxytoluene (BHT)/g and 190.467 ± 0.009 mg gallic acid (GAE)/g respectively. Taken together, the results extracts show the R. tomentosa as a potential source of antioxidant and antiproliferative efficacy.

Matched MeSH terms: Antineoplastic Agents, Phytogenic/pharmacokinetics*
Fulltext Exposure-effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

Abd Rahman AN, Tett SE, Abdul Gafor HA, McWhinney BC, Staatz CE

Br J Clin Pharmacol, 2015 Nov;80(5):1064-75.
PMID: 25959850 DOI: 10.1111/bcp.12678

AIMS: The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.
METHODS: Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.
RESULTS: Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l(-1) h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l(-1) , P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l(-1) h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l(-1) h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l(-1) h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).
CONCLUSIONS: This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.
KEYWORDS: lupus nephritis; mycophenolic acid; pharmacodynamics; pharmacokinetics; prednisolone; treatment outcome
Study site: Nephrology and SLE Clinics, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia

Matched MeSH terms: Immunosuppressive Agents/pharmacokinetics*; Mycophenolic Acid/pharmacokinetics*; Prednisolone/pharmacokinetics*
How accurate and precise are limited sampling strategies in estimating exposure to mycophenolic acid in people with autoimmune disease?

Abd Rahman AN, Tett SE, Staatz CE

Clin Pharmacokinet, 2014 Mar;53(3):227-245.
PMID: 24327238 DOI: 10.1007/s40262-013-0124-z

Mycophenolic acid (MPA) is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. Dosing to achieve a specific target MPA area under the concentration-time curve from 0 to 12 h post-dose (AUC12) is likely to lead to better treatment outcomes in patients with autoimmune disease than a standard fixed-dose strategy. This review summarizes the available published data around concentration monitoring strategies for MPA in patients with autoimmune disease and examines the accuracy and precision of methods reported to date using limited concentration-time points to estimate MPA AUC12. A total of 13 studies were identified that assessed the correlation between single time points and MPA AUC12 and/or examined the predictive performance of limited sampling strategies in estimating MPA AUC12. The majority of studies investigated mycophenolate mofetil (MMF) rather than the enteric-coated mycophenolate sodium (EC-MPS) formulation of MPA. Correlations between MPA trough concentrations and MPA AUC12 estimated by full concentration-time profiling ranged from 0.13 to 0.94 across ten studies, with the highest associations (r (2) = 0.90-0.94) observed in lupus nephritis patients. Correlations were generally higher in autoimmune disease patients compared with renal allograft recipients and higher after MMF compared with EC-MPS intake. Four studies investigated use of a limited sampling strategy to predict MPA AUC12 determined by full concentration-time profiling. Three studies used a limited sampling strategy consisting of a maximum combination of three sampling time points with the latest sample drawn 3-6 h after MMF intake, whereas the remaining study tested all combinations of sampling times. MPA AUC12 was best predicted when three samples were taken at pre-dose and at 1 and 3 h post-dose with a mean bias and imprecision of 0.8 and 22.6 % for multiple linear regression analysis and of -5.5 and 23.0 % for maximum a posteriori (MAP) Bayesian analysis. Although mean bias was less when data were analysed using multiple linear regression, MAP Bayesian analysis is preferable because of its flexibility with respect to sample timing. Estimation of MPA AUC12 following EC-MPS administration using a limited sampling strategy with samples drawn within 3 h post-dose resulted in biased and imprecise results, likely due to a longer time to reach a peak MPA concentration (t max) with this formulation and more variable pharmacokinetic profiles. Inclusion of later sampling time points that capture enterohepatic recirculation and t max improved the predictive performance of strategies to predict EC-MPS exposure. Given the considerable pharmacokinetic variability associated with mycophenolate therapy, limited sampling strategies may potentially help in individualizing patient dosing. However, a compromise needs to be made between the predictive performance of the strategy and its clinical feasibility. An opportunity exists to combine research efforts globally to create an open-source database for MPA (AUC, concentrations and outcomes) that can be used and prospectively evaluated for AUC target-controlled dosing of MPA in autoimmune diseases.

Matched MeSH terms: Antibiotics, Antineoplastic/pharmacokinetics*; Mycophenolic Acid/pharmacokinetics*
Development of improved dosing regimens for mycophenolate mofetil based on population pharmacokinetic analyses in adults with lupus nephritis

Abd Rahman AN, Tett SE, Abdul Gafor HA, McWhinney BC, Staatz CE

Eur J Drug Metab Pharmacokinet, 2017 Dec;42(6):993-1004.
PMID: 28536776 DOI: 10.1007/s13318-017-0420-3

BACKGROUND AND OBJECTIVE: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-β-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements.
METHODS: MPA and MPAG concentration-time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions.
RESULTS: A total of 225 and 226 concentration-time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM® software. A two-compartment model with first-order absorption and elimination for MPA and a one-compartment model with first-order elimination and enterohepatic circulation (EHC) for MPAG best described the data. Apparent clearance of MPAG (CL/F MPAG) significantly decreased with reducing renal function and extent of EHC was reduced with concomitant CsA use. Simulations using the final model showed that a 70-kg subject with a creatinine clearance of 90 mL/min receiving concomitant CsA would require 1.25 g of MMF twice daily while a similar subject who did not receive concomitant CsA would require 0.75 g twice daily to achieve a MPA area under the concentration-time curve from 0 to 12 h (AUC0-12) of 45 mg·h/L.
CONCLUSION: A 'tiered' dosing approach considering patient renal function and CsA co-therapy, rather than a 'one dose fits all' approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.
Study site: Nephrology and Systemic Lupus Erythematosus (SLE) Clinics, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia

Matched MeSH terms: Immunosuppressive Agents/pharmacokinetics; Mycophenolic Acid/pharmacokinetics*; Glucuronides/pharmacokinetics
Fulltext Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Abdul-Aziz MH, Abd Rahman AN, Mat-Nor MB, Sulaiman H, Wallis SC, Lipman J, et al.

Antimicrob Agents Chemother, 2016 01;60(1):206-14.
PMID: 26482304 DOI: 10.1128/AAC.01543-15

Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CL(CR)), such that a 30-ml/min increase in the estimated CL(CR) would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL(CR) of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL(CR) of >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.

Matched MeSH terms: Anti-Bacterial Agents/pharmacokinetics*; Carbapenems/pharmacokinetics*
A review on the use of statins and tocotrienols, individually or in combination for the treatment of osteoporosis

Abdul-Majeed S, Mohamed N, Soelaiman IN

Curr Drug Targets, 2013 Dec;14(13):1579-90.
PMID: 23848479

Skeletal tissue undergoes continuous remodeling which makes it unique among other body tissues. Osteoporosis is a common bone metabolic disorder affecting both men and women. Osteoporosis and its complications mainly osteoporotic fractures, have a high impact on health and economy. Current approved medications are associated with numerous side effects, which limit their use. Identification of a new and safe therapy is mandatory. Statins, also known as HMGCoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia and for the prevention of morbidity and mortality associated with cardiovascular disease. Statins improved bone health status in intact and ovariectomised rodents following high clinically intolerable oral doses. However, this beneficial effect of statins could not be significantly demonstrated in humans. The reason behind this discrepancy might be due to the safety and bioavailability of the currently used oral statins. Vitamin E, especially the tocotrienols at the dose 60 mg/kg/day provided significant antiosteoporotic effects in different animal models of osteoporosis. The use of the aforementioned dose of tocotrienols was shown to be safe in both humans and animals. Enhancement of bone formation and reduction of bone resorption were achieved more effectively by a combination of tocotrienols and statins than by either treatment when supplemented separately at clinically tolerable doses. Therefore, the adverse effects associated with high statin doses might be avoided with the coadministration of tocotrienols. Moreover, the combination therapy strategy might be useful for patients who are at high risk of osteoporosis, cardiovascular events and hypercholesterolaemia.

Matched MeSH terms: Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics; Tocotrienols/pharmacokinetics
Fulltext Topical piroxicam in vitro release and in vivo anti-inflammatory and analgesic effects from palm oil esters-based nanocream

Abdulkarim MF, Abdullah GZ, Chitneni M, Salman IM, Ameer OZ, Yam MF, et al.

Int J Nanomedicine, 2010 Nov 04;5:915-24.
PMID: 21116332 DOI: 10.2147/IJN.S13305

INTRODUCTION: During recent years, there has been growing interest in use of topical vehicle systems to assist in drug permeation through the skin. Drugs of interest are usually those that are problematic when given orally, such as piroxicam, a highly effective anti-inflammatory, anti-pyretic, and analgesic, but with the adverse effect of causing gastrointestinal ulcers. The present study investigated the in vitro and in vivo pharmacodynamic activity of a newly synthesized palm oil esters (POEs)-based nanocream containing piroxicam for topical delivery.
METHODS: A ratio of 25:37:38 of POEs: external phase: surfactants (Tween 80:Span 20, in a ratio 80:20), respectively was selected as the basic composition for the production of a nanocream with ideal properties. Various nanocreams were prepared using phosphate-buffered saline as the external phase at three different pH values. The abilities of these formulae to deliver piroxicam were assessed in vitro using a Franz diffusion cell fitted with a cellulose acetate membrane and full thickness rat skin. These formulae were also evaluated in vivo by comparing their anti-inflammatory and analgesic activities with those of the currently marketed gel.
RESULTS: After eight hours, nearly 100% of drug was transferred through the artificial membrane from the prepared formula F3 (phosphate-buffered saline at pH 7.4 as the external phase) and the marketed gel. The steady-state flux through rat skin of all formulae tested was higher than that of the marketed gel. Pharmacodynamically, nanocream formula F3 exhibited the highest anti- inflammatory and analgesic effects as compared with the other formulae.
CONCLUSION: The nanocream containing the newly synthesized POEs was successful for trans-dermal delivery of piroxicam.

Matched MeSH terms: Analgesics/pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics; Piroxicam/pharmacokinetics
Adsorption, desorption, and mobility of metsulfuron methyl in Malaysian agricultural soils

Abdullah AR, Sinnakkannu S, Tahir NM

Bull Environ Contam Toxicol, 2001 Jun;66(6):762-9.
PMID: 11353379
Matched MeSH terms: Arylsulfonates/pharmacokinetics; Herbicides/pharmacokinetics
The effect of food deprivation on the rate of sulfamethazine elimination in goats

Abdullah AS, Baggot JD

Vet Res Commun, 1988;12(6):441-6.
PMID: 3222919

The disposition kinetics and cumulative urinary excretion of sulfamethazine were compared in goats fed normally (control) and following a 72-hour period of starvation (fasting). The only pharmacokinetic parameter which showed a statistically significant difference between the two groups was the body (systemic) clearance. This decreased from 2.26 +/- 0.28 ml/min.kg (means +/- SD, n = 6) in the control group to 1.16 +/- 0.54 ml/min.kg in the fasting group (p less than 0.01). Since the apparent volume of distribution was not affected by starvation, the decreased clearance was attributed to slower metabolism of the drug. Because of the analytical method used to measure sulfamethazine concentrations in plasma and urine, no conclusion could be drawn as to whether the rates of hydroxylation or of acetylation, or both metabolic pathways were decreased in the starved condition.

Matched MeSH terms: Sulfamethazine/pharmacokinetics*
Fulltext In vitro permeation and in vivo anti-inflammatory and analgesic properties of nanoscaled emulsions containing ibuprofen for topical delivery

Abdullah GZ, Abdulkarim MF, Salman IM, Ameer OZ, Yam MF, Mutee AF, et al.

Int J Nanomedicine, 2011;6:387-96.
PMID: 21499428 DOI: 10.2147/IJN.S14667

As a topical delivery system, a nanoscaled emulsion is considered a good carrier of several active ingredients that convey several side effects upon oral administration, such as nonsteroidal anti-inflammatory drugs (NSAIDs).

Matched MeSH terms: Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics*; Ibuprofen/pharmacokinetics*
Preparation and in vitro evaluation of mebeverine HCl colon-targeted drug delivery system

Abdullah GZ, Abdulkarim MF, Chitneni M, Mutee AF, Ameer OZ, Salman IM, et al.

Pharm Dev Technol, 2011 Aug;16(4):331-42.
PMID: 20429815 DOI: 10.3109/10837451003739255

Mebeverine HCl is a water soluble drug commonly used to treat irritable bowel syndrome by acting directly on the smooth muscles of the colon. This work was aimed at the formulation and in vitro evaluation of a colon-targeted drug delivery system containing mebeverine HCl. Matrix tablets were prepared using ethyl cellulose (EC), Eudragit RL 100 either solely or in combination by wet granulation technique. Dissolution was carried out in 0.1 N HCl for 2?h followed by pH 6.8 phosphate buffer for eight hours. Uncoated forms released more than 5% drug in 0.1 N HCl therefore, Eudragit L100 was used as a coat. The results indicated very slow release profile. As a result, single retardant was used to prepare the matrix and coated by Eudragit L 100. The matrix containing 7% Eudragit RL 100 and 6% of binder was subjected to further studies to assess the effect of different coats (Eudragit L 100-55 and cellulose acetate phthalate) and different binders (pectin and sodium alginate) on the release profile. Eudragit L 100 and pectin were the best coating agent and binder, respectively. The final formula was stable and it can be concluded that the prepared system has the potential to deliver mebeverine HCl in vivo to the colon.

Matched MeSH terms: Phenethylamines/pharmacokinetics; Tablets, Enteric-Coated/pharmacokinetics
Carbopol 934, 940 and Ultrez 10 as viscosity modifiers of palm olein esters based nano-scaled emulsion containing ibuprofen

Abdullah GZ, Abdulkarim MF, Mallikarjun C, Mahdi ES, Basri M, Sattar MA, et al.

Pak J Pharm Sci, 2013 Jan;26(1):75-83.
PMID: 23261730

Micro-emulsions and sometimes nano-emulsions are well known candidates to deliver drugs locally. However, the poor rheological properties are marginally affecting their acceptance pharmaceutically. This work aimed to modify the poor flow properties of a nano-scaled emulsion comprising palm olein esters as the oil phase and ibuprofen as the active ingredient for topical delivery. Three Carbopol ® resins: 934, 940 and Ultrez 10, were utilized in various concentrations to achieve these goals. Moreover, phosphate buffer and triethanolamine solutions pH 7.4 were used as neutralizing agents to assess their effects on the gel-forming and swelling properties of Carbopol ® 940. The addition of these polymers caused the produced nano-scaled emulsion to show a dramatic droplets enlargement of the dispersed globules, increased intrinsic viscosity, consistent zeta potential and transparent-to-opaque change in appearance. These changes were relatively influenced by the type and the concentration of the resin used. Carbopol ® 940 and triethanolamine appeared to be superior in achieving the proposed tasks compared to other materials. The higher the pH of triethanolamine solution, the stronger the flow-modifying properties of Carbopol ® 940. Transmission electron microscopy confirmed the formation of a well-arranged gel network of Carbopol ® 940, which was the major cause for all realized changes. Later in vitro permeation studies showed a significant decrease in the drug penetration, thus further modification using 10% w/w menthol or limonene as permeation promoters was performed. This resulted in in vitro and in vivo pharmacodynamics properties that are comparably higher than the reference chosen for this study.

Matched MeSH terms: Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics; Ibuprofen/pharmacokinetics
Physicochemical and sorption characteristics of Malaysian Ceiba pentandra (L.) Gaertn. as a natural oil sorbent

Abdullah MA, Rahmah AU, Man Z

J Hazard Mater, 2010 May 15;177(1-3):683-91.
PMID: 20060641 DOI: 10.1016/j.jhazmat.2009.12.085

Ceiba pentandra (L.) Gaertn (kapok) is a natural sorbent that exhibits excellent hydrophobic-oleophilic characteristics. The effect of packing density, the oil types and solvent treatment on the sorption characteristics of kapok was studied in a batch system. Oil sorption capacity, retention capacity, entrapment stability and kapok reusability were evaluated. Based on SEM and FTIR analyses, kapok fiber was shown to be a lignocellulosic material with hydrophobic waxy coating over the hollow structures. Higher packing density at 0.08 g/ml showed lower sorption capacity, but higher percentage of dynamic oil retention, with only 1% of oil drained out from the test cell. Kapok remained stable after fifteen cycles of reuse with only 30% of sorption capacity reduction. The oil entrapment stability at 0.08 g/ml packing was high with more than 90% of diesel and used engine oil retained after horizontal shaking. After 8h of chloroform and alkali treatment, 2.1% and 26.3% reduction in sorption capacity were observed, respectively, as compared to the raw kapok. The rigid hollow structure was reduced to flattened-like structure after alkali treatment, though no major structural difference was observed after chloroform treatment. Malaysian kapok has shown great potential as an effective natural oil sorbent, owing to high sorption and retention capacity, structural stability and high reusability.

Matched MeSH terms: Oils/pharmacokinetics*
Defining a threshold for tacrolimus intra-patient variability associated with late acute cellular rejection in paediatric kidney transplant recipients

Abu Bakar K, Mohamad NA, Hodi Z, McCulloch T, Williams A, Christian M, et al.

Pediatr Nephrol, 2019 12;34(12):2557-2562.
PMID: 31520127 DOI: 10.1007/s00467-019-04346-z

BACKGROUND: Late acute cellular rejection (LACR) is associated with poorer graft outcomes and non-adherence. Non-adherence to tacrolimus can be indirectly assessed by the intra-patient variability (IPV) of tacrolimus trough levels. The threshold of IPV associated with rejection is not known.
METHODS: We conducted a case-control study comparing 25 patients with biopsy-proven LACR against 25 stable controls matched for age group, primary diagnosis and time post-transplant. IPV was calculated using coefficient of variance (CV) and mean absolute deviation (MAD) using tacrolimus levels in the preceding 12 months. We also assessed the percentage time for tacrolimus levels

Matched MeSH terms: Immunosuppressive Agents/pharmacokinetics; Tacrolimus/pharmacokinetics
The influence of genetic polymorphisms on the efficacy and side effects of anastrozole in postmenopausal breast cancer patients

Abubakar MB, Wei K, Gan SH

Pharmacogenet Genomics, 2014 Dec;24(12):575-81.
PMID: 25203739 DOI: 10.1097/FPC.0000000000000092

Breast cancer is a common cause of cancer mortality among women. Several genetic factors have been implicated in its development. Current treatment guidelines for estrogen receptor-positive breast cancer recommend that anastrozole [or any of the other two aromatase inhibitors (letrozole and exemestane)] is used as an alternative to tamoxifen or following several years of tamoxifen treatment. Nevertheless, this approach is still associated with many challenges, ranging from the recurrence of breast cancer to considerable interindividual variability in the tolerability of anastrozole, which may cause adverse effects, such as musculoskeletal symptoms, and lead to the withdrawal of many patients from treatment. Variabilities in the genes encoding the drug target (aromatase) or its metabolizing enzymes (CYP3A and UGT1A) contribute toward the interindividual variability in anastrozole's pharmacokinetics and/or pharmacodynamics. This paper reviews the role of genetic polymorphisms of CYP19A1, CYP3A4, and UGT1A4 in the responses of female hormone receptor-positive postmenopausal breast cancer patients to anastrozole. Many reviews in the literature have suggested that the study of functional polymorphisms and investigation of relevant genetic markers may provide valuable information in predicting responses to anastrozole in terms of its therapeutic and adverse effects. Nevertheless, more studies are required before the knowledge of its pharmacogenomics can be applied to the individualization of treatment to ensure that patients receive the maximum benefits. Therefore, future analyses, including but not limited to genome-wide association studies, are encouraged to address some of the gray areas in the pharmacogenomics of anastrozole therapy in postmenopausal breast cancer cases; this will help in providing guidance for future pharmacogenomics protocols when anastrozole is utilized in patients' management.

Matched MeSH terms: Nitriles/pharmacokinetics*; Triazoles/pharmacokinetics*; Antineoplastic Agents, Hormonal/pharmacokinetics*
Liposomes in topical ophthalmic drug delivery: an update

Agarwal R, Iezhitsa I, Agarwal P, Abdul Nasir NA, Razali N, Alyautdin R, et al.

Drug Deliv, 2016 May;23(4):1075-91.
PMID: 25116511 DOI: 10.3109/10717544.2014.943336

Topical route of administration is the most commonly used method for the treatment of ophthalmic diseases. However, presence of several layers of permeation barriers starting from the tear film till the inner layers of cornea make it difficult to achieve the therapeutic concentrations in the target tissue within the eye. In order to circumvent these barriers and to provide sustained and targeted drug delivery, tremendous advances have been made in developing efficient and safe drug delivery systems. Liposomes due to their unique structure prove to be extremely beneficial drug carriers as they can entrap both the hydrophilic and hydrophobic drugs. The conventional liposomes had several drawbacks particularly their tendency to aggregate, the instability and leakage of entrapped drug and susceptibility to phagocytosis. Due to this reason, for a long time, liposomes as drug delivery systems did not attract much attention of researchers and clinicians. However, over recent years development of new generation liposomes has opened up new approaches for targeted and sustained drug delivery using liposomes and has rejuvenated the interest of researchers in this field. In this review we present a summary of current literature to understand the anatomical and physiological limitation in achieving adequate ocular bioavailability of topically applied drugs and utility of liposomes in overcoming these limitations. The recent developments related to new generation liposomes are discussed.

Matched MeSH terms: Ophthalmic Solutions/pharmacokinetics
Role of genetic algorithms and artificial neural networks in predicting the phase behavior of colloidal delivery systems

Agatonovic-Kustrin S, Alany RG

Pharm Res, 2001 Jul;18(7):1049-55.
PMID: 11496944

PURPOSE: A genetic neural network (GNN) model was developed to predict the phase behavior of microemulsion (ME), lamellar liquid crystal (LC), and coarse emulsion forming systems (W/O EM and O/W EM) depending on the content of separate components in the system and cosurfactant nature.
METHOD: Eight pseudoternary phase triangles, containing ethyl oleate as the oil component and a mixture of two nonionic surfactants and n-alcohol or 1,2-alkanediol as a cosurfactant, were constructed and used for training, testing, and validation purposes. A total of 21 molecular descriptors were calculated for each cosurfactant. A genetic algorithm was used to select important molecular descriptors, and a supervised artificial neural network with two hidden layers was used to correlate selected descriptors and the weight ratio of components in the system with the observed phase behavior.
RESULTS: The results proved the dominant role of the chemical composition, hydrophile-lipophile balance, length of hydrocarbon chain, molecular volume, and hydrocarbon volume of cosurfactant. The best GNN model, with 14 inputs and two hidden layers with 14 and 9 neurons, predicted the phase behavior for a new set of cosurfactants with 82.2% accuracy for ME, 87.5% for LC, 83.3% for the O/W EM, and 91.5% for the W/O EM region.
CONCLUSIONS: This type of methodology can be applied in the evaluation of the cosurfactants for pharmaceutical formulations to minimize experimental effort.

Matched MeSH terms: Surface-Active Agents/pharmacokinetics

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