Stimuli-responsive drug release and controlled delivery play crucial roles in enhancing the therapeutic efficacy and lowering over-dosage induced side effects. In this paper, we report magnetically-triggered drug release and in-vitro anti-colon cancer efficacy of Fe3O4@cellulose nanocrystal (MCNC)-stabilized Pickering emulsions containing curcumin (CUR). The loading efficiency of CUR in the micron-sized (≈7 μm) MCNC-stabilized Pickering emulsions (MCNC-PE) template was found to be 99.35%. The drug release profiles showed that the exposure of MCNC-PE to external magnetic field (EMF) (0.7 T) stimulated the release of bioactive from MCNC-PE achieving 53.30 ± 5.08% of the initial loading over a 4-day period. The MTT assay demonstrated that the CUR-loaded MCNC-PE can effectively inhibits the human colon cancer cells growth down to 18% in the presence of EMF. The formulation also resulted in 2-fold reduction on the volume of the 3-D multicellular spheroids of HCT116 as compared to the control sample. The MCNC particle was found to be non-toxic to brine shrimp up to a concentration of 100 μg/mL. Our findings suggested that the palm-based MCNC-PE could be a promising yet effective colloidal drug delivery system for magnetic-triggered release of bioactive and therapeutics.
Inhaled corticosteroids provide unique systems for local treatment of asthma or chronic obstructive pulmonary disease. However, the use of poorly soluble drugs for nebulization has been inadequate, and many patients rely on large doses to achieve optimal control of their disease. Theoretically, nanotechnology with a sustained-release formulation may provide a favorable therapeutic index. The aim of this study was to determine the feasibility of using sterically stabilized phospholipid nanomicelles of budesonide for pulmonary delivery via nebulization.
The potential of using poly-(ethylene oxide)-block-distearoyl phosphatidyl-ethanolamine (mPEG-DSPE) polymer to prepare BDP-loaded micelles with high entrapment efficiency and mass median aerodynamic diameter of less than 5 microm demonstrating sustained release properties was evaluated. The result showed that lyophilized BDP-loaded polymeric micelles with entrapment efficiency of more than 96% could be achieved. Entrapment efficiency was affected by both the drug to polymer molar ratio and the amount of drug used. Investigation using FTIR and DSC confirmed that there was no chemical or physical interaction and the drug was molecularly dispersed within the micelles. TEM images showed that the drug-loaded polymeric micelles were spherical in shape with multivesicular morphology. Further analysis by photon correlation spectroscopy indicated that the particle size of the BDP-loaded micelles was about 22 nm in size. In vitro drug release showed a promising sustained release profile over six days following the Higuchi model. The mass median aerodynamic diameter and fine particle fraction were suitable for pulmonary delivery. Moreover, the small amount of deposited drug in the induction port (throat deposition) suggested possible reduction in incidence of oropharyngeal candidiasis, a side effect normally associated with inhaled corticosteroids therapy. The high encapsulation efficiency, comparable inhalation properties, sustained release behavior together with biocompatibility nature of the polymer support the potential of BDP-loaded polymeric micelles as a versatile delivery system to be used in the treatment of asthma and chronic obstructive pulmonary disease.
Although the general pharmacokinetics of cephalexin is quite established up-to-date, however, no population-based study on Cephalexin pharmacokinetics profile in Malay population has been reported yet in the literature.
Cell-internalizing peptides (CIPs) can be used to mediate specific delivery of nanoparticles across cellular membrane. The objective of this study was to develop a display technique using hepatitis B virus (HBV) capsid-binding peptide as a "nanoglue" to present CIPs on HBV nanoparticles for cell-targeting delivery. A CIP was selected from a phage display library and cross-linked specifically at the tips of the spikes of the HBV capsid nanoparticle via the "nanoglue" by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysulfosuccinimide (sulfo-NHS). Fluorescent oligonucleotides packaged in the nanoparticles and the fluorescein molecules conjugated on the nanoparticles were delivered to cells by using this display technique. This study demonstrated a proof of principle for cell-targeting delivery via "nanoglue" bioconjugation.
Multifunctional nanocarriers harbouring specific targeting moieties and with pH-responsive properties offer great potential for targeted cancer therapy. Several synthetic drug carriers have been studied extensively as drug delivery systems but not much information is available on the application of virus-like nanoparticles (VLNPs) as multifunctional nanocarriers. Here, we describe the development of pH-responsive VLNPs, based on truncated hepatitis B virus core antigen (tHBcAg), displaying folic acid (FA) for controlled drug delivery. FA was conjugated to a pentadecapeptide containing nanoglue bound on tHBcAg nanoparticles to increase the specificity and efficacy of the drug delivery system. The tHBcAg nanoparticles loaded with doxorubicin (DOX) and polyacrylic acid (PAA) demonstrated a sustained drug release profile in vitro under tumour tissue conditions in a controlled manner and improved the uptake of DOX in colorectal cancer cells, leading to enhanced antitumour effects. This study demonstrated that DOX-PAA can be packaged into VLNPs without any modification of the DOX molecules, preserving the pharmacological activity of the loaded DOX. The nanoglue can easily be used to display a tumour-targeting molecule on the exterior surface of VLNPs and can bypass the laborious and time-consuming genetic engineering approaches.
Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.
Cyclosporine is a substrate of cytochrome P-450 3A (CYP3A) subfamily of enzymes and characterized by a narrow therapeutic range with wide interindividual variation in pharmacokinetics. A few single-nucleotide polymorphisms detected in CYP3A genes have been shown to correlate significantly with the CYP3A protein expression and activity. We therefore postulated that these polymorphisms could be responsible for some of the interindividual variation in cyclosporine pharmacokinetics. The objective of our study is to determine correlation if any between single-nucleotide polymorphisms of CYP3A5 and CYP3AP1 on cyclosporine dose requirement and concentration-to-dose ratio in renal allograft recipients. Cyclosporine-dependent renal allograft recipients were genotyped for CYP3A5 A6986G and CYP3AP1 G-44A. The cyclosporine dosages prescribed and the corresponding cyclosporine trough levels for each patient were recorded so that cyclosporine dose per weight (mg/kg/day) and concentration-to-dose ratio (C(0)/D, whereby C(0) is trough level and D is daily dose per weight) could be calculated. A total of 67 patients were recruited for our study. The dose requirement for 1, 3, and 6 months post-transplantation ranged 2.3-11.4, 1.0-9.0, and 1.4-7.2 mg/kg/day, respectively. Patients with *1*1*1*1 (n=5) CYP3A5- and CYP3AP1-linked genotypes needed higher dose of cyclosporine compared to patients with *1*3*1*3 (n = 27) and *3*3*3*3 (n = 33) linked genotypes in months 3 and 6 post-transplantation (P < 0.016). The identification of patients with *1*1*1*1 by CYP3A5 and CYP3AP1 genotyping may have a clinically significant and positive impact on patient outcome with reduced rejection rate by providing pretransplant pharmacogenetic information for optimization of cyclosporine A dosing.
Multivariate analysis including correlation, multiple stepwise linear regression, and cluster analyses were applied to investigate the heavy metal concentrations (Cd, Cu, Fe, Ni, Pb, and Zn) in the different parts of bivalves and gastropods. It was also aimed to distinguish statistically the differences between the marine bivalves and the gastropods with regards to the accumulation of heavy metals in the different tissues. The different parts of four species of bivalves and four species of gastropods were obtained and analyzed for heavy metals. The multivariate analyses were then applied on the data. From the multivariate analyses conducted, there were correlations found between the soft tissues of bivalves and gastropods, but none was found between the shells and the soft tissues of most of the molluscs (except for Cerithidea obtusa and Puglina cochlidium). The significant correlations (P < 0.05) found between the soft tissues were further complemented by the multiple stepwise linear regressions where heavy metals in the total soft tissues were influenced by the accumulation in the different types of soft tissues. The present study found that the distributions of heavy metals in the different parts of molluscs were related to their feeding habits and living habitats. The statistical approaches proposed in this study are recommended for use in biomonitoring studies, since multivariate analyses can reduce the cost and time involved in identifying an effective tissue to monitor the heavy metal(s) bioavailability and contamination in tropical coastal waters.
Matched MeSH terms: Water Pollutants/pharmacokinetics; Metals, Heavy/pharmacokinetics
The distributions of Cu, Zn, and Pb concentrations in the selected soft tissues (foot, cephalic tentacle, mantle, muscle, gill, digestive caecum, and remaining soft tissues) and shells of the mud-flat snail Telescopium telescopium were determined in snails from eight geographical sites in the south-western intertidal area of Peninsular Malaysia. Generally, the digestive caecum compared with other selected soft tissues, accumulated higher concentration of Zn (214.35+/-14.56 microg/g dry weight), indicating that the digestive caecum has higher affinity for the essential Zn to bind to metallothionein. The shell demonstrated higher concentrations of Pb (41.23+/-1.20 microg/g dry weight) when compared to the selected soft tissues except gill from Kuala Sg. Ayam (95.76+/-5.32 microg/g dry weight). The use of different soft tissues also can solve the problem of defecation to reduce error in interpreting the bioavailability of heavy metals in the intertidal area.
The concentrations of Cu, Pb, and Zn in the crystalline style (CS) and in the remaining soft tissues (ST) of the green-lipped mussel Perna viridis from 10 geographical sites along the coastal waters off peninsular Malaysia were determined. The CS, compared with the remaining ST, accumulated higher levels of Cu in both contaminated and uncontaminated samples, indicating that the style has a higher affinity for the essential Cu to bind with metallothioneins. The similar pattern of Cu accumulation in the different ST of mussels collected from clean and Cu-contaminated sites indicated that the detoxification capacity of the metallothioneins had not been overloaded. For Pb, higher levels of the metal in the CS than in the remaining ST were found only in mussels collected from a contaminated site at Kg. Pasir Puteh. This indicated a tissue redistribution of Pb due to its binding to metallothioneins for Pb detoxification and the potential of the CS as an indicator organ of Pb bioavailability and contamination. For Zn, the above two phenomena were not found since no obvious patterns were observed (lower levels of Zn in the CS than in the remaining ST) in contaminated and uncontaminated samples due to the mechanism of partial regulation. Generally, all the different STs studied (foot, mantle, gonad, CS, gill, muscle, and byssus) are good biomonitoring tissues for Cu and Pb bioavailabilities and contamination. Among these organs, the CS was found to be the best organ for biomonitoring Cu. The present data also suggest the use of the tissue redistribution of Pb in P. viridis as an indicator of Pb bioavailability and contamination in coastal waters.
Concentrations of cadmium (Cd), lead (Pb) and zinc (Zn) in total soft tissues (ST) and byssus (BYS) of the green-lipped mussel Perna viridis from 11 different geographical locations off the west coast of Peninsular Malaysia were determined. The metal concentrations distributed between the BYS and ST were compared. The results of this study indicated that higher levels of Cd (1.31 microg/g), Pb (38.49 microg/g) and Zn (206.52 microg/g) were accumulated in the BYS than in the total ST (Cd: 0.29 microg/g; Pb: 8.27 microg/g; Zn: 102.6 microg/g). Semi-static and short period controlled laboratory experiments were also conducted for the accumulation and depuration of Cd, Pb and Zn in the total ST and BYS of P. viridis. The ratios (BYS/ST) for Pb and Cd from the laboratory experiments showed that the total ST accumulated more metals than the BYS. Therefore, these laboratory results disagreed with those found for the field samples. However, the laboratory results for the Zn ratio (BYS/ST) agreed with those of the field samples. It was evident that when compared to the ST, the BYS was a more sensitive biomonitoring organ for Zn while it could be a complementary organ for Cd and Pb in the total ST. Since total ST of P. viridis had been reported to have regulative mechanism for Zn, its BYS can be used as a biomonitoring organ for the identification of coastal areas exposed to Zn pollution.
Matched MeSH terms: Cadmium/pharmacokinetics; Lead/pharmacokinetics; Water Pollutants/pharmacokinetics; Zinc/pharmacokinetics
The knowledge of venom pharmacokinetics is essential to improve the understanding of envenomation pathophysiology. Using a double-sandwich ELISA, this study investigated the pharmacokinetics of the venom of hump-nosed pit viper (Hypnale hypnale) following intravenous and intramuscular injections into rabbits. The pharmacokinetics of the venom injected intravenously fitted a three-compartment model. There is a rapid (t1/2π = 0.4 h) and a slow (t1/2α = 0.8 h) distribution phase, followed by a long elimination phase (t1/2β = 19.3 h) with a systemic clearance of 6.8 mL h(-1) kg(-1), consistent with the prolonged abnormal hemostasis reported in H. hypnale envenomation. On intramuscular route, multiple peak concentrations observed in the beginning implied a more complex venom absorption and/or distribution pattern. The terminal half-life, volume of distribution by area and systemic clearance of the venom injected intramuscularly were nevertheless not significantly different (p > 0.05) from that of the venom injected intravenously. The intramuscular bioavailability was exceptionally low (Fi.m. = 4%), accountable for the highly varied median lethal doses between intravenous and intramuscular envenomations in animals. The findings indicate that the intramuscular route of administration does not significantly alter the pharmacokinetics of H. hypnale venom although it significantly reduces the systemic bioavailability of the venom.
Andrographolide, a major bioactive compound isolated from Andrographis paniculata (Burm. F.) Nees, was evaluated for its effects on the hOAT1 membrane transporter. Substrate determination and inhibition of hOAT1-mediated uptake transport assay was carried out using recombinant CHO-hOAT1 cells. The results showed that the uptake ratio of andrographolide was less than 2.0 at all concentrations tested, indicating that andrographolide is not a hOAT1 substrate. Andrographolide has no significant effects on the p-aminohippuric acid uptake and on the mRNA and protein expression of hOAT1. In conclusion, andrographolide may not pose a drug-herb interaction risk related to hOAT1.
Methyl eugenol (ME), is converted into two major phenylpropanoids, 2-allyl-4,5-dimethoxyphenol and trans-coniferyl alcohol, following consumption by the male fruit fly Bactrocera papayae. Chemical analysis of wild male B. papayae rectal glands, where the compounds are sequestered, revealed the presence of ME metabolites in varying quantities. These phenylpropanoids are shown to be involved in the fruit fly defense both in no-choice and choice feeding tests against the Malayan spiny gecko, Gekko monarchus. After being acclimatized to feeding on fruit flies, geckos consumed significantly fewer ME-fed male flies than controls that consumed all the ME-deprived male flies offered throughout a two-week period. Diagnosis of dissected livers from geckos that consumed ME-fed male flies revealed various abnormalities. These included discoloration and hardening of liver tissue, whitening of the gallbladder, or presence of tumor-like growths in all geckos that consumed ME-fed male flies. Control geckos fed on ME-deprived male flies had healthy livers. When given an alternative prey, geckos preferred to eat untreated house flies, Musca domestica to avoid preying on ME-fed fruit flies.
Acute severe intoxication with carbamazepine is associated with seizures, coma and respiratory depression. Traditionally, charcoal haemoperfusion is used to remove the drug. We present a case of carbamazepine intoxication, successfully treated with three hours of high-flux haemodialysis. Thus, haemodialysis using high-flux membranes is a feasible and effective therapeutic option for carbamazepine intoxication.
Hearing loss has been reported with valproic acid (VPA) use. However, this is the first case of VPA-induced hearing loss that was tested and confirmed with a VPA rechallenge, supported by serial audiometry and pharmacokinetic modelling. A 39-year-old truck driver with temporal lobe epilepsy was treated with VPA at 400 mg, twice daily, and developed hearing loss after each dose, but recovered within three hours. Hearing loss fully resolved after VPA discontinuation. Audiometry performed five hours after VPA rechallenge showed significant improvement in hearing thresholds. Pharmacokinetic modelling during the VPA rechallenge showed that hearing loss occurred at a level below the therapeutic range. Brainstem auditory evoked potential at three months after VPA discontinuation showed bilateral conduction defect between the cochlear and superior olivary nucleus, supporting a pre-existing auditory deficit. VPA may cause temporary hearing threshold shift. Pre-existing auditory defect may be a risk factor for VPA-induced hearing loss. Caution should be taken while prescribing VPA to patients with pre-existing auditory deficit.