Despite the fact that pharmacokinetic exposure of kinase inhibitors (KIs) is highly variable and clear relationships exist between exposure and treatment outcomes, fixed dosing is still standard ...practice. This review aims to summarize the available clinical pharmacokinetic and pharmacodynamic data into practical guidelines for individualized dosing of KIs through therapeutic drug monitoring (TDM). Additionally, we provide an overview of prospective TDM trials and discuss the future steps needed for further implementation of TDM of KIs.
There is accumulating evidence for potential benefits of therapeutic drug monitoring (TDM) in the treatment of cancer with tyrosine kinase inhibitors (TKIs). Relationships between exposure and ...response (efficacy/toxicity) have been established for several TKIs. For example, the pharmacokinetic targets for efficacy of imatinib, sunitinib and pazopanib have been defined as trough plasma concentrations (Ctrough) of >1,000, >50 and >20,000 ng/mL for selected indications, respectively. Dose adjustment based on pharmacokinetic targets could therefore increase response rates and duration. Furthermore, with appropriate target concentrations defined, excessive side effects in patients using the current fixed dosing strategy may be prevented. This review provides a practical guideline for TDM for the currently approved TKIs at 28 February 2013. The focus of this article is on the elaboration of exposure and response relationships of TKIs with proposed pharmacokinetic targets, mainly Ctrough, and further on the interpretation of the pharmacokinetic targets with recommendations for dose titrations.
Abstract Objective To verify the safety and effectiveness of traditional Chinese red yeast rice-extract (RYR) for reduction of LDL cholesterol. Methods Systematic literature review and meta-analysis. ...Medline and EMBASE were searched until November 2014. We selected randomized studies in which RYR with a known content of the active substance monacolin K was tested against placebo or an active control group. Outcome measures were the effect of RYR on LDL cholesterol and incidence of adverse reactions with emphasis on liver and kidney injury and muscle symptoms. Results Twenty studies were analyzed. Quality of safety assessment was low in the majority of studies. RYR lowered LDL cholesterol with 1.02 mmol/L −1.20; −0.83 compared to placebo. Effect of RYR on LDL was not different from statin therapy (0.03 mmol/L −0.36; 0.41). The incidence of liver and kidney injury was 0–5% and the risk was not different between treatment and control groups (risk difference −0.01 −0.01; 0.0 and 0.0 −0.01; 0.02). Conclusions RYR exerts a clinically and statistically significant reduction of 1.02 mmol/L LDL cholesterol. Only when the mild profile of adverse reactions can be affirmed in studies with adequate methodology for safety assessment, RYR might be a safe and effective treatment option for dyslipidemia and cardiovascular risk reduction in statin intolerant patients.
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•Patterned nanofiber membrane was fabricated through electrospinning, patterned ultraviolet crosslinking and solution rinsing.•A pressure sensing array was fabricated utilizing ...graphene electrode arrays and sandwiched H3PO4@PVPP dielectric units.•The microstructures on the surface of electrode and the nanofiber membrane offer high sensitivity and wide pressure ranges.•Based on a 10 × 10 pressure sensing array with a crosstalk of 1.3%, a foot-arch diagnostic system was developed.
Flexible pressure sensors have found widespread application in medical diagnosis and human–computer interaction. These practical applications often require large-area pressure sensing arrays (PSAs) to explore spatial pressure distributions. However, the development of high-performance PSAs still presents significant challenges. Here, a new method is proposed for the fabrication of a high-resolution capacitive PSA in a 10 × 10 configuration. The array comprises the upper and lower electrode arrays of laser-induced graphene patterned on polyimide films, as well as the sandwiched dielectric units based on electrospun nanofiber membranes of H3PO4@PVPP (cross-linked polyvinyl pyrrolidone). Experimental results indicate that the PSA exhibits high sensitivity across a wide pressure range (0–200 kPa), while offering a rapid response/recovery time of 24/41 ms (at 1 kPa), an exceptionally low detection limit of ∼1.2 Pa, and a good stability of 4000 cycles. Moreover, the crosstalk of the PSA was found to be as low as 1.3%. By employing the PSA in conjunction with a convolutional neural network algorithm, a human foot-arch diagnostic system was developed for accurate detection and quantification of the plantar pressure for different types of foot arches. Such technology has significant potential in clinical detection and disease diagnosis of human foot.
Beta-amyloid (Aβ) peptide, the hallmark of Alzheimer's disease (AD), invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. In this study, salidroside (Sald), an ...active compound isolated from a traditional Chinese medicinal plant, Rhodiola rosea L., was investigated to assess its protective effects and the underlying mechanisms against Aβ-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Aβ25–35-induced neuronal toxicity was characterized by the decrease of cell viability, the release of lactate dehydrogenase (LDH), morphological alterations, neuronal DNA condensation, and the cleavage of poly(ADP-ribose) polymerase (PARP) by activated caspase-3. Pretreatment with salidroside markedly attenuated Aβ25–35-induced loss of cell viability and apoptosis in a dose-dependent manner. The mechanisms of salidroside protected neurons from oxidative stress included the induction of antioxidant enzymes, thioredoxin (Trx), heme oxygenase-1 (HO-1), and peroxiredoxin-I (PrxI); the downregulation of pro-apoptotic protein Bax and the upregulation of anti-apoptotic protein Bcl-XL. Furthermore, salidroside dose-dependently restored Aβ25–35-induced loss of mitochondrial membrane potential (MMP) as well as suppressed the elevation of intracellular reactive oxygen species (ROS) level. It was also observed that Aβ25–35 stimulated the phosphorylation of mitogen-activated protein (MAP) kinases, including c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, but not extracellular signal-regulated kinase1/2 (ERK1/2). Salidroside inhibited Aβ25–35-induced phosphorylation of JNK and p38 MAP kinase, but not ERK1/2. These results suggest that salidroside has protective effects against Aβ25–35-induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases.
Oxidative stress plays an important role in Alzheimer's disease and other neurodegenerative disorders. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L, shows potent ...antioxidant property. In this paper, the neuroprotective effects of salidroside on hydrogen peroxide (H2O2)-induced apoptosis in SH-SY5Y cells were investigated. Pretreatment with salidroside markedly attenuated H2O2-induced cell viability loss and apoptotic cell death in a dose-dependent manner. The mechanisms by which salidroside protected neuron cells from oxidative stress included the induction of several antioxidant enzymes, thioredoxin, heme oxygenase-1, and peroxiredoxin-I; the downregulation of pro-apoptotic gene Bax and the upregulation of anti-apoptotic genes Bcl-2 and Bcl-XL. Furthermore, salidroside dose-dependently restored H2O2-induced loss of mitochondrial membrane potential as well as the elevation of intracellular calcium level. These results suggest that salidroside has protective effects against oxidative stress-induced cell apoptosis, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases implicated with oxidative stress.
Apigenin, abundantly present in fruits and vegetables, is recognized as a flavonoid with anti-inflammatory, antioxidant and anticancer properties. In this study, we first investigated the ...anti-neoplastic effects of apigenin on papillary thyroid carcinoma (PTC) cell line BCPAP cells. Our results show that apigenin inhibited the viability of BCPAP cells in a dose-dependent manner. A large body of evidence demonstrates that autophagy contributes to cell death in certain contexts. In the present study, autophagy was induced by apigenin treatment in BCPAP cells, as evidenced by Beclin-1 accumulation, conversion of LC3 protein, p62 degradation as well as the significantly increased formation of acidic vesicular organelles (AVOs) compared to the control group. 3-MA, an autophagy inhibitor, rescued the cells from apigenin-induced cell death. Notably, apigenin enhanced production of reactive oxygen species (ROS), and subsequent induction of significant DNA damage as monitored by the TUNEL assay. In addition, apigenin treatment caused a significant accumulation of cells in the G2/M phase
via
down-regulation of Cdc25C expression. Our findings reveal that apigenin inhibits papillary thyroid cancer cell viability by the stimulation of reactive oxygen species (ROS) production, induction of DNA damage, leading to G2/M cell cycle arrest followed by autophagic cell death. Thus, our results provide new insights into the molecular mechanisms underlying apigenin-mediated autophagic cell death and suggest apigenin as a potential chemotherapeutic agent which is able to fight against papillary thyroid cancer.
Apigenin-induced autophagic cell death in human papillary thyroid carcinoma BCPAP cells is associated with ROS generation, DNA damage and cell cycle arrest.
Obesity can lead to excessive lipid accumulation in non-adipose tissues, such as the liver and skeletal muscles, leading to ectopic lipid deposition and damaging target organ function through ...lipotoxicity. FGF-21 is a key factor in regulating lipid metabolism, so we aim to explore whether FGF-21 is involved in improving ectopic lipid deposition. We observed the characteristics of ectopic lipid deposition in the liver and skeletal muscles of obesity-resistant mice, detected the expression of FGF-21 and perilipin, and found that obesity-resistant mice showed a decrease in ectopic lipid deposition in the liver and skeletal muscles and increased expression of FGF-21. After inhibiting the expression of FGF-21, a more severe lipid deposition in liver cells and skeletal muscle cells was found. The results indicate that inhibiting FGF-21 can exacerbate ectopic lipid deposition via regulating lipid droplet synthesis and decomposition, as well as free fatty acid translocation and oxidation. In conclusion, FGF-21 is involved in improving ectopic lipid deposition caused by obesity in the liver and skeletal muscles.
Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib ...in cancer patients.
Pharmacokinetic data were available from 96 patients from three clinical studies. A multi-compartment model including (i) a complex absorption profile, (ii) the potential non-linear dose-concentration relationship and (iii) the potential long-term decrease in exposure was developed.
A two-compartment model best described pazopanib pharmacokinetics. The absorption phase was modelled by two first-order processes: 36 % (relative standard error RSE 34 %) of the administered dose was absorbed with a relatively fast rate (0.4 h
RSE 31 %); after a lag time of 1.0 h (RSE 6 %), the remaining dose was absorbed at a slower rate (0.1 h
RSE 28 %). The relative bioavailability (rF) at a dose of 200 mg was fixed to 1. With an increasing dose, the rF was strongly reduced, which was modelled with an E
(maximum effect) model (E
was fixed to 1, the dose at half of maximum effect was estimated as 480 mg RSE 23 %). Interestingly, the plasma exposure to pazopanib also decreased over time, modelled on rF with a maximum magnitude of 50 % (RSE 27 %) and a first-order decay constant of 0.15 day
(RSE 43 %). The inter-patient and intra-patient variability on rF were estimated as 36 % (RSE 16 %) and 75 % (RSE 22 %), respectively.
A popPK model for pazopanib was developed that illustrated the complex absorption process, the non-linear dose-concentration relationship, the high inter-patient and intra-patient variability, and the first-order decay of pazopanib concentration over time. The developed popPK model can be used in clinical practice to screen covariates and guide therapeutic drug monitoring.
Background and Objective
As pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib ...affect systemic pazopanib concentrations.
Methods
The decreased function alleles
CYP3A4 15389 C
>
T (*22)
,
ABCB1 3435 C
>
T
,
ABCG2 421 C
>
A
, and
ABCG2 34G
>
A
were analyzed within a recently developed population-pharmacokinetic model.
Results
Incorporation of
CYP3A4*22
in the model resulted in a 35% lower clearance for variant carriers (0.18 vs. 0.27 L/h; difference in objective function value: − 9.7;
p
< 0.005). Simulated median trough concentrations of cancer patients with
CYP3A4*22
with 600 mg once daily or 800 mg once daily were 31 and 35 mg/L, respectively. The simulated trough concentrations for the population excluding the
CYP3A4*22
carriers after 600 mg once daily or 800 mg once daily were 18 and 20 mg/L, respectively.
Conclusion
This analysis shows that
CYP3A4*22
heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on
CYP3A4*22
status could be considered.
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