Pharmcokinetic and pharmacodynamic considerations for the anticholinergic burden scale of drugs.

Older adults frequently have many systemic diseases that require treatment with multiple drugs, and thus anticholinergic adverse effect by polypharmacy is a significant concern in the management of older adults. The accuracy of the anticholinergic burden rating may be increased by considering pharmacokinetic and pharmacodynamic factors such as biophase drug concentrations, the pharmacologically active metabolites formed after drug administration, and muscarinic receptor-mediated effects. Therefore, a pharmacological evidence-based burden scale that considers pharmacokinetic and pharmacodynamic factors is expected to be a more optimal tool for precisely assessing the anticholinergic burden, specifically risk reductions in anticholinergic adverse events in the poly-medicated elderly.

Kanechlor 500-mediated changes in serum and hepatic thyroxine levels primarily occur in a transthyretin-unrelated manner.

The effects of Kanechlor-500 (KC500) on the levels of serum total thyroxine (T ) and hepatic T in wild-type C57BL/6 (WT) and its transthyretin (TTR)-deficient (TTR-null) mice were comparatively examined. Four days after a single intraperitoneal injection with KC500 (100 mg/kg body weight), serum total T levels were significantly decreased in both WT and TTR-null mice. The KC500 pretreatment also promoted serum [ I]T clearance in both strains of mice administrated with [ I]T , and the promotion of serum [ I]T clearance in WT mice occurred without inhibition of the [ I]T -TTR complex formation.

Possible mechanism for the polychlorinated bipheny-linduced liver-selective accumulation of thyroxine in rats.

We have previously reported that decrease in level of serum thyroxine T by Kanechor 500 (KC500) in rats would occur through the increase in hepatic T accumulation rather than the increase in hepatic T-glucuronyl transferase activity. In the present study, to understand the mechanism underlying the KC500-mediated increase in hepatic T accumulation, we examined the relationship between the KC500-mediated changes in hepatic T accumulation and the expression levels of mRNAs of hepatic transporters including T transporters. [I]T was intravenously injected into KC500-pretreated and control (KC500-untreated) Wistar rats, and [I]T uptake levels of liver parenchymal cells were comparatively examined.

Selective determination of mono- and dihydroxylated analogs of polybrominated diphenyl ethers in marine sponges by liquid-chromatography tandem mass spectrometry.

A number of bioactive brominated secondary metabolites, including hydroxylated polybrominated diphenyl ethers, have been isolated from algae, sponges, and bacteria. In the present study, a screening method using liquid-chromatography tandem mass spectrometry was developed for the identification and selective determination of dihydroxy (diOH), hydroxy-methoxy (OH-MeO), and dimethoxy (diMeO) analogs of tetra- to hexa-BDEs in marine biota. In negative atmospheric pressure chemical ionization (APCI) mode, diOH and OH-MeO analogs provided intense [M-H](-) ions, whereas diMeO analogs provided characteristic [M-Br+O](-) and [M-CH(3)](-) ions.

Simultaneous determination by APCI-LC/MS/MS of hydroxylated and methoxylated polybrominated diphenyl ethers found in marine biota.

A method has been developed for the simultaneous analysis of hydroxylated and methoxylated analogs of tetrabromodiphenyl ethers (OH-tetraBDEs and MeO-tetraBDEs) and of hydroxylated and methoxylated analogs of tetrabromobiphenyl (diOH-tetraBB and diMeO-tetraBB) using high performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry (APCI-LC/MS/MS) in negative ion mode. Chromatographic separation was performed on a 150 mm ODS column with acetonitrile:water (9:1, v/v) in mobile phase. Multiple reaction monitoring (MRM) was performed using the precursor [M-H]- ion for hydroxylated analogs, and the [M-Br+O]- ion for tetraBDEs and tetraBB, and their methoxylated analogs.

Negative APCI-LC/MS/MS method for determination of natural persistent halogenated products in marine biota.

A sensitive and selective method utilizing high performance liquid chromatography coupled to negative atmospheric pressure chemical ionization tandem mass spectrometry (APCI-LC/MS/MS) was developed to enable analysis of selected natural persistent organohalogens accumulated in marine biota. The analytes were three methoxylated tetrabromodiphenyl ethers (6-MeO-BDE47, 2'-MeO-BDE68, and 2',6-diMeO-BDE68), a dimethoxylated tetrabromobiphenyl (2,2'-diMeO-BB80), and two halogenated methyl bipyrroles (Cl(7)-MBP and Br(4)Cl(2)-DBP). These products were well resolved on a 150 mm reversed-phase column with methanol as the mobile phase.

In vitro efficacy of a sterically stabilized immunoliposomes targeted to membrane type 1 matrix metalloproteinase (MT1-MMP).

The poor selective cytotoxicity of anticancer drugs lead to dose-limiting adverse effects which compromise the clinical outcome. Solid tumors recruit new blood vessels to support their growth, and epitopes that are uniquely expressed on tumor cells and tumor endothelial cells (ECs) can function as targets for immunoliposomal anticancer drugs. Membrane type 1 matrix metalloproteinase (MT1-MMP), an important protein related to tumor growth and angiogenesis, is expressed on malignant tumor cells and is activated ECs.

Complex formation with plasmid DNA increases the cytotoxicity of cationic liposomes.

Cationic liposomes (CL) are one of the most widely studied non-viral vectors for gene delivery. It is well-known that CL induces cytotoxicity following lipofection. However, little is known regarding the mechanism involved in the cytotoxicity.

Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection.

The "accelerated blood clearance (ABC) phenomenon", causing PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection, has been reported to occur in rodents and rhesus monkeys. This rapid clearance was reported to be caused by the binding of PEG-specific IgM, which was generated by the first dose of injected liposomes, to the second dose of liposomes and the subsequent activation of complement, serving in turn as an opsonin. Although there are several PEGylated liposomal formulations, such as Doxil/Caelyx loaded with doxorubicin (DXR), in clinical use, the rapid clearance phenomenon has never been reported for such formulations.