RESUMEN
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. Geriatr Gerontol Int 2024; 24: 81-87.
Asunto(s)
Antagonistas Colinérgicos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Anciano , Antagonistas Colinérgicos/efectos adversos , Preparaciones Farmacéuticas , PolifarmaciaRESUMEN
Marine foods can be contaminated with organochlorines and the risk to human beings who consume these foods needs to be evaluated. We examined the teratogenic effects of contaminants extracted from whale bacon on rat embryos using a whole-embryo culture system. Embryonic day 11.5 embryos were cultured for 48 h with organohalogens extracted from whale bacon at low (polychlorinated biphenyls (PCBs): 0.32 ppm, dichlorodiphenyltrichloroethanes (DDTs): 0.16 ppm, chlordanes (CHLs): 0.02 ppm) and high (PCBs: 2.15 ppm, DDTs: 1.99 ppm, CHLs: 0.20 ppm) doses. The levels of organohalogen compounds in cultured embryos were determined. The organochlorine contaminants extracted from whale products were readily transferred to the cultured rat embryos. The number of heartbeats, yolk sac circulation score, and embryonic body circulation score of embryos did not change during the culture period in either exposure group. Cultured embryos treated with the low-dose contaminated medium for 48 h showed abnormalities of the mandible, and craniofacial or forelimb hematomas with an incidence of 50%. All embryos treated with the high-dose medium showed craniofacial abnormalities and cleft lip, and limb abnormalities and hematomas. These results indicate that the organohalogen contaminants in whale bacon may be teratogenic in a dose-dependent manner. Further studies are necessary to determine the dose-effect relationship.
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Hidrocarburos Clorados , Bifenilos Policlorados , Carne de Cerdo , Animales , Clordano , Hematoma , Humanos , Hidrocarburos Clorados/toxicidad , Bifenilos Policlorados/toxicidad , Ratas , BallenasRESUMEN
The effects of Kanechlor-500 (KC500) on the levels of serum total thyroxine (T4 ) and hepatic T4 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 T4 levels were significantly decreased in both WT and TTR-null mice. The KC500 pretreatment also promoted serum [125 I]T4 clearance in both strains of mice administrated with [125 I]T4 , and the promotion of serum [125 I]T4 clearance in WT mice occurred without inhibition of the [125 I]T4 -TTR complex formation. Furthermore, the KC500 pretreatment led to significant increases in liver weight, steady-state distribution volume of [125 I]T4 , hepatic accumulation level of [125 I]T4 , and concentration ratio of the liver to serum in both strains of mice. The present findings indicate that the KC500-mediated decrease in serum T4 level occurs in a TTR-unrelated manner and further suggest that KC500-promoted T4 accumulation in the liver occurs through the development of liver hypertrophy and the promotion of T4 transportation from serum to liver.
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Hígado/efectos de los fármacos , Bifenilos Policlorados/toxicidad , Prealbúmina/metabolismo , Tiroxina/sangre , Animales , Glucuronosiltransferasa/metabolismo , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Bifenilos Policlorados/sangre , Prealbúmina/genética , Tirotropina/sangre , Tiroxina/metabolismo , Triyodotironina/sangreRESUMEN
We have previously reported that decrease in level of serum thyroxine T4 by Kanechor 500 (KC500) in rats would occur through the increase in hepatic T4 accumulation rather than the increase in hepatic T4-glucuronyl transferase activity. In the present study, to understand the mechanism underlying the KC500-mediated increase in hepatic T4 accumulation, we examined the relationship between the KC500-mediated changes in hepatic T4 accumulation and the expression levels of mRNAs of hepatic transporters including T4 transporters. [125I]T4 was intravenously injected into KC500-pretreated and control (KC500-untreated) Wistar rats, and [125I]T4 uptake levels of liver parenchymal cells were comparatively examined. The amount of [125I]T4 uptake by hepatic cells increased in a time-dependent manner up to 96 hr after KC500 treatment. Following KC500 treatment, a time-dependent increase in the mRNA level of hepatic T4 influx transporter LAT1 was observed up to 96 hr later, while a significant increase in hepatic T4 influx transporter Oatp2 mRNA occurred only at 96 hr later. No KC500-mediated increases in the mRNAs of other hepatic transporters (Oatp1, Oatp3, Oatp4, Ntcp, LAT2, and Mrp2) were observed at any timepoints, although the mRNA expression of the T4 conjugate(s) efflux transporter Mrp3 significantly increased in a time-dependent manner 24-96 hr following KC500 treatment. The present findings suggest that KC500-mediated increase in hepatic T4 accumulation occurs, at least in part, through the increase in the expression of hepatic T4-transporters, such as LAT1 and Oatp2.
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Hígado/metabolismo , Bifenilos Policlorados/efectos adversos , Tiroxina/metabolismo , Animales , Expresión Génica/efectos de los fármacos , Masculino , ARN Mensajero/metabolismo , Ratas Wistar , Proteínas de Unión a Tiroxina/genética , Proteínas de Unión a Tiroxina/metabolismo , Factores de Tiempo , Distribución TisularRESUMEN
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. This enabled the diOH-, OH-MeO-, and diMeO-PBDEs to be distinguished using selected reaction monitoring transitions in the APCI source. Recoveries of 2'-OH-6-MeO-2,3',4,5'-tetra-BDE in spiked marine samples were 84 ± 5 %, with a limit of quantification at 9.1 ng mL(-1) (signal-to-noise ratio = 10). The developed method was used to analyze two sponge species collected from Palau, Micronesia; the concentration ratio of diOH-tetra-BDE:OH-MeO-tetra-BDE was 10:1 for the Lamellodysidea sp., whereas it was 1:30 for the Callyspongia sp.
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Cromatografía Liquida/métodos , Éteres Difenilos Halogenados/química , Poríferos/química , Espectrometría de Masas en Tándem/métodos , Animales , Éteres Difenilos Halogenados/metabolismo , Estructura Molecular , Poríferos/metabolismoRESUMEN
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. The method was validated using cod liver oil samples spiked with nine analytes (100 ng/g) for linearity (r2 > 0.998), recovery (75-95%), repeatability (8-36% RSD), and sensitivity (limits of quantification (LOQ), 0.1-0.25 ng/g lipid for phenolic analytes and 6-80 ng/g lipid for neutral brominated compounds). The APCI-LC/MS/MS was applied to analyze tiger shark and bull shark liver samples, where their concentrations were up to 8 ng/g (lipid weight) for OH-BDEs, whereas they were up to 540 ng/g (lipid weight) for MeO-BDEs. The results were consistent with values determined by electron ionization (EI)-GC/MS. The first detection of 2,2'-dihydroxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diOH-BB80) by this method was in marine sponge from Micronesia. The advantage of the LC/MS/MS method over GC/MS is that it provides rapid and simultaneous determination of OH-BDEs, MeO-BDEs, and their related analogs with a single preparation step and without the involvement of chemical derivatives. Although the method provides the different LOQ ranges between hydroxylated and neutral brominated analogs, future work could apply the method to the full range of PBDE-like contaminants present in the environment and in biota tissues.
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Contaminantes Ambientales/análisis , Contaminantes Ambientales/química , Éteres Difenilos Halogenados/análisis , Éteres Difenilos Halogenados/química , Biología Marina , Animales , Presión Atmosférica , Cromatografía Liquida , Electrones , Monitoreo del Ambiente , Humanos , Hidroxilación , Océanos y Mares , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Factores de TiempoRESUMEN
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. The fragmentation pathways of the Cl(7)-MBP and Br(4)Cl(2)-DBP produced characteristic multiple reaction monitoring (MRM) transitions. Determination was performed in the MRM mode using phenoxide ion [M-Br+O](-) and product Br(-) ions for MeO-BDE analogues, or the precursor [M-Cl+O](-) to Br(-) ion for Br(4)Cl(2)-DBP, and to C(4)NCl(4)(-) ion for Cl(7)-MBP. The APCI-LC/MS/MS method is acceptable for calibration of the linearity and repeatability of all products studied in the low ng/g (lipid weight) level and with similar sensitivity to the electron ionization (EI)-GC/MS method. The proposed method was applied for quantification of natural organohalogens accumulated in melon-headed whale (Peponocephala electra) blubber (N = 15) in the Asia-Pacific Ocean. The concentration was positively correlated between different groups of compounds except for 2'-MeO-BDE68. The use of the analytical method based on negative ion APCI-LC/MS/MS would provide a new way for rapid monitoring of halogenated natural products from marine biota, such as sponges or algae.
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Cromatografía Líquida de Alta Presión , Éteres Difenilos Halogenados/análisis , Halógenos/análisis , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Ballenas/metabolismo , Animales , Presión Atmosférica , Éteres Difenilos Halogenados/química , Halógenos/química , Control de CalidadRESUMEN
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. Selective delivery could be achieved by targeting MT1-MMP, as well as other angiogenic ECs. In this regard, an anti-MT1-MMP Fab' antibody was used to prepare a MT1-MMP targeted sterically stabilized immunoliposomes (SIL[anti-MT1-MMP(Fab')]). The binding and intracellular distribution of SIL[anti-MT1-MMP(Fab')] and a non-targeted sterically stabilized liposomes (SL) were examined using human fibrosarcoma HT-1080 cells. SIL[anti-MT1-MMP(Fab')] was taken up by the cells in a lipid concentration, temperature, and time dependent manner, ultimately accumulating in the lysosomes. The cytotoxicity of doxorubicin (DXR)-containing SIL[anti-MT1-MMP(Fab')] (DXR-SIL[anti-MT1-MMP(Fab')]) was significantly higher than that of DXR-containing SL. The cellular internalization of SIL[anti-MT1-MMP(Fab')] was inhibited by endocytosis inhibitors, suggesting that their internalization was mediated via clathrin- or caveolae-dependent endocytosis. Furthermore, the efficient binding of SIL[anti-MT1-MMP(Fab')] was observed on human umbilical vein endothelial cells (HUVEC). Based on these results, it would be expected that DXR-SIL[anti-MT1-MMP(Fab')] may achieve direct tumor cell kill and indirect tumor cell kill via the destruction of the tumor endothelium in vivo. This strategy may have the potential for overcoming some major limitations in conventional chemotherapy in vivo.
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Anticuerpos Monoclonales/inmunología , Antineoplásicos/administración & dosificación , Células Endoteliales/efectos de los fármacos , Fragmentos Fab de Inmunoglobulinas/inmunología , Metaloproteinasa 14 de la Matriz/biosíntesis , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Estabilidad de Medicamentos , Células Endoteliales/enzimología , Citometría de Flujo , Humanos , Liposomas , Metaloproteinasa 14 de la Matriz/inmunología , Microscopía ConfocalRESUMEN
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. In this study, the in vitro cytotoxicity of CL and its complex with pDNA (lipoplex) was investigated, and a part of the mechanism of induction as well. While free pDNA did not show any cytotoxicity, pDNA increased the cytotoxicity of CL via the formation of lipoplex. In addition, the lipoplex-induced cytotoxicity increased in a lipoplex dose-dependent manner, irrespective of the type of pDNA, cell line and the absence or presence of serum. An assay showed that apoptosis was largely induced by treatment with the lipoplex (lipofection), but not with CL alone, in the tested range of concentration of CL and pDNA. Furthermore, following treatment with lipoplexes, the cells exhibited the morphological features of apoptosis and DNA fragmentation. A cDNA microarray study showed that the lipofection up-regulated 45 genes related to apoptosis, transcription regulation and immune response. These results clearly indicate that pDNA in the lipoplex increases the cytotoxicity of CL as a result of inducing apoptosis. The fundamental principle for gene therapy is to deliver gene-based therapeutics to target cells for specific gene targeting with minimal cytotoxicity. Our results suggest the possibility that cytotoxicity induced by lipofection, accompanied by gene changes, could intrinsically exacerbate, attenuate or even mask the desired effects of gene-based therapy.
Asunto(s)
ADN/metabolismo , Vectores Genéticos/toxicidad , Liposomas/toxicidad , Plásmidos/metabolismo , Animales , Apoptosis/efectos de los fármacos , Cationes/química , Línea Celular Tumoral , ADN/administración & dosificación , ADN/química , ADN/clasificación , ADN/genética , Fragmentación del ADN/efectos de los fármacos , ADN Complementario/análisis , ADN Complementario/genética , Relación Dosis-Respuesta a Droga , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Terapia Genética/métodos , Glioma/metabolismo , Glioma/patología , Glioma/terapia , Células HeLa , Humanos , Técnicas In Vitro , Liposomas/administración & dosificación , Liposomas/química , Liposomas/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , TransfecciónRESUMEN
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. In the present article, we report that a first injection of PEGylated liposomes containing encapsulated DXR failed to induce the ABC phenomenon. Likewise, no rapid clearance of the test dose was observed when the first dose of "empty" PEGylated liposomes (without DXR) exceeded 5 micromol phospholipids/kg. By contrast, "empty" PEGylated liposomes at a low dose (1 micromol phospholipids/kg) induced the phenomenon as before. Western blot analysis revealed abundant binding of IgM to PEGylated liposomes when these were incubated in serum from rats that had received "empty" PEGylated liposomes. Substantially less binding of IgM was found when the liposomes were incubated in serum from rats treated with DXR-loaded PEGylated liposomes. For both the empty and the DXR-containing liposomes the amounts of IgM binding to the liposomes decreased with an increasing dose of injected liposomes. Serum obtained from rats following injection of empty PEGylated liposomes caused complement activation by addition of PEGylated liposomes in an inversely dose-dependent manner: the lower the dose, the higher the complement activation. By contrast, no complement activation was detected with serum from rats that had been treated with DXR-loaded PEGylated liposomes. These findings suggest that encapsulation of DXR as well as a relatively high lipid dose abrogate the immune response against PEGylated liposomes which is observed with the same liposomes but without DXR and at low doses. Our observations may thus have important implications for the development, evaluation and therapeutic use of liposomal cytotoxic drug formulations requiring multiple injection schemes.