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Nanoparticles have shown an enormous potential as drug delivery systems in the lab. However, translation to the clinics or even market approval often fails. So far, the reason for this discrepancy is manifold. Physicochemical properties such as size, surface potential, and surface chemistry are in focus of research for many years. Other equally important parameters, influencing whether a successful drug delivery can be achieved, are mechanical properties of nanoparticles. Even though this is often not even considered during formulation development, and it is not requested for approval, an increasing number of studies show that it is important to have knowledge about these characteristics. In this article, we discuss examples highlighting the influence of elasticity in nanoscale biological interactions focusing on mucosal delivery and on tumor targeting. Besides this, we discuss the influence of different measurement settings using atomic force microscopy for the determination of mechanical properties of drug carriers.
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Background & Aims: In Wilson disease (WD), copper accumulation and increased non-ceruloplasmin-bound copper in plasma lead to liver and brain pathology. To better understand the fate of non-ceruloplasmin-bound copper, we used PET/CT to examine the whole-body distribution of intravenously injected 64-copper (64Cu). Methods: Eight patients with WD, five heterozygotes, and nine healthy controls were examined by dynamic PET/CT for 90 min and static PET/CT up to 20 h after injection. We measured 64Cu activity in blood and tissue and quantified the kinetics by compartmental analysis. Results: Initially, a large fraction of injected 64Cu was distributed to extrahepatic tissues, especially skeletal muscle. Thus, across groups, extrahepatic tissues accounted for 45-58% of the injected dose (%ID) after 10 min, and 45-55% after 1 h. Kinetic analysis showed rapid exchange of 64Cu between blood and muscle as well as adipose tissue, with 64Cu retention in a secondary compartment, possibly mitochondria. This way, muscle and adipose tissue may protect the brain from spikes in non-ceruloplasmin-bound copper. Tiny amounts of cerebral 64Cu were detected (0.2%ID after 90 min and 0.3%ID after 6 h), suggesting tight control of cerebral copper in accordance with a cerebral clearance that is 2-3-fold lower than in muscle. Compared to controls, patients with WD accumulated more hepatic copper 6-20 h after injection, and also renal copper at 6 h. Conclusion: Non-ceruloplasmin-bound copper is initially distributed into a number of tissues before being redistributed slowly to the eliminating organ, the liver. Cerebral uptake of copper is extremely slow and likely highly regulated. Our findings provide new insights into the mechanisms of copper control. Impact and implications: Maintaining non-ceruloplasmin-bound copper within the normal range is an important treatment goal in WD as this "free" copper is considered toxic to the liver and brain. We found that intravenously injected non-ceruloplasmin-bound copper quickly distributed to a number of tissues, especially skeletal muscle, subcutaneous fat, and the liver, while uptake into the brain was slow. This study offers new insights into the mechanisms of copper control, which may encourage further research into potential new treatment targets. Clinical trial number: 2016-001975-59.
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BACKGROUND: Little is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various 68Ga-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compare organ and tumor distribution of [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE using a physiologically based pharmacokinetic (PBPK) model and to identify factors that might cause biodistribution and tumor uptake differences between both peptides. In addition, the effect of tumor burden on peptide biodistribution in gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients was assessed. METHODS: A PBPK model was developed for [68Ga]Ga-(HA-)DOTATATE in GEP-NET patients. Three tumor compartments were added, representing primary tumor, liver metastases and other metastases. Furthermore, reactions describing receptor binding, internalization and recycling, renal clearance and intracellular degradation were added to the model. Scan data from GEP-NET patients were used for evaluation of model predictions. Simulations with increasing tumor volumes were performed to assess the tumor sink effect. RESULTS: Data of 39 and 59 patients receiving [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE, respectively, were included. Evaluations showed that the model adequately described image-based patient data and that different receptor affinities caused organ uptake dissimilarities between both peptides. Sensitivity analysis indicated that tumor blood flow and blood volume impacted tumor distribution most. Tumor sink predictions showed a decrease in spleen uptake with increasing tumor volume, which seemed clinically relevant for patients with total tumor volumes higher than ~ 550 mL. CONCLUSION: The developed PBPK model adequately predicted tumor and organ uptake for this GEP-NET population. Relevant organ uptake differences between [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE were caused by different affinity profiles, while tumor uptake was mainly affected by tumor blood flow and blood volume. Furthermore, tumor sink predictions showed that for the majority of patients a tumor sink effect is not expected to be clinically relevant.
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Bexmarilimab is a new humanized monoclonal antibody against common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) and is in clinical trials for macrophage-guided cancer immunotherapy. In addition being associated with cancer, CLEVER-1 is also associated with fibrosis. To facilitate prospective human PET studies, we preclinically evaluated 89Zr-labeled bexmarilimab in rabbits. Methods: Bexmarilimab was conjugated with desferrioxamine (DFO) and radiolabeled with 89Zr. Retained immunoreactivity was confirmed by flow cytometry. The distribution kinetics of intravenously administered 89Zr-DFO-bexmarilimab (0.1 mg/kg) were determined for up to 7 d in a rabbit model of renal fibrosis mediated by unilateral ureteric obstruction. The in vivo stability of 89Zr-DFO-bexmarilimab was evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in combination with autoradiography. Additionally, we estimated the human radiation dose from data obtained in healthy rabbits. Results: 89Zr-DFO-bexmarilimab cleared rapidly from the blood circulation and distributed to the liver and spleen. At 24 h after injection, PET/CT, ex vivo γ-counting, and autoradiography demonstrated that there was significantly higher 89Zr-DFO-bexmarilimab uptake in unilateral ureteric obstruction-operated fibrotic renal cortex, characterized by abundant CLEVER-1-positive cells, than in contralateral or healthy kidneys. The estimated effective dose for a 70-kg human was 0.70 mSv/MBq. Conclusion: The characteristics of 89Zr-DFO-bexmarilimab support future human PET studies to, for example, stratify patients for bexmarilimab treatment, evaluate the efficacy of treatment, or monitor disease progression.
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Nefropatias , Neoplasias , Animais , Humanos , Coelhos , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Desferroxamina , Fibrose , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Radioisótopos/uso terapêutico , Zircônio/uso terapêutico , Moléculas de Adesão Celular Neuronais/metabolismo , Receptores de Retorno de Linfócitos/metabolismoRESUMO
Background: Deep brain stimulation (DBS) is a typical intervention treating drug-refractory dystonia. Currently, the selection of the better target, the GPi or STN, is debatable. The outcomes of DBS treating dystonia classified by body distribution and etiology is also a popular question. Objective: To comprehensively compare the efficacy, quality of life, mood, and adverse effects (AEs) of GPi-DBS vs. STN-DBS in dystonia as well as in specific types of dystonia classified by body distribution and etiology. Methods: PubMed, Embase, the Cochrane Library, and Google Scholar were searched to identify studies of GPi-DBS and STN-DBS in populations with dystonia. The efficacy, quality of life, mood, and adverse effects were quantitatively compared. Meta-regression analyses were also performed. This analysis has been registered in PROSPERO under the number CRD42020146145. Results: Thirty five studies were included in the main analysis, in which 319 patients underwent GPI-DBS and 113 patients underwent STN-DBS. The average follow-up duration was 12.48 months (range, 3-49 months). The GPI and STN groups were equivalent in terms of efficacy, quality of life, mood, and occurrence of AEs. The focal group demonstrated significantly better disability symptom improvement (P = 0.012) than the segmental and generalized groups but showed less SF-36 enhancement than the segmental group (P < 0.001). The primary groups exhibited significantly better movement and disability symptom improvements than the secondary non-hereditary group (P < 0.005), which demonstrated only disability symptom improvement compared with the secondary hereditary group (P < 0.005). The primary hereditary and idiopathic groups had a significantly lower frequency of AEs than the secondary non-hereditary group (P < 0.005). The correlation between disability symptom improvement and movement symptom improvement was also significant (P < 0.05). Conclusion: GPi-DBS and STN-DBS were both safe and resulted in excellent improvement in efficacy and quality of life in patients with dystonia. Compared with patients with segmental dystonia, patients with focal dystonia demonstrated better improvement in dystonia symptoms but less enhancement of quality of life. Those with primary dystonia had a better response to DBS in terms of efficacy than those with secondary dystonia. Patients who exhibit a significant improvement in movement symptoms might also exhibit excellent improvement in disability symptoms.
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BACKGROUND: Physiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokinetic behavior of drugs. The aim of this study was to develop a PBPK model to describe organ distribution of 68Ga-DOTATATE in a population of patients without detectable neuroendocrine tumors (NETs). METHODS: Clinical 68Ga-DOTATATE PET/CT data from 41 patients without any detectable somatostatin receptor (SSTR) overexpressing tumors were included. Scans were performed at 45 min (range 30-60 min) after intravenous bolus injection of 68Ga-DOTATATE. Organ (spleen, liver, thyroid) and blood activity levels were derived from PET scans, and corresponding DOTATATE concentrations were calculated. A whole-body PBPK model was developed, including an internalization reaction, receptor recycling, enzymatic reaction for intracellular degradation and renal clearance. SSTR2 expression was added for several organs. Input parameters were fixed or estimated using a built-in Monte Carlo algorithm for parameter identification. RESULTS: 68Ga-DOTATATE was administered with a median peptide amount of 12.3 µg (range 8.05-16.9 µg) labeled with 92.7 MBq (range 43.4-129.9 MBq). SSTR2 amounts for spleen, liver and thyroid were estimated at 4.40, 7.80 and 0.0108 nmol, respectively. Variability in observed organ concentrations was best described by variability in SSTR2 expression and differences in administered peptide amounts. CONCLUSIONS: To conclude, biodistribution of 68Ga-DOTATATE was described with a whole-body PBPK model, where tissue distribution was mainly determined by variability in SSTR2 organ expression and differences in administered peptide amounts.
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Acetone cyanohydrin (ACH) is a readily available source of cyanide and is widely used in basic and applied sciences. In toxicology, ACH is classified as extremely hazardous as it readily decomposes on contact with water, with the potential rapid release of highly toxic hydrogen cyanide (HCN). We report the case of a young woman found dead from the intentional ingestion of ACH and citalopram, an antidepressant of the selective serotonin reuptake inhibitor class. The autopsy findings included bright reddish-purple hypostasis and mild pulmonary edema. As ACH can decompose to acetone and HCN, we quantified the concentration of each compound and thiocyanate separately in various body fluids and organs and determined their whole-body distributions by using gas chromatography-mass spectrometry (GC-MS). We observed high concentrations of both acetone and cyanide in the blood (0.63 mg/mL and 17.99 mM, respectively) and gastric contents (9.76 mg/mL and 472.44 mM). The whole-body distributions of acetone and cyanide were similar (i.e., the concentration of each compound was the highest in the lung, followed by the heart, and then the liver). Our results suggest that not only the route of administration but also the dose taken could greatly affect the body distributions of cyanide in humans. In addition, as toxicological screening detected citalopram, which was not prescribed to the deceased, we performed a chiral analysis by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We determined that only (S)-citalopram was ingested antemortem; its concentration was 0.36 µg/mL, which is in the toxic range.
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Citalopram , Espectrometria de Massas em Tandem , Cromatografia Líquida , Feminino , Humanos , NitrilasRESUMO
Vitamine B1 thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, 11C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [11C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [11C]TTFD, along with radiation dosimetry of [11C]TTFD in humans. METHODS: Synthesis of [11C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [11C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [11C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: We succeeded in developing the improved synthetic method of [11C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [11C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [11C]TTFD calculated was 5.5 µSv/MBq (range 5.2-5.7). CONCLUSION: Novel synthetic method enabled clinical PET study with [11C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common 11C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B1 deficiency in human tissues.
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Fursultiamina/síntese química , Fursultiamina/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Fursultiamina/administração & dosagem , Humanos , Masculino , Radiometria/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/síntese química , Distribuição Tecidual , Imagem Corporal Total/métodosRESUMO
Sialic acid-binding immunoglubulinlike lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1. A 68Ga-labeled peptide of Siglec-9, 68Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-humans study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Methods: Six healthy men underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1 to 240 min after intravenous injection of 162 ± 4 MBq of 68Ga-DOTA-Siglec-9. In addition to γ-counting, the plasma samples were analyzed by high-performance liquid chromatography to detect intact tracer and radioactive metabolites. Radiation doses were calculated using the OLINDA/EXM software, version 2.2. In addition, a patient with early rheumatoid arthritis was studied with both 68Ga-DOTA-Siglec-9 and 18F-FDG PET/CT to determine the ability of the new tracer to detect arthritis. Results:68Ga-DOTA-Siglec-9 was well tolerated by all subjects. 68Ga-DOTA-Siglec-9 was rapidly cleared from the blood circulation, and several radioactive metabolites were detected. The organs with the highest absorbed doses were the urinary bladder wall (0.38 mSv/MBq) and kidneys (0.054 mSv/MBq). The mean effective dose was 0.022 mSv/MBq (range, 0.020-0.024 mSv/MBq). Most importantly, however, 68Ga-DOTA-Siglec-9 was comparable to 18F-FDG in detecting arthritis. Conclusion: Intravenous injection of 68Ga-DOTA-Siglec-9 was safe and biodistribution was favorable for testing of the tracer in larger group of patients with rheumatoid arthritis, as is planned for the next phase of clinical trials. The effective radiation dose of 68Ga-DOTA-Siglec-9 was within the same range as the effective radiation doses of other 68Ga-labeled tracers. Injection of 150 MBq of 68Ga-DOTA-Siglec-9 would expose a subject to 3.3 mSv. These findings support the possible repeated clinical use of 68Ga-DOTA-Siglec-9, such as in trials to elucidate the treatment efficacy of novel drug candidates.
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Amina Oxidase (contendo Cobre)/metabolismo , Antígenos CD/química , Moléculas de Adesão Celular/metabolismo , Radioisótopos de Gálio/química , Compostos Heterocíclicos com 1 Anel/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/química , Adulto , Feminino , Humanos , Ligantes , Masculino , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , Segurança , Solubilidade , Distribuição TecidualRESUMO
Historical (or legacy) contaminants, such as metals and persistent organic pollutants (POPs; e.g., polychlorinated biphenyls) have been measured in circumpolar subpopulations of polar bears, especially from Hudson Bay, East Greenland, and Svalbard, but substantially less is currently known about new and/or emerging contaminants such as polychlorinated naphthalenes, current-use pesticides, organotins, and polycyclic aromatic compounds (PACs). The polar bear (Ursus maritimus) is an apex Arctic predator that accumulates high levels of bioaccumulative POPs and mercury (Hg), but there is currently no comprehensive profiling of the present knowledge on contaminants in tissue and body compartments in polar bears. Based on current literature reports and data, and including archived museum samples (as far back as the 1300s) and up to 2018, the aim of this review is to utilize available data to examine the comparative distribution and burden of mainly lipophilic contaminants in kidney, liver, fat, and other body compartments, such as milk, blood, and brain. Highlight outcomes from this review include the following: (1) the kidneys are one of the most important tissue depots of contaminants in polar bears; (2) there is a critical lack of data concerning the presence of metals of concern (other than Hg); and (3) there currently are no data available on the concentrations of many newer and emerging contaminants, such as PACs, which is especially relevant given the increasing oil and gas development in regions, such as the Beaufort Sea (Canada). Additionally, given the vulnerability of polar bear populations worldwide, there is a need to develop non-invasive approaches to monitor contaminant exposure in polar bears.
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Poluentes Ambientais/análise , Ursidae , Animais , Regiões Árticas , Canadá , Groenlândia , SvalbardRESUMO
Chlorophyllum rhacodes, typically regarded as a rich grassland or open forest "mushroom" species, was found fruiting abundantly on nests of Formica lugubris, occurring in a Pinus silvestris plantation. Fruiting was absent from the rest of the woodland.Research focussed on the activities in the nests that could explain this. Within nests, there was a spatial relationship between C. rhacodes mycelium, insect cadavers, fruitbody initiation, and roots of adjacent trees.In vitro experiments found that C. rhacodes was not mycorrhizal with P. silvestris, but that it had qualities which rendered it suitable for colonization of the rhizosphere in the conditions of the nest mound and for further niche development.Implications of the unusual presence of fruit-bodies and the distribution of associated hyphae are discussed in relation to the nutritional biology (and recent taxonomical reassignment) of the fungus. This includes reference to the relevant physiology of insects and to the accepted evolution of mutualistic symbioses between fungi and the Attini and Termitidae.An argument is presented that the situation observed in vivo provides evidence of a degree of facultative association and what could be tangible support for the theory for the developmental origin of mutualistic fungus cultivation by insects. It is presented as a context for continued experimental research.
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The death of dozens of manatees Trichechus manatus recently in Tabasco, Mexico, has captured international attention. Speculation about possible causes include water and food contamination by metals. Although federal authorities have ruled out water chemical pollution, the cause of these deaths is still awaiting conclusive laboratory results. Present work seeks to summarize information currently available on non-essential metals and those of great toxicological relevance in Sirenia (dugongs and manatees), highlighting its body distribution, presence in blood, and its relationship with their geographical distribution, gender and age, whenever possible. This paper focuses on the five elements: As, Cr, Hg, Pb and Cd, which are commonly considered as threats for marine mammals and reported in Sirenia. Some of these metals (Cr and Cd) were thought to be related to the recent deaths in Tabasco. All five elements are accumulated by Sirenia at different levels. Metal presence is associated to their diet but does not necessarily imply adverse effects for dugongs and manatees. Toxicological aspects and the human consumption risk in case of any illegal or traditional consumption in some cultures are discussed. Important toxicological research areas that need to be addressed are highlighted.
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Arsênio/metabolismo , Dugong/metabolismo , Metais Pesados/metabolismo , Trichechus manatus/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Arsênio/toxicidade , Carga Corporal (Radioterapia) , Dieta/efeitos adversos , Humanos , Metais Pesados/toxicidade , Distribuição Tecidual , Poluentes Químicos da Água/toxicidadeRESUMO
INTRODUCTION: The incidence of central nervous system disease has increased in recent years. However, the transportation of drug is restricted by the blood-brain barrier, contributing to the poor therapeutic effect in the brain. Therefore, the development of a new brain-targeting drug delivery system has become the hotspot of pharmacy. MATERIALS AND METHODS: Borneol, a simple bicyclic monoterpene extracted from Dryobalanops aromatica, can direct drugs to the upper body parts according to the theory of traditional Chinese medicine. Dioleoyl phosphoethanolamine (DOPE) was chemically modified by borneol as one of the lipid materials of solid lipid nanoparticle (SLN) in the present study. RESULTS: The borneol-modified chemically solid lipid nanoparticle (BO-SLN/CM), borneol-modified physically solid lipid nanoparticle (BO-SLN/PM), and SLN have similar diameter (of about 87 nm) and morphological characteristics. However, BO-SLN/CM has a lower cytotoxicity, higher cell uptake, and better blood-brain barrier permeability compared with BO-SLN/PM and SLN. BO-SLN/CM has a remarkable targeting function to the brain, while BO-SLN/ PM and SLNs are concentrated at the lung. CONCLUSION: The present study provides an excellent drug delivery carrier, BO-SLN/CM, having the application potential of targeting to the brain and permeating to the blood-brain barrier.
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Barreira Hematoencefálica/efeitos dos fármacos , Canfanos/química , Portadores de Fármacos/química , Nanopartículas/administração & dosagem , Animais , Encéfalo , Sistemas de Liberação de Medicamentos/métodos , Lipídeos/química , Camundongos , Nanopartículas/química , Tamanho da Partícula , Permeabilidade , Fosfatidiletanolaminas/química , Distribuição TecidualRESUMO
Ectoparasites are temporary or permanent skin dwellers. Megninia ginglymura (Mégnin) (Analgidae) causes economic damage in commercial poultry farms as a result of lower egg production or even death of the host. Little is known about Megninia ginglymura's life cycle and infestation. This study aimed to evaluate the preference of M. ginglymura for different body regions of the host Gallus gallus L. and its abundance and population dynamics in different laying hen houses. Samples were collected from August 2013 to August 2014 in three different commercial laying hen systems: automatic production systems (A1,2,3); semiautomatic systems (S1 (free of pesticides) and S2) and free-range system (FR). Ten laying hen were sampled each laying hen house and it were collected feathers were collected from different body regions form 10 hens in each laying house. A total of 28,305 specimens belonging to M. ginglymura were collected. Higher abundance was noted in S1 (9,234), S2 (9,121), and FR (5,873) and lower in A2 (2,211), A3 (1,628), and A1 (238). The dorsum (back of the body) region showed the highest abundance, mean abundance, and prevalence, representing 29.5% of the total specimens collected. The cloacal region was the second with 21.1% of the total of this ectoparasite. The abdomen and neck represented 20.8% and 19.6%, respectively. The inner wings presented the lowest abundance, mean abundance, and prevalence in all laying hen houses (9.0% of specimens). The prevalence was significantly different in automatic, semiautomatic, and free-range systems. The population peaks seems to coincide with periods of high temperatures and precipitation. Populations of this species already exhibit resistance to synthetic chemical pesticide.
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Criação de Animais Domésticos/métodos , Galinhas , Infestações por Ácaros/veterinária , Ácaros/fisiologia , Doenças das Aves Domésticas/epidemiologia , Animais , Brasil/epidemiologia , Plumas/parasitologia , Feminino , Interações Hospedeiro-Parasita , Masculino , Infestações por Ácaros/epidemiologia , Infestações por Ácaros/parasitologia , Dinâmica Populacional , Doenças das Aves Domésticas/parasitologia , PrevalênciaRESUMO
OBJECTIVE: To assess body distribution and timing of appearance of rest tremor in Parkinson's disease. METHODS: Information was obtained by a computerized database containing historical information collected at the first visit and data collected during the subsequent follow-up visits. Information on rest tremor developed during the follow-up could be therefore obtained by our own observation in a proportion of patients. RESULTS: Among 289 patients, rest tremor was reported at disease onset in 65.4% of cases and detected at last follow-up examination in 74.4% of patients. Analysis of patients who did not report rest tremor at disease onset indicated that 26% of such patients (9% in the overall population) manifested rest tremor over the disease course. Rest tremor spread to new sites in 39% of patients who manifested rest tremor at disease onset. Regardless of tremor presentation at disease onset or during the follow-up, upper limb was the most frequent tremor localization. Over the follow-up, rest tremor developed faster in the upper limb than in other body sites. The risk of developing rest tremor during the follow-up was not affected by sex, side of motor symptom onset and site of tremor presentation. However, age of disease onset >63years was associated with an increased risk of rest tremor spread. CONCLUSIONS: This study provides new information about body distribution and timing of rest tremor appearance during the course of early stages of Parkinson's disease that may help clinicians in patients' counselling.
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Doença de Parkinson/complicações , Tremor/etiologia , Tremor/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais/estatística & dados numéricos , Progressão da Doença , Feminino , Seguimentos , Corpo Humano , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de TempoRESUMO
PURPOSE: This study was designed to determine safety, tolerability, and radiation burden of a [(68)Ga]NODAGA-RGD-PET for imaging integrin αvß3 expression in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Moreover, metabolic stability and biokinetic data were compiled. METHODS: After injection of 154-184 MBq [(68)Ga]NODAGA-RGD three consecutive PET/CT scans were acquired starting 8.3 ± 2.1, 36.9 ± 2.8, and 75.1 ± 3.4 min after tracer injection. For metabolite analysis, blood and urine samples were analyzed by HPLC. For dosimetry studies, residence time VOIs were placed in the corresponding organs. The OLINDA/EXM program was used to estimate the absorbed radiation dose. RESULTS: The radiopharmaceutical was well tolerated and no drug-related adverse effects were observed. No metabolites could be detected in blood (30 and 60 min p.i.) and urine (60 min p.i.). [(68)Ga]NODAGA-RGD showed rapid and predominantly renal elimination. Background radioactivity in blood, intestine, lung, and muscle tissue was low (%ID/l 60 min p.i. was 0.56 ± 0.43, 0.54 ± 0.39, 0.22 ± 0.05, and 0.16 ± 0.8, respectively). The calculated effective dose was 21.5 ± 5.4 µSv/MBq, and the highest absorbed radiation dose was found for the urinary bladder wall (0.26 ± 0.09 mSv/MBq). No increased uptake of the tracer was found in HCC compared with the background liver tissue. CONCLUSIONS: [(68)Ga]NODAGA-RGD uptake in the HCCs lesions was not sufficient to use this tracer for imaging these tumors. [(68)Ga]NODAGA-RGD was well tolerated and metabolically stable. Due to rapid renal excretion, background radioactivity was low in most of the body, resulting in low radiation burden and indicating the potential of [(68)Ga]NODAGA-RGD PET for non-invasive determination of integrin αvß3 expression.
Assuntos
Carcinoma Hepatocelular/metabolismo , Complexos de Coordenação/farmacocinética , Integrina alfaVbeta3/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Peptídeos Cíclicos/farmacocinética , Exposição à Radiação/análise , Idoso , Carcinoma Hepatocelular/diagnóstico por imagem , Feminino , Humanos , Cirrose Hepática/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Imagem Molecular/métodos , Especificidade de Órgãos , Tomografia por Emissão de Pósitrons/métodos , Doses de Radiação , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual , Contagem Corporal TotalRESUMO
In this study, a nano-preparation based on nanoemulsome (NES) modified with cetyltrimethylammonium bromide (CTAB) loading paclitaxel (PTX) was designed, and its biodistribution were explored after intratumoral (i.t.) administration on Heps tumor-bearing mice. The PTX-loaded nanoemulsome (PTX-NES) was prepared by using a solvent evaporation method and CTAB, chosen as a cationic material, was absorbed onto the surface of the NES via electrostatic interaction to yield paclitaxel-loaded cationic nanoemulsome (PTX-CTAB-NES). The MTT results exhibited that PTX-CTAB-NES (IC50: 0.50±0.035µg/mL in MCF-7 cells and 0.13±0.048µg/mL in SMMC-7721 cells) had the strongest cytotoxicity compared to Taxol (IC50: 0.88±0.054µg/mL in MCF-7 and 0.15±0.011µg/mL in SMMC-7721) and PTX-NES (IC50: 1.93±0.062µg/mL in MCF-7 and 0.32±0.027µg/mL in SMMC-7721). Body distribution of PTX revealed that the percent of PTX retained in the tumor after i.t. administration of PTX-CTAB-NES (approximately 92.99% at 0.167h and 15.35% at 48h) was higher when compared to that after i.t. injection of Taxol (approximately 58.94% at 0.167h and 0.83% at 48h) or PTX-NES (approximately 83.63% at 0.167h and 6.52% at 48h). Moreover, less PTX accumulated in liver, spleen, kidney, lung and heart after i.t. administration of PTX-CTAB-NES when compared with that after i.v. administration of PTX-CTAB-NES. In conclusion, PTX-CTAB-NES was a prospective in-situ delivery system for the therapy of tumor.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Compostos de Cetrimônio/química , Portadores de Fármacos , Lipídeos/química , Paclitaxel/farmacocinética , Animais , Antineoplásicos Fitogênicos/farmacologia , Área Sob a Curva , Cetrimônio , Composição de Medicamentos , Humanos , Concentração Inibidora 50 , Injeções Intralesionais , Células MCF-7 , Masculino , Camundongos , Micelas , Paclitaxel/farmacologia , Tamanho da Partícula , Propriedades de Superfície , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Nano-silicon dioxide (SiO2) is used nowadays in several biomedical applications such as drug delivery and cancer therapy, and is produced on an industrial scale as additive to paints and coatings, cosmetics and food. Data regarding the long-term biokinetics of SiO2 engineered nanoparticles (ENPs) is lacking. In this study, the whole-body biodistribution of SiO2 core-shell ENPs containing a paramagnetic core of Fe3O4 was investigated after a single exposure via intravenous injection or intratracheal instillation in mice. The distribution and accumulation in different organs was evaluated for a period of 84 days using several techniques, including magnetic resonance imaging, inductively coupled plasma mass spectrometry, X-ray fluorescence and X-ray absorption near edge structure spectroscopy. We demonstrated that intravenously administered SiO2 ENPs mainly accumulate in the liver, and are retained in this tissue for over 84 days. After intratracheal instillation, an almost complete particle clearance from the lung was seen after 84 days with distribution to spleen and kidney. Furthermore, we have strong evidence that the ENPs retain their original core-shell structure during the whole observation period. This work gives an insight into the whole-body biodistribution of SiO2 ENPs and will provide guidance for further toxicity studies.
Assuntos
Óxido Ferroso-Férrico/farmacocinética , Pulmão/metabolismo , Nanopartículas , Dióxido de Silício/farmacocinética , Administração por Inalação , Animais , Óxido Ferroso-Férrico/administração & dosagem , Óxido Ferroso-Férrico/química , Humanos , Injeções Intravenosas , Instilação de Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/química , Especificidade de Órgãos , Dióxido de Silício/administração & dosagem , Dióxido de Silício/sangue , Dióxido de Silício/química , Espectrometria por Raios X , Propriedades de Superfície , Distribuição Tecidual , Espectroscopia por Absorção de Raios XRESUMO
Aquatic organisms are often subject to intermittent exposure to pollutants in real ecosystems. This study aimed to compare mercury accumulation and the physiological responses of mussels, Mytilus edulis during continuous and intermittent exposure to the metal. Mussels were treated in a semi-static, triplicated design to either a control (no added Hg) or 50 µg l(-1) Hg as HgCl2 in continuous (daily) or intermittent (2 day exposure, 2 days in clean seawater alternately) exposure for 14 days. A time-dependent increase in Hg accumulation was observed in the continuous exposure, while the intermittent treatment showed step-wise changes in Hg concentrations with the exposure profile, especially in the gills. At the end of the experiment, tissue Hg concentrations were significantly increased in the continuous compared to the intermittent exposure for digestive gland (4 fold), gonad and remaining soft tissue (>2 fold), but not for the gill and adductor muscle. There was no observed oxidative damage at the end of the experiment as measured by the thiobarbituric acid reactive substances (TBARS) concentrations in tissues from all treatments. However, total glutathione was significantly decreased in the gill and digestive gland of both the continuous and intermittent exposure by the end of the experiment. The neutral red retention ability of the haemocytes was not affected, but total haemocyte counts were significantly decreased (<2 fold) in the intermittent compared to the continuous exposure. Histopathological examinations showed less pathology in the gill, but more inflammation in the digestive gland of mussels for the intermittent compared to the continuous exposure. Overall, the results showed that Hg accumulation from intermittent exposure was less than that of the continuous exposure regime, but the sub-lethal responses are sometimes more severe than expected in the former.
Assuntos
Mercúrio/metabolismo , Mercúrio/toxicidade , Mytilus edulis/efeitos dos fármacos , Água do Mar/análise , Poluentes Químicos da Água/toxicidade , Animais , Exposição Ambiental , Brânquias/química , Brânquias/efeitos dos fármacos , Glutationa/metabolismo , Hemócitos/química , Hemócitos/citologia , Hemócitos/efeitos dos fármacos , Espectrometria de Massas , Mercúrio/análise , Músculos/química , Músculos/metabolismo , Mytilus edulis/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Fatores de Tempo , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/metabolismoRESUMO
Little is known about the bioaccumulation responses of shellfish to metals during intermittent compared to continuous exposure. There is also the concern that the toxicity of intermittent events may not be the same as that from the steady-state continuous exposures. The aim of the present study was to determine whether there was any difference between cadmium (Cd) accumulation, or Cd-dependent biological responses, in tissues of blue mussels (Mytilus edulis) during intermittent compared to continuous Cd exposure. Tissues and hemolymph were collected from M. edulis exposed for 14 days to either control (no added Cd, only seawater), or 50 µg/l Cd as CdCl2 in continuous or intermittent profile (2 day exposure, 2 days in clean seawater alternately); and sub-lethal responses examined using a suite of assays including total glutathione, thiobarbituric acid reactive substances (TBARS), neutral red retention, total hemocyte counts, hemolymph Na(+) and K(+), plasma glucose and histopathology. A time-dependent accumulation of the Cd was observed in tissues of mussels after continuous exposure, while the intermittent exposure showed step-wise changes in the hemolymph and gonad. Tissue Cd concentration in the continuous exposure was significantly increased (≥2 fold) for most tissues compared to the intermittent exposure. No clear differences were seen between the continuous and intermittent exposure for most end points measured apart from a 2 fold significant increase in hemocyte infiltration in the digestive gland of the continuous exposure compared to the intermittent exposure. Overall, the data showed that the Cd accumulation was generally greater in the continuous exposure regime, but despite this, most of the biological responses being similar in both regimes.