Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.660
Filtrar
1.
Mater Sci Eng C Mater Biol Appl ; 104: 109896, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499977

RESUMO

Zinc alloys have been explored as potential materials for biodegradable vascular stents due to their tolerable corrosion rates and tunable mechanical properties. However, the performances of Zn alloys were not supported with enough toxicity or biological compatibility evaluation, particularly hemocompatibility for vascular scaffolding application. In this work, the hemocompatibility of three zinc alloys (Zn-0.8Cu, Zn-0.8Mn and Zn-0.8Li) was evaluated with 316 L stainless steel and pure zinc as controls. The hemolysis ratios of 316 L stainless steel, pure Zn, Zn-0.8Cu, Zn-0.8Mn and Zn-0.8Li were 0.38 ±â€¯0.08%, 1.04 ±â€¯0.21%, 0.47 ±â€¯0.21%, 0.57 ±â€¯0.14% and 0.52 ±â€¯0.22%, respectively, for direct contact method. Platelets aggregation on the 316 L stainless steel was observed, while the adhered platelets on the Zn alloys exhibited round shape with few pseudopodia spreading. The number of adhered platelets on the three zinc alloys (Zn-0.8Cu, Zn-0.8Mn and Zn-0.8Li) had no statistically difference compared with 316 L stainless steel, while significant fewer than the pure Zn group. None remarkable platelet activation, hematocyte aggregation, coagulation or complement activation was observed in any Zn alloy group. Furthermore, the Zn alloys prolonged prothrombin time and partial thromboplastin time, demonstrating a potential function of anticoagulation. The results demonstrated that Zn alloys presented in this work are indeed meeting the hemocompatible requirements of implant and showing the promise for perspective application as biodegradable stent.


Assuntos
Ligas/química , Materiais Biocompatíveis/química , Lítio/química , Magnésio/química , Zinco/química , Implantes Absorvíveis , Ligas/administração & dosagem , Materiais Biocompatíveis/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Corrosão , Hemólise/efeitos dos fármacos , Humanos , Lítio/administração & dosagem , Teste de Materiais/métodos , Ativação Plaquetária/efeitos dos fármacos , Aço Inoxidável/química , Stents , Zinco/administração & dosagem
2.
Redox Biol ; 26: 101275, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31349118

RESUMO

Transition of acute kidney injury (AKI) to chronic kidney disease (CKD) represents an important cause of kidney failure. However, how AKI is transformed into CKD remains elusive. Following folic acid injury, mice developed AKI with ensuing CKD transition, featured by variable degrees of interstitial fibrosis and tubular cell atrophy and growth arrest. This lingering injury of renal tubules was associated with sustained oxidative stress that was concomitant with an impaired Nrf2 antioxidant defense, marked by mitigated Nrf2 nuclear accumulation and blunted induction of its target antioxidant enzymes, like heme oxygenase (HO)-1. Activation of the canonical Keap1/Nrf2 signaling, nevertheless, seems intact during CKD transition because Nrf2 in injured tubules remained activated and elevated in cytoplasm. Moreover, oxidative thiol modification and activation of Keap1, the cytoplasmic repressor of Nrf2, was barely associated with CKD transition. In contrast, glycogen synthase kinase (GSK)3ß, a key modulator of the Keap1-independent Nrf2 regulation, was persistently overexpressed and hyperactive in injured tubules. Likewise, in patients who developed CKD following AKI due to diverse etiologies, like volume depletion and exposure to radiocontrast agents or aristolochic acid, sustained GSK3ß overexpression was evident in renal tubules and coincided with oxidative damages, impaired Nrf2 nuclear accumulation and mitigated induction of antioxidant gene expression. Mechanistically, the Nrf2 response against oxidative insult was sabotaged in renal tubular cells expressing a constitutively active mutant of GSK3ß, but reinforced by ectopic expression of dominant negative GSK3ß in a Keap1-independent manner. In vivo in folic acid-injured mice, targeting GSK3ß in renal tubules via conditional knockout or by weekly microdose lithium treatment reinstated Nrf2 antioxidant response in the kidney and hindered AKI to CKD transition. Ergo, our findings suggest that GSK3ß-mediated Keap1-independent regulation of Nrf2 may serve as an actionable therapeutic target for modifying the long-term sequelae of AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Antioxidantes/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Animais , Biomarcadores , Biópsia , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Ácido Fólico/efeitos adversos , Imuno-Histoquímica , Lítio/administração & dosagem , Lítio/farmacologia , Masculino , Camundongos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia
3.
Mol Pharmacol ; 95(5): 573-583, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30858164

RESUMO

This is the first work to use a newly designed Li+-selective photoswitchable probe Sabrina Heng Lithium (SHL) in living colon cancer cells to noninvasively monitor cation channel activity in real time by the appearance of lithium hot spots detected by confocal microscopy. Punctate Li+ hot spots are clustered in the lamellipodial leading edges of HT29 human colon cancer cells and are colocalized with aquaporin-1 (AQP1) channels. AQP1 is a dual water and cyclic-nucleotide-gated cation channel located in lamellipodia and is essential for rapid cell migration in a subset of aggressive cancers. Both the Li+ hot spots and cell migration are blocked in HT29 cells by the AQP1 ion channel antagonist AqB011. In contrast, Li+ hot spots are not evident in a poorly migrating colon cancer cell line, SW620, which lacks comparable membrane expression of AQP1. Knockdown of AQP1 by RNA interference in HT29 cells significantly impairs Li+ hot spot activity. The SHL probe loaded in living cells shows signature chemical properties of ionic selectivity and reversibility. Dynamic properties of the Li+ hot spots, turning on and off, are confirmed by time-lapse imaging. SHL is a powerful tool for evaluating cation channel function in living cells in real time, with particular promise for studies of motile cells or interlinked networks not easily analyzed by electrophysiological methods. The ability to reset SHL by photoswitching allows monitoring of dynamic signals over time. Future applications of the Li+ probe could include high-throughput optical screening for discovering new classes of channels, or finding new pharmacological modulators for nonselective cation channels.


Assuntos
Movimento Celular/fisiologia , Neoplasias do Colo/metabolismo , Canais Iônicos/metabolismo , Lítio/administração & dosagem , Animais , Aquaporina 1/metabolismo , Linhagem Celular Tumoral , GMP Cíclico/metabolismo , Células HT29 , Humanos , Ativação do Canal Iônico/fisiologia , Oócitos/metabolismo , Oócitos/fisiologia , Transdução de Sinais/fisiologia , Xenopus laevis/metabolismo , Xenopus laevis/fisiologia
4.
Biochem Biophys Res Commun ; 511(2): 394-397, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30791983

RESUMO

Lithium, a well-known inhibitor of glycogen synthase kinase-3ß (GSK3ß), can improve bone formation by activating the Wnt/ß-catenin signalling pathway. However, most studies have used higher doses of lithium, which potentially have adverse effects. Herein, we report that low dose lithium supplementation (10 mg/kg/d for 6 weeks) in mice results in a serum lithium concentration of 0.02 mM significantly inhibiting GSK3ß while activating Wnt/ß-catenin in bone. In turn, we observed a significant increase in the expression of osteoprotegerin (OPG), with unaltered expression of nuclear-factor kß ligand (RANKL), ultimately leading to a significant increase in the OPG/RANKL ratio. Altogether, our findings provide initial evidence that low dose lithium supplementation can promote the signalling pathways associated with bone formation.


Assuntos
Lítio/farmacologia , Osteoprotegerina/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ligante RANK/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Lítio/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteogênese/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , beta Catenina/metabolismo
5.
BMJ Case Rep ; 12(1)2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30659009

RESUMO

After 25 years of continuous lithium therapy, a woman with moderate intellectual disability and bipolar disorder developed symptoms suggestive of dementia. In fact, she had developed lithium neurotoxicity, but this was overlooked for 18 months as serial lithium levels were in the therapeutic range.


Assuntos
Demência/induzido quimicamente , Lítio/toxicidade , Síndromes Neurotóxicas/etiologia , Transtorno Bipolar/tratamento farmacológico , Feminino , Humanos , Lítio/administração & dosagem , Pessoa de Meia-Idade , Resultado do Tratamento
6.
Biol Trace Elem Res ; 189(1): 18-27, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30066063

RESUMO

Lithium compounds have been widely used in psychopharmacology, particularly in the treatment of bipolar disorder. Their normothymic and neuroprotective properties when used at high doses have been well established. However, a number of observations suggest that environmentally relevant lithium doses may also exert beneficial health effects, leading to a decrease in the rate of suicides and levels of violence. Despite the fact that this element is not officially considered to be a micronutrient, some authors have suggested provisional recommended intakes set at 1000 µg/day for a 70-kg adult (14.3 µg/kg body weight). The present paper reviews the biological action of lithium, its bioavailability and metabolism, and content in different foodstuffs and water. It also assesses epidemiological data on potential correlations between lithium intake and suicide rate as well as examines the concept of fortifying food with this element as a strategy in the primary prevention of mood disorders and pre-suicidal syndrome.


Assuntos
Lítio/uso terapêutico , Micronutrientes/uso terapêutico , Alimentos Fortificados , Humanos , Lítio/administração & dosagem , Transtornos do Humor/prevenção & controle , Suicídio/prevenção & controle
7.
Neurosci Lett ; 692: 64-68, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30391321

RESUMO

The blood-brain barrier (BBB) is a unique structure that controls substances exchange between the systemic circulation and the brain. Disruption of its integrity contributes to the development and progression of a variety of brain disorders including stroke, epilepsy and neurodegenerative diseases. It was shown that intracerebral thrombin level substantially increases following status epilepticus (SE). Inhibition of protease-activated receptor 1 (PAR1), the major thrombin receptor in the brain, produces an anti-epileptogenic and neuroprotective effects in an experimental model of temporal lobe epilepsy (TLE). Since serine proteases and PAR1 are implicated in the synaptic plasticity and memory formation, the aim of the present study was to elucidate the involvement of PAR1 in synaptic plasticity and behavior deficits following SE. Using lithium-pilocarpine model of TLE, we demonstrate that inhibition of PAR1 rescues SE-induced synaptic plasticity deficits in CA1 region of hippocampus. Although treatment with PAR1 antagonist does not ameliorate spatial learning deficits, it attenuates anxiolytic-like behavior in experimental rats after SE. Taken together; our data suggest an important role of PAR1 in SE-induced synaptic and behavioral alterations and provide a new insight into cellular mechanisms underlying behavioral impairments associated with epilepsy.


Assuntos
Região CA1 Hipocampal/fisiopatologia , Epilepsia do Lobo Temporal/fisiopatologia , Potenciação de Longa Duração , Receptor PAR-1/antagonistas & inibidores , Estado Epiléptico/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Lítio/administração & dosagem , Masculino , Pilocarpina/administração & dosagem , Pirróis/administração & dosagem , Quinazolinas/administração & dosagem , Ratos Wistar , Estado Epiléptico/induzido quimicamente
8.
Eur J Pharm Sci ; 128: 1-7, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30419292

RESUMO

Lithium is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, lithium has been used as a measure to determine proximal tubule reabsorption based on the assumption that lithium and sodium transport go in parallel in the proximal tubule. However, the exact mechanism by which lithium is reabsorbed remains elusive. The majority of proximal tubule sodium reabsorption is directly or indirectly mediated by the sodium-hydrogen exchanger 3 (NHE3). In addition, sodium-phosphate cotransporters have been implicated in renal lithium reabsorption. In order to better understand the role of sodium-phosphate cotransporters involved in lithium (re)absorption, we studied lithium pharmacokinetics in: i) tubule-specific NHE3 knockout mice (NHE3loxloxPax8Cre), and ii) mice challenged with low or high phosphate diets. Intravenous or oral administration of lithium did not result in differences in lithium bioavailability, half-life, maximum plasma concentrations, area under the curve, lithium clearance, or urinary lithium/creatinine ratios between control and NHE3loxloxPax8Cre mice. After one week of dietary phosphate challenges, lithium bioavailability was ~30% lower on low versus high dietary phosphate, possibly the consequence of a smaller area under the curve after oral administration. This was associated with higher apparent lithium clearance after oral administration and lower urinary lithium/creatinine ratios on low versus high dietary phosphate. Collectively, renal NHE3 does not play a role in lithium pharmacokinetics; however, dietary phosphate could have an indirect effect on lithium bioavailability and lithium disposition.


Assuntos
Lítio/farmacocinética , Fosfatos/administração & dosagem , Fósforo na Dieta/administração & dosagem , Trocador 3 de Sódio-Hidrogênio/metabolismo , Administração Oral , Ração Animal , Animais , Dieta , Injeções Intravenosas , Lítio/administração & dosagem , Lítio/sangue , Lítio/urina , Camundongos , Camundongos Knockout , Trocador 3 de Sódio-Hidrogênio/genética
9.
São José dos Campos; s.n; 2019. 118 p. il., tab., graf..
Tese em Português | LILACS, BBO - Odontologia | ID: biblio-1024042

RESUMO

O desempenho das cerâmicas odontológicas é um aspecto bastante explorado na literatura, uma vez que o aprimoramento das suas características permite desenvolver materiais com maior longevidade. Trincas, delaminações, lascamentos e fraturas catastróficas são as falhas mais encontradas em restaurações cerâmicas. O objetivo dessa pesquisa foi conhecer o comportamento mecânico de coroas monolíticas gradadas e avaliar a possibilidade de produzir uma vitrocerâmica experimental a base de dissilicato de lítio com gradiente funcional de porosidade. Este trabalho foi dividido em duas partes: a primeira, teórico/computacional e a segunda, a fabricação do produto. 1) Através de software CAD foi modelado um molar inferior com preparo tradicional para coroa total e uma coroa total monolítica com camada de cimento resinoso entreposto. Quatro grupos foram compostos pela variação da composição das coroas totais: Coroa rígida (E=80 GPa), flexível (E=30 GPa), gradação bioinspirada (de 80 até 30 GPa) e gradação inversa (de 30 até 80 GPa). O modelo foi exportado para o software de análise. Os materiais foram considerados isotrópicos, linearmente elásticos e homogêneos, com contatos ideais. Uma força de 300N foi aplicada na face oclusal, a base do modelo foi fixada em todas as direções. A tensão máxima principal, tensão de Von-Mises e deslocamento foram utilizadas para observar o comportamento mecânico. 2) Uma mistura de óxidos foi homogeneizada e submetida à fusão. As fritas obtidas por resfriamento foram moídas e passaram por diferentes tratamentos térmicos, seguido das análises de DSC e DRX. Seis grupos experimentais foram obtidos: DL-E (vitrocerâmica densa a base de dissilicato de lítio simulando esmalte); DL-D (vitrocerâmica densa a base de dissilicato de lítio simulando dentina); DLGrad (vitrocerâmica gradada a base de dissilicato de lítio); YTZP-E (vitrocerâmica densa reforçada por YTZP simulando esmalte); YTZP-D (vitrocerâmica densa reforçada por YTZP simulando dentina); YGrad (vitrocerâmica gradada reforçada por YTZP). Suspensões aquosas contendo 23 e 30%-vol. de pó de vidro foram preparadas e submetidos à técnica de gel casting para formar um gradiente funcional. As vitrocerâmicas com e sem gradiente funcional de porosidade foram caracterizadas pelas técnicas de DRX, FEG, densidade e porosidade aparentes. Também foram realizados ensaios mecânicos de resistência à flexão biaxial e fractografia. Os resultados obtidos foram estatisticamente avaliados por Anova 1 fator e Tukey (p<0,05). As micrografias mostraram formação de gradiente funcional de porosidade apenas nas vitrocerâmicasa base de dissilicato de lítio. Não houve diferença entre as densidades de todos as vitrocerâmicas estudadas, porém YTZP-E, YTZP-D e YTZP-Grad apresentaram porosidade 10% maior do que as vitrocerâmicassem zircônia. Os defeitos críticos na superfície das vitrocerâmicas são semelhantes em todas condições estudadas, porém a aleatoriedade de poros internos das vitrocerâmicas contendo YTZP proporcionaram diminuição da resistência à flexão, com diferença estatisticamente significante em relação às vitrocerâmicas sem YTZP. Entre as vitrocerâmicas densas e gradadas não houve diferença na resistência à flexão. Conclui-se que a adição de zircônia em sistema a base de SiO2-Li2O alterou a temperatura de sinterização, o padrão de porosidade, a resistência flexural e comprometeu a formação do gradiente funcional de porosidade. O comportamento mecânico das vitrocerâmicas à base de dissilicato de lítio densas e gradadas são similares(AU)


The performance of dental ceramics is very explorated at literature, once the enhancement of yours features allow the development of materials with higher longevity. Cracks, delamination, chipping and catastrophic fracture are the faillures most finds at ceramics restorations. The aim of this research was knew the mechanical behavior of monolithics graded crows and it was evaluated the possibility to produce a glass ceramic based of lithium disilicate with gradient of porosity. This research was divided into two parts: the first one, theoretical computational and the second, the manufacturing product. 1) Using a CAD software, a lower molar received a full-crown preparation. The monolithic crown was modeled with a resin cement layer of 0.1 mm. Four groups were distributed according to the full crown elastic modulus (E):(a)Bioinspired crown with regressive elastic gradation (from 80 to 30 GPa); (b) Crown with regressive elastic gradation (from 30 to 80 GPa); (c) Rigid crowns and (d) Flexible crown. The model was exported to the analysis software and meshed into 385,240 tetrahedral elements and 696,310 nodes. Materials were considered isotropic, linearly elastic, and homogeneous, with ideal contacts. A 300-N load was applied at the occlusal surface and the base of the model was fixed in all directions. The results were required in Maximum principal stress, Von-Mises Stress and Displacement. 2) A mixture of oxides was homogenized and it was melted at fusion. The glass frits get by cooling were grinded and passed through heat treatment accordin to CSD and RXD. Six groups were obtained: DL-E (glass ceramic dense based of lithium disilicate simulating enamel); DL-D (glass ceramic dense based of lithium disilicate simulating dentin); DL-Grad (glass ceramic graded based of lithium disilicate); YTZP-E (glass ceramic dense reforced by YTZP simulating enamel); YTZP-D (glass ceramic dense reforced by YTZP simulating dentin); YTZP-Grad (glass ceramic graded and reforced by YTZP). Twenty-three and 40% of glass powder were prepared through dispersion water and it was submitted for techinique of gel casting to form functional gradient. The samples with and without functional gradient of porosity were characterized by RXD, FEG, density of all the groups, however YTZP-E, YTZP-D and YTZP-Grad showed porosity 10% greater the groups without zirconia. The critical flaw at surface of the ceramics were similar to the groups, however the random of internal pores at groups with YTZP get the flexural strength lower, with statistical difference with the groups without YTZP. Among the dense and graded groups were not statistical differences at flexural strength. It concluded that add of zirconia at ceramic system based of SiO2-Li2O changed the temperature of sintering, the standard of porosity, flexural strength and compromised the development of functional gradient of porosity. The mechanical behavior of ceramics based at lithium disilicate dense and graded were similar(AU)


Assuntos
Humanos , Materiais Dentários/efeitos adversos , Porosidade , Cristalização/métodos , Gradiente , Lítio/administração & dosagem
10.
BMC Nephrol ; 19(1): 305, 2018 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-30390660

RESUMO

BACKGROUND: Despite lithium being the most efficacious treatment for bipolar disorder, its use has been decreasing at least in part due to concerns about its potential to cause significant nephrotoxicity. Whilst the ability of lithium to cause nephrogenic diabetes insipidus is well established, its ability to cause chronic kidney disease is a much more vexing issue, with various studies suggesting both positive and negative causality. Despite these differences, the weight of evidence suggests that lithium has the potential to cause end stage kidney disease, albeit over a prolonged period. METHODS: A search strategy for this review was developed to identify appropriate studies, sourced from the electronic databases EMBASE, PubMed (NLM) and MEDLINE. Search terms included lithium with the AND operator to combine with nephrotoxicity or nephropathy or chronic kidney disease or nephrogenic diabetes insipidus or renal and pathophysiology. RESULTS: The risks for the development of lithium induced nephropathy are less well defined but appear to include the length of duration of therapy as well as increasing age, as well as episodes of over dosage/elevated lithium levels. Whilst guidelines exist for the routine monitoring of lithium levels and renal function, it remains unclear when nephrological evaluation should occur, as well as when cessation of lithium therapy is appropriate balancing the significant attendant mental health risks as well as the potential for progression to occur despite cessation of therapy against the risks and morbidity of bipolar disorder itself. CONCLUSION: This paper will elucidate on the current evidence pertaining to the topic of the clinical management of lithium induced nephrotoxicity and provide a guide for clinicians who are faced with the long-term management of these patients.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/epidemiologia , Gerenciamento Clínico , Lítio/efeitos adversos , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/epidemiologia , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/epidemiologia , Transtorno Bipolar/diagnóstico , Esquema de Medicação , Taxa de Filtração Glomerular , Humanos , Lítio/administração & dosagem , Insuficiência Renal Crônica/diagnóstico , Medição de Risco
11.
Br J Psychiatry ; 213(5): 664-666, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30246666

RESUMO

Lithium is widely prescribed, but the timing of key effects remains uncertain. The timing of onset of its relapse prevention effects is clarified by placebo-controlled randomised trials (3 studies, n = 1120). Lithium reduced relapse into any mood episode over the first 2 weeks of treatment (hazard ratio 0.40, 95% CI 0.16-0.97). Fewer manic relapses were evident within the first 4 weeks, however, early effects on depressive relapse were not demonstrated. There is an early onset of lithium relapse prevention effects in bipolar disorder, particularly against manic relapse. Full effects against depressive relapse may develop over a longer period.Declaration of interestM.J.T. reports personal fees from Sunovion, Otsuka, Lundbeck, outside the submitted work.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Lítio/administração & dosagem , Lítio/uso terapêutico , Esquema de Medicação , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária
12.
Transl Psychiatry ; 8(1): 163, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135493

RESUMO

Prion diseases still remain incurable despite multiple efforts to develop a treatment. Therefore, it is important to find strategies to at least reduce the symptoms. Lithium has been considered as a neuroprotective agent for years, and the objective of this preclinical study was to evaluate the efficacy of lithium delivered as a water-in-oil microemulsion (Aonys®). This delivery system allows using low doses of lithium and to avoid the toxicity observed in chronic treatments. C57BL/6J mice were intracranially inoculated with ME7 prion-infected brain homogenates and then were treated with lithium from day 90 post inoculation until their death. Lithium was administered at traditional doses (16 mg/kg/day) by the gavage route and at lower doses (40 or 160 µg/kg/day; Aonys®) by the rectal mucosa route. Low doses of lithium (Aonys®) improved the survival of prion-inoculated mice, and also decreased vacuolization, astrogliosis, and neuronal loss compared with controls (vehicle alone). The extent of the protective effects in mice treated with low-dose lithium was comparable or even higher than what was observed in mice that received lithium at the traditional dose. These results indicate that lithium administered using this innovative delivery system could represent a potential therapeutic approach not only for prion diseases but also for other neurodegenerative diseases.


Assuntos
Lítio/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Doenças Priônicas/tratamento farmacológico , Príons/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Emulsões , Feminino , Camundongos , Camundongos Endogâmicos C57BL
13.
J Affect Disord ; 238: 666-673, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29966931

RESUMO

BACKGROUND: Successful medication management for bipolar disorder requires clinicians to monitor and adjust regimens as needed, to achieve maximum effectiveness and patient adherence. This study aims to measure the prevalence of indications for medication adjustment at visits for bipolar disorder treatment; the frequency with which physicians recommend medication adjustments; and how strongly the indications predict the adjustments. METHODS: Data included 3,094 visits for 457 patients in Bipolar CHOICE, a comparative effectiveness study that compared treatment with lithium versus quetiapine. A set of indications for adjustment was matched to reports of whether the physician recommended a medication adjustment at that visit, and what type. Associations between indication and adjustment were examined using bivariate tests and hierarchical logistic mixed effects models. RESULTS: Medication adjustment was recommended at 63% of the visits where one of the indications was present, and at 53% of all visits. In multivariable analyses, adjustment was more likely to be recommended if there was an indication of non-response or side effects, for patients who started on quetiapine rather than lithium, or for patients who were female, married, employed or more educated. LIMITATIONS: The study's cross-sectional design implies that observed associations could result from confounding variables. Also, the CHOICE trial placed certain restrictions on physicians' medication choices, although this is not likely to have resulted in major alterations of prescribing patterns. CONCLUSIONS: Clinical inertia may help explain the lack of any adjustment recommendation at 37% of the visits where one of the indications was present. Other explanations could also apply, such as watchful waiting.


Assuntos
Antipsicóticos/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Lítio/administração & dosagem , Padrões de Prática Médica/estatística & dados numéricos , Fumarato de Quetiapina/administração & dosagem , Adulto , Pesquisa Comparativa da Efetividade , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência
14.
Med Hypotheses ; 115: 94-102, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29685207

RESUMO

INTRODUCTION: Lithium is a medication used to treat bipolar disorder and may also prevent cognitive decline and suicide. Lithium is also found naturally, in levels well below clinical doses, in drinking water worldwide, and levels have been inversely associated with rates of psychiatric disorders. Lead (Pb) is another element in the environment but is a toxin of public health concern. Negative effects of chronic lead exposure and possible benefits of environmental lithium exposure appear complementary. HYPOTHESIS: Exposure to environmental lithium has associated benefits, which may be due to the mitigation of lead toxicity by lithium. METHODS: A series of reviews tested each element of the hypothesis. A systematic review clarified the psychiatric and medical correlates of lithium in drinking water. Non-systematic reviews clarified the harms of environmental lead, summarized experimental studies of lithium used to prevent lead toxicity, and explored overlapping biological mechanisms in lithium and lead exposure. RESULTS: Higher levels of lithium in drinking water were associated with lower suicide rates in 13 of 15 identified studies. While fewer studies were available for other outcomes, lithium was associated with lower rates of homicide, crime, dementia, and mortality. Lead was reported to be ubiquitous in the environment, and chronic low-level exposure has been associated with adverse effects, including effects opposite to the outcomes associated with lithium. Animal studies demonstrated that lithium pre-treatment mitigates lead toxicity. Neurophysiological correlates of lead and lithium exposure overlap. CONCLUSIONS: Microdose lithium is associated with better psychiatric and medical outcomes, which are complementary to harms of environmental lead exposure. Experimental animal evidence is supportive, and lead and lithium impact overlapping neurophysiologic pathways. Therefore, several lines of circumstantial evidence suggest that lithium protects against the neurotoxic effects of lead. Further studies are required to clarify the benefits and mechanisms of low-dose lithium. There are significant public health implications if this paper's hypothesis is true.


Assuntos
Água Potável/efeitos adversos , Água Potável/análise , Chumbo/toxicidade , Lítio/análise , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Animais , Antimaníacos/administração & dosagem , Antimaníacos/análise , Transtorno Bipolar/tratamento farmacológico , Demência/prevenção & controle , Exposição Ambiental , Humanos , Lítio/administração & dosagem , Modelos Biológicos , Suicídio/prevenção & controle
15.
Br J Pharmacol ; 175(13): 2599-2610, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29488218

RESUMO

BACKGROUND AND PURPOSE: Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq -protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here, we investigated both ebselen and lithium in models of the 5-HT2A receptor, a Gq -protein coupled receptor involved in lithium's actions. EXPERIMENTAL APPROACH: 5-HT2A receptor function was assessed in mice by measuring the behavioural (head-twitches, ear scratches) and molecular (cortical immediate early gene [IEG] mRNA; Arc, c-fos, Egr2) responses to 5-HT2A receptor agonists. Ebselen and lithium were administered either acutely or repeatedly prior to assessment of 5-HT2A receptor function. Because lithium and 5-HT2A receptor antagonists augment the action of selective serotonin reuptake inhibitors (SSRIs), ebselen was tested for this activity by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. KEY RESULTS: Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen enhanced the increase in extracellular 5-HT induced by citalopram, and also increased regional brain 5-HT synthesis. CONCLUSIONS AND IMPLICATIONS: Our data demonstrated lithium-mimetic effects of ebselen in different experimental models of 5-HT2A receptor function, probably mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorders, including as an antidepressant augmenting agent.


Assuntos
Antioxidantes/farmacologia , Azóis/farmacologia , Lítio/farmacologia , Compostos Organosselênicos/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Antioxidantes/administração & dosagem , Azóis/administração & dosagem , Relação Dose-Resposta a Droga , Lítio/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organosselênicos/administração & dosagem
16.
Ther Drug Monit ; 40(2): 252-256, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29420333

RESUMO

BACKGROUND: Therapeutic drug monitoring (TDM) for lithium is recommended in guidelines; however, the prevalence of TDM for lithium is seldom reported. We have therefore investigated the prevalence of TDM for lithium and evaluated the impact of the regulatory warnings requiring routine TDM for lithium. METHODS: Monthly claims data covering around 1.7 million persons aged 20-74 years old during the period January 1, 2005, and March 31, 2015, were evaluated. All patients who had at least one prescription for lithium were selected and included to calculate the annual prevalence of TDM for lithium. Also we assessed whether the 2 regulatory warnings requiring routine TDM for lithium and issued in April 2012 and September 2012 had an impact on TDM for lithium, using segmented regression analysis. RESULTS: Between 2005 and 2014, 136,956 prescriptions of lithium were issued to 5823 patients, and the annual prevalence of TDM for lithium was 14.9% (95% confidence interval, 14.7%-15.1%). The analysis revealed that the mean prevalence increased abruptly by 6.9% (P = 0.001) after the regulatory warning in April 2012, whereas that the warning in September 2012 decreased by 1.2% (P = 0.47). There was no significant change in trends of period prevalence after the warning in April 2012 (April 2012-August 2012) compared with prevalence before the warning (April 2010-March 2012). Similarly, no significant change was observed in the trends before (April 2012-August 2012) and after (September 2012-March 2014) the subsequent warning in September 2012. CONCLUSIONS: Results showed that the prevalence of TDM for lithium was low, although TDM for lithium was strongly recommended by the guidelines. Regulatory warnings requiring compliance with the measurement of blood levels during treatment with lithium, issued twice during the five-month period, were associated with an increase in the prevalence of TDM for lithium. However, the impact of the second warning was not remarkable compared with the first warning.


Assuntos
Monitoramento de Medicamentos/normas , Lítio/administração & dosagem , Lítio/efeitos adversos , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
17.
Biomater Sci ; 6(3): 519-537, 2018 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-29369309

RESUMO

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common debilitating disease that occurs in young and middle-aged adults. To treat early GIONFH, core decompression and bone graft are regarded as effective measures. However, the ideal bone graft should possess bioactivity as well as biomechanical properties. The most commonly used bone graft materials are currently unsatisfactory. In this study, we fabricated a composited scaffold using lithium (Li) to activate the Wnt signal pathway and erythrogenin (EPO) to upregulate the HIF-1/VEGF pathway to improve the osteogenic and angiogenic effects of the scaffold. We obtained the porous gelatin/nano-lithium-hydroxyapatite/gelatin microsphere/rhEPO (Li-nHA/GMs/rhEPO) composited scaffold and assessed its mechanical properties, release properties, and in vitro bioactivity. Then, we implanted the scaffold into the femoral heads of GIONFH rabbits after core decompression surgery and evaluated the osteogenic and angiogenic abilities of the scaffold in vivo as well as its bone defect repair efficacy. As the results show, the Li-nHA/GM/rhEPO scaffold possessed good mechanical compression strength and enabled continuous release of Li and rhEPO. Moreover, the scaffold improved the viability of glucocorticoid-treated BMMSCs and vascular endothelial cells and increased the expression of osteogenic and angiogenic factors. In the in vivo study, the composited scaffold improved new bone formation and exerted effects on repairing femoral head defects in GIONFH rabbits. Additionally, the osteogenic and angiogenic factors were increased along with the activation of factors in the Wnt signal pathway and the HIF-1/VEGF pathway. In conclusion, the Li-nHA/GM/rhEPO scaffold can upregulate the Wnt and HIF-1/VEGF pathways at same time and has effects on improving osteogenesis and angiogenesis, which benefits the repair of GIONFH.


Assuntos
Regeneração Óssea , Eritropoetina/farmacologia , Necrose da Cabeça do Fêmur/terapia , Lítio/farmacologia , Nanoestruturas/química , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Transplante Ósseo/métodos , Diferenciação Celular , Células Cultivadas , Eritropoetina/administração & dosagem , Necrose da Cabeça do Fêmur/etiologia , Gelatina/química , Glucocorticoides/toxicidade , Hidroxiapatitas/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lítio/administração & dosagem , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Microesferas , Porosidade , Coelhos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Via de Sinalização Wnt
18.
Acta Paediatr ; 107(8): 1379-1388, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29150869

RESUMO

AIM: This study evaluated whether maternal mood disorders (MMD), particularly bipolar disorder, and lithium treatment during pregnancy influenced the neonatal health and cognition of children born from 2006 to 2010. METHODS: Our study at Karolinska University Hospital, Stockholm, Sweden, focused on women with and without mood disorders and their children. Information on pharmacotherapy, mental health, delivery and neonatal complications was retrospectively collected from electronic patient records. Children were tested in a blinded manner at four to five years of age with the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition. Maternal health, child health and social situations were evaluated. RESULTS: Of the 39 children, 20 were exposed to lithium and MMD during pregnancy, eight were exposed to MMD but not lithium and 11 were not exposed to MMD or lithium. The children's full scale intelligence quotient (IQ), performance IQ and verbal IQ results did not differ significantly between the groups. The processing speed quotient was significantly lower in children exposed to mood disorders, but there was a high level of missing data for this subtest. CONCLUSION: This small, clinical cohort showed no significant association between mothers' prenatal exposure to lithium or mood disorders and their offspring's IQ.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Saúde do Lactente , Lítio/administração & dosagem , Transtornos do Humor/tratamento farmacológico , Gravidez de Alto Risco , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Centros Médicos Acadêmicos , Adulto , Transtorno Bipolar/diagnóstico , Criança , Análise por Conglomerados , Estudos de Coortes , Feminino , Seguimentos , Humanos , Recém-Nascido , Testes de Inteligência , Masculino , Transtornos do Humor/diagnóstico , Gravidez , Resultado da Gravidez , Cuidado Pré-Natal/métodos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Análise de Regressão , Estudos Retrospectivos , Suécia , Fatores de Tempo
19.
Eur J Drug Metab Pharmacokinet ; 43(1): 25-34, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28555320

RESUMO

BACKGROUND AND OBJECTIVES: Even though lithium has been used for the treatment of bipolar disorder for several decades, its toxicities are still being reported. The major limitation in the use of lithium is its narrow therapeutic window. Several methods have been proposed to predict lithium doses essential to attain therapeutic levels. One of the methods used to guide lithium therapy is population pharmacokinetic approach which accounts for inter- and intra-individual variability in predicting lithium doses. Several population pharmacokinetic studies of lithium have been conducted. The objective of this review is to provide information on population pharmacokinetics of lithium focusing on nonlinear mixed effect modeling approach and to summarize significant factors affecting lithium pharmacokinetics. METHODS: A literature search was conducted from PubMed database from inception to December, 2016. Studies conducted in humans, using lithium as a study drug, providing population pharmacokinetic analyses of lithium by means of nonlinear mixed effect modeling, were included in this review. RESULTS: Twenty-four articles were identified from the database. Seventeen articles were excluded based on the inclusion and exclusion criteria. A total of seven articles were included in this review. Of these, only one study reported a combined population pharmacokinetic-pharmacodynamic model of lithium. Lithium pharmacokinetics were explained using both one- and two-compartment models. The significant predictors of lithium clearance identified in most studies were renal function and body size. One study reported a significant effect of age on lithium clearance. The typical values of lithium clearance ranged from 0.41 to 9.39 L/h. The magnitude of inter-individual variability on lithium clearance ranged from 12.7 to 25.1%. Only two studies evaluated the models using external data sets. CONCLUSIONS: Model methodologies in each study are summarized and discussed in this review. For future perspective, a population pharmacokinetic-pharmacodynamic study of lithium is recommended. Moreover, external validation of previously published models should be performed.


Assuntos
Lítio/farmacocinética , Humanos , Lítio/administração & dosagem , Modelos Biológicos , Dinâmica não Linear
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA