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1.
J Clin Psychiatry ; 81(5)2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32841553

RESUMO

OBJECTIVE: Lithium is an important mood disorder treatment; however, the renal risks of its use in older adults are unclear. We wished to determine in older adults (1) whether lithium is associated with increased risk of renal decline compared to valproate and (2) whether this association differs with higher vs lower baseline serum lithium concentrations. METHOD: We conducted a population-based cohort study using linked health care databases (Ontario, Canada). The cohort consisted of older adults (mean age 71 years) accrued 2007-2015; 3,113 lithium users were propensity-score matched 1:1 to 3,113 valproate users. Users with higher (> 0.7 mmol/L) or lower concentration of serum lithium were further examined. The primary outcome was ≥ 30% loss in estimated glomerular filtration rate from baseline. RESULTS: Matched lithium users and valproate users demonstrated similar indicators of baseline health over a median (maximum) follow-up of 3.1 (8.3) years. Lithium was associated with increased risk of renal function loss compared to valproate (674/3,113 [21.7%] vs 584/3,113 [18.8%]; 6.5 vs 5.7 events per 100 person years; hazard ratio = 1.14 [95% CI = 1.02-1.27]). When baseline serum lithium concentrations were > 0.7 mmol/L, the risk of renal decline compared to valproate use was 1.26 (95% CI = 1.06-1.49); when baseline lithium concentrations were ≤ 0.7 mmol/L, the risk was 1.06 (95% CI = 0.92-1.22). CONCLUSION: In older adults, lithium use is associated with a statistically significant increased risk of renal decline compared to valproate use, although the decline is less than previously reported. Further studies should confirm whether this effect is primarily in patients with higher serum lithium concentrations.


Assuntos
Antimaníacos/uso terapêutico , Lítio/uso terapêutico , Insuficiência Renal/induzido quimicamente , Idoso , Antimaníacos/efeitos adversos , Antimaníacos/sangue , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Lítio/efeitos adversos , Lítio/sangue , Estudos Longitudinais , Masculino , Pontuação de Propensão , Fatores de Risco , Ácido Valproico/efeitos adversos , Ácido Valproico/uso terapêutico
2.
PLoS One ; 15(5): e0233357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32433650

RESUMO

Trace elements and minerals are compounds that are essential for the support of a variety of biological functions and play an important role in the formation of and the defense against oxidative stress. Here we describe a technique, allowing sequential detection of the trace elements (K, Zn, Se, Cu, Mn, Fe, Mg) in serum and whole blood by an ICP-MS method using single work-up, which is a simple, quick and robust method for the sequential measurement and quantification of the trace elements Sodium (Na), Potassium (K), Calcium (Ca), Zinc (Zn), Selenium (Se), Copper (Cu), Iron (Fe), Manganese (Mn) and Magnesium (Mg) in whole blood as well as Copper (Cu), Selenium (Se), Zinc (Zn), Iron (Fe), Magnesium (Mg), Manganese (Mn), Chromium (Cr), Nickel (Ni), Gold (Au) and Lithium (Li) in human serum. For analysis, only 100 µl of serum or whole blood is sufficient, which make this method suitable for detecting trace element deficiency or excess in newborns and infants. All samples were processed and analyzed by ICP-MS (Agilent Technologies). The accuracy, precision, linearity and the limit of quantification (LOQ), Limit of Blank (LOB) and the limit of detection (LOD) of the method were assessed. Recovery rates were between 80-130% for most of the analyzed elements; repeatabilities (Cv %) calculated were below 15% for most of the measured elements. The validity of the proposed methodology was assessed by analyzing a certified human serum and whole blood material with known concentrations for all elements; the method described is ready for routine use in biomonitoring studies.


Assuntos
Espectrofotometria Atômica/métodos , Espectrometria de Massas em Tandem/métodos , Oligoelementos/sangue , Cálcio/sangue , Cromo/sangue , Cobre/sangue , Ouro/sangue , Humanos , Ferro/sangue , Limite de Detecção , Lítio/sangue , Magnésio/sangue , Manganês/sangue , Níquel/sangue , Potássio/sangue , Selênio/sangue , Sódio/sangue , Zinco/sangue
3.
Ecotoxicol Environ Saf ; 199: 110697, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32416368

RESUMO

OBJECTIVES: Based on a prospective birth cohort, we aimed to investigate the associations between maternal circulating metals exposure and gestational weight gain (GWG) across pregnancy, and explore whether maternal inflammatory cytokines could contribute to the GWG changes associated with metals exposure. METHODS: A total of 234 pregnant women from the Shanghai Maternal-Child Pairs cohort were enrolled in this panel study. 547 blood and serum samples were collected from pregnant women during three follow-up visits, and the circulating concentrations of 27 metals were determined by using the ICP-MS method. Five inflammatory cytokines in serum samples were measured through multiplexed immunoassays. The linear mixed models were used to estimate the association between each ln-transformed metal concentration and GWG across pregnancy. Robust generalized linear regression models were used to estimate the associations among circulating metals, GWG, and inflammatory cytokines. RESULTS: The GWG during pregnancy was 13.76 ± 1.40 kg. The concentrations Co, Zn, Mo, B, Ag and Te in second or third trimesters were significantly higher than those in early second trimester. The concentration of Mg decreased with the increase of pregnant weeks and no significant statistical differences were found in the concentrations of other metals in different trimesters. Among the detected 26 metals, Li and Sr concentrations were positively associated with GWG in the third trimester. The GWG increased by 0.100 kg (95% CI 0.005, 0.195) and 0.120 kg (95% CI 0.009, 0.232) with each one ln-concentration increase in circulating Li and Sr concentrations, respectively. Concentrations of Li and Sr in the third trimester were positively associated with tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, but negatively associated with growth differentiation factor-15 (GDF-15) significantly. Besides, IL-6 and GDF-15 levels were associated with the increase or decrease of overall pregnancy GWG, respectively. CONCLUSIONS: Results showed that maternal exposure to Li and Sr were associated with increased GWG, in which maternal IL-6 and GDF-15 could contribute to the associations between metal exposures and GWG in pregnant women.


Assuntos
Poluentes Ambientais/sangue , Ganho de Peso na Gestação/efeitos dos fármacos , Fator 15 de Diferenciação de Crescimento/sangue , Interleucina-6/sangue , Lítio/sangue , Exposição Materna/efeitos adversos , Estrôncio/sangue , Adulto , China , Estudos de Coortes , Feminino , Humanos , Gravidez , Trimestres da Gravidez , Estudos Prospectivos
4.
Regul Toxicol Pharmacol ; 111: 104581, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31935483

RESUMO

INTRODUCTION: Lithium salts have numerous industrial uses and are also used in the treatment of bipolar disorders. The main source of lithium exposure to the general population is drinking water and foods. Lithium is nephrotoxic at higher doses. Thus, oral exposure guidelines for lithium have been derived, including ICH's permitted daily exposure (PDE = 0.008 mg lithium/kg-bw/day) adopted by Health Canada and the United States Environmental Protection Agency's (U.S. EPA) provisional peer reviewed toxicity value (PPRTV = 0.002 mg lithium/kg-bw/day), both based on human data. OBJECTIVE: To derive whole blood biomonitoring equivalents (BEs) associated with PDE and PPRTV to interpret population-level biomonitoring data in health risk context. METHOD: A simple kinetic relationship based on plasma clearance value (0.5 L/kg-bw/day) and the oral absorption fraction (100%) was used to derive blood BEs for PDE and PPRTV. RESULTS: This analysis resulted in BE values in plasma and whole blood of 16 and 10 µg/L, respectively, based on the PDE values developed by the Health Canada and of 4.2 and 2.7 µg/L, respectively, based on the PPRTV developed by U.S. EPA. CONCLUSION: The derived BE values can be used to interpret population-level biomonitoring data.


Assuntos
Monitoramento Biológico , Exposição Ambiental/análise , Monitoramento Ambiental , Poluentes Ambientais/sangue , Lítio/sangue , Canadá , Humanos , Medição de Risco , Estados Unidos
7.
Clin Lab ; 65(12)2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31850716

RESUMO

BACKGROUND: Blood from patients who are receiving anticoagulant therapy may take longer to clot. Anticoagulation is an important component of the dialysis prescription. We compared BD Vacutainer® Barricor™ Plasma Blood Collection Tubes (BD BarrricorTM), BD Vacutainer® PST™ Lithium Heparin Tubes (BD PST™), and BD (Becton-Dickinson, Franklin Lakes, NJ, USA) Vacutainer Serum Separator Tubes (BD SST), as reference tube in dialysis patients to examine whether they had an effect on routine biochemical tests. MATERIALS AND METHODS: A total of 29 chronic hemodialysis patients were included in this study. Samples were collected into BD BarrricorTM, BD PST™, and BD SST tubes after the dialysis. All the tubes were centrifuged by NF 1200R rotor (1,300 g for 10 minutes at 22°C, 1,200 g for 10 minutes at 4°C, 2,400 g for 10 minutes at 22°C, respectively) after the incubation period. Eleven routine clinical chemistry parameters (Creatinine, Urea, Na, K, Cl, AST, ALT, Total Bilirubin, Direct Bilirubin, Calcium, Cholesterol) were analyzed on a Beckman Coulter AU 5800. RESULTS: Results of creatinine, K and cholesterol were statistically significantly different between the SST and LiH (p = 0.014, p = 0.009, and p < 0.001, respectively). In terms of other biochemical parameters we tested for all three tubes there was no clinically significance inspite of the statistically significance. CONCLUSIONS: BD Barricor™ tubes provide fast, clean, high-quality plasma samples, safe results, and may lower times and costs.


Assuntos
Anticoagulantes/sangue , Coleta de Amostras Sanguíneas/instrumentação , Testes Hematológicos/métodos , Diálise Renal , Anticoagulantes/administração & dosagem , Coleta de Amostras Sanguíneas/métodos , Colesterol/sangue , Creatinina/sangue , Heparina/sangue , Humanos , Lítio/sangue , Potássio/sangue , Reprodutibilidade dos Testes
10.
Int Rev Psychiatry ; 31(3): 295-304, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31180257

RESUMO

The continuation of lithium while breastfeeding is a controversial topic, and clinical recommendations vary. A systematic review was completed of available data on lithium and breastfeeding to determine the degree of lithium exposure through breast milk and assess the potential risk to the infant. Databases, including PubMed MEDLINE, Embase, PsycINFO, Web of Science, Scopus, and Cochrane CENTRAL Register of Controlled Trials databases, were searched for articles on lithium and breastfeeding from the start dates of the databases through December 2018. Articles were included if the report included at least one maternal serum/plasma and/or breast milk lithium concentration and one infant serum/plasma lithium concentration. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Twelve articles, all case reports, were selected for inclusion out of 441 articles that were found and 230 that were reviewed from the search. Data are limited on the safety of lithium continuation while breastfeeding. Among the adverse effects reported, it is difficult to differentiate poor outcomes from factors affecting infant health, concomitant medications, and gestational lithium exposure. Recommendations on whether to continue lithium while breastfeeding must be personalized to the individual woman and her infant.


Assuntos
Aleitamento Materno/efeitos adversos , Lítio/toxicidade , Lítio/uso terapêutico , Leite Humano/química , Medição de Risco , Feminino , Humanos , Lactente , Lítio/sangue
11.
Neuro Endocrinol Lett ; 40(1): 17-21, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31184818

RESUMO

Lithium is widely used in psychiatry to treat bipolar affective disorders since 1970 but little is known about the incidence, clinical course and associated factors of acute lithium intoxication. Moderate and severe cases of lithium intoxication are rare. This case reports a patient with acute lithium intoxication (serum level of 3.7 mmol/L) with neurological symptoms imitating stroke, which affects the differential diagnosis in the pre-hospital and hospital care. Patient was treated with forced diuresis and dismissed 21 days after admission.


Assuntos
Antimaníacos/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Overdose de Drogas/diagnóstico , Carbonato de Lítio/efeitos adversos , Acidente Vascular Cerebral/diagnóstico , Idoso , Antimaníacos/uso terapêutico , Diagnóstico Diferencial , Overdose de Drogas/sangue , Feminino , Humanos , Lítio/sangue , Carbonato de Lítio/uso terapêutico
12.
BMC Psychiatry ; 19(1): 194, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234824

RESUMO

BACKGROUND: Safety monitoring of medicines is essential during therapy for bipolar disorder (BD). We determined the extent of safety monitoring performed according to the International Society for Bipolar Disorders (ISBD) guidelines in patients with BD attending the main tertiary care psychiatry clinics in Sri Lanka to give realistic recommendations for safety monitoring in resource limited settings. METHODS: Patients diagnosed with BD on mood stabilizer medications for more than 1 year were recruited. Data were collected retrospectively from clinic and patient held records and compared with the standards of care recommended by ISBD guidelines for safety monitoring of medicines. RESULTS: Out of 256 patients diagnosed with BD, 164 (64.1%) were on lithium. Only 75 (45.7%) had serum lithium measurements done in the past 6 months and 96 (58.5%) had concentrations recorded at least once in the past year. Blood urea or creatinine was measured in the last 6 months only in 30 (18.3%). Serum electrolytes and thyroid-stimulating hormone (TSH) concentrations were measured in the last year only in 34 (20.7%) and 30 (18.3%) respectively. Calcium concentrations were not recorded in any patient. None of the patients on sodium valproate (n = 119) or carbamazepine (n = 6) had blood levels recorded to establish therapeutic concentrations. Atypical antipsychotics were prescribed for 151 (59%), but only 13 (8.6%) had lipid profiles and only 31 (20.5%) had blood glucose concentration measured annually. Comorbidities experienced by patients influenced monitoring more than the medicines used. Patients with diabetes, hypothyroidism and hypercholesterolemia were more likely to get monitored for fasting blood glucose and (p < 0.001), TSH (p < 0.001) and lipid profiles (p < 0.001). Lithium therapy was associated with TSH monitoring (p < 0.05). Therapy with atypical antipsychotics was not associated with fasting blood glucose or lipid profile monitoring (p > 0.05). A limitation of the study is that although some tests were performed, the results may not have been recorded. CONCLUSIONS: Safety monitoring in BD was suboptimal compared to the ISBD guidelines. ISBD standards are difficult to achieve in resource limited settings due to a multitude of reasons. Realistic monitoring benchmarks and recommendations are proposed for methods to improve monitoring in resource limited settings based on our experience.


Assuntos
Antipsicóticos/sangue , Transtorno Bipolar/sangue , Transtorno Bipolar/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Recursos em Saúde , Atenção Terciária à Saúde/métodos , Adolescente , Adulto , Idoso , Antipsicóticos/economia , Antipsicóticos/uso terapêutico , Transtorno Bipolar/economia , Transtorno Bipolar/epidemiologia , Monitoramento de Medicamentos/economia , Feminino , Seguimentos , Recursos em Saúde/economia , Humanos , Lítio/sangue , Lítio/economia , Lítio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sri Lanka/epidemiologia , Atenção Terciária à Saúde/economia , Resultado do Tratamento , Adulto Jovem
13.
Diagnosis (Berl) ; 6(4): 369-375, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31054249

RESUMO

Background The use of alternative sample matrices may be an advantageous perspective when the laboratory falls short of serum or lithium-heparin plasma for performing clinical chemistry and/or immunochemistry testing. This study was aimed at exploring whether some tests may be performed in citrate plasma as an alternative to lithium-heparin plasma. Methods Paired lithium-heparin and citrate plasma samples collected from 55 inpatients were analyzed on Roche Cobas 8000 for 28 different clinical chemistry and immunochemistry parameters. Data obtained in citrate plasma were adjusted for either the dilution factor or using an equation corresponding to the linear regression calculated by comparing unadjusted lithium-heparin and citrate plasma values. Results Except for magnesium (+17%) and sodium (+11%), unadjusted values of all remaining analytes were significantly lower in citrate than in lithium-heparin plasma, with bias ranging between -6.4% and -25.9%. The correlation between lithium-heparin and citrate plasma values was generally excellent (i.e. >0.90). The adjustment of citrate plasma values for the dilution factor (i.e. 1.1) was only effective in harmonizing the results of albumin and lipase, whilst the concentration of all other analytes remained significantly different between the two sample matrices. The adjustment of plasma citrate values using corrective formulas was instead effective in harmonizing all parameters, with no results remaining statistically different between the two sample matrices. Conclusions Citrate plasma may be used in exceptional circumstances for clinical chemistry and immunochemistry testing as a replacement for lithium-heparin plasma, provided that citrate plasma values are adjusted by using validated corrective equations.


Assuntos
Anticoagulantes/sangue , Química Clínica/métodos , Ácido Cítrico/sangue , Imunoquímica/métodos , Fase Pré-Analítica/normas , Idoso , Viés , Quelantes de Cálcio , Testes Diagnósticos de Rotina/normas , Feminino , Heparina/sangue , Heparina/química , Humanos , Lipase/sangue , Lítio/sangue , Lítio/química , Masculino , Pessoa de Meia-Idade , Albumina Sérica/análise
14.
Clin Biochem ; 70: 46-48, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31059687

RESUMO

OBJECTIVE: Develop sample acceptability rules by determining the relationship between free hemoglobin level (hemolysis) and potassium or ionized calcium in blood gas samples collected intraoperatively. DESIGN AND METHODS: Hemolysis was assessed visually or by H index for lithium heparin blood gas samples collected intraoperatively. During periods one and three this was done using two different rules for visual assessment of centrifuged lithium heparin plasma. During period two H index was measured for all visually hemolyzed samples on a Roche Cobas c501 analyzer to determine acceptability. Potassium and ionized calcium were measured in 75 lithium heparin whole blood samples on a Radiometer ABL90 to correlate H index and potassium or ionized calcium. RESULTS: During period one 35 of 5808 (0.6%) blood gas samples had visual hemolysis levels exceeding tolerance for reporting of potassium. By switching to measured H index using a laboratory-established threshold, during period 2 we estimate that 171 of 5396 (3.2%) blood gas samples exceeded the H index threshold for reporting of potassium. In 75 intraoperative blood gas samples with H index and whole blood potassium and ionized calcium measured; we observed no relationship between H index and potassium or ionized calcium. During period 3 we switched to visual assessment of hemolysis with a greater tolerance for hemolysis; with only 3 of 5345 (0.06%) samples exceeding the new visual hemolysis threshold. CONCLUSION: For blood gas samples collected intraoperatively, there is no relationship between hemolysis and measured potassium or ionized calcium. The results suggest that only grossly hemolyzed intraoperative blood gas samples should be rejected for measurement of whole blood potassium and ionized calcium.


Assuntos
Gasometria/métodos , Cálcio/sangue , Hemoglobinas/análise , Hemólise , Heparina/sangue , Lítio/sangue , Potássio/sangue , Testes Hematológicos , Período Intraoperatório , Manejo de Espécimes
16.
Int Clin Psychopharmacol ; 34(3): 143-150, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30907774

RESUMO

Some women affected by mood disorders experience mood instability during the premenstrual phase. Assuming that fluctuations in drug serum levels may contribute to the worsening of mood symptoms, we carried out a systematic review of available studies that investigated changes in lithium and valproate levels in relation to menstrual phases. We selected five studies; four of which assessed menstrual fluctuations in lithium serum levels and one in valproate levels. Study samples included women in their fertile age affected by bipolar disorder, epilepsy as well as healthy ones. Preliminary results showed a close relationship between cyclic premenstrual exacerbation of affective symptoms and a significant decrease in lithium levels during the luteal phase, despite stable oral doses, in bipolar women. In healthy women, lithium levels were influenced by neither menstrual cycle phases nor oral contraceptives use. Valproate serum levels in epileptic women showed a small, nonsignificant decline during the mid-luteal phase. Pharmacokinetic sex differences in adsorption, volume distribution, hepatic metabolism, and renal excretion of mood stabilizers have been supposed to partly explain such menstrual serum level fluctuations. A better understanding in this field could help to counteract the distress related to premenstrual phase, improving therapeutic management of mood disorders in women.


Assuntos
Afeto/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Lítio/sangue , Ciclo Menstrual/psicologia , Ácido Valproico/sangue , Feminino , Humanos , Masculino , Transtornos do Humor
17.
J Anal Toxicol ; 43(7): 571-578, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-30877800

RESUMO

A 38-year-old man was admitted in the intensive care unit (ICU) after supposed ingestion of 504 sustained-release tablets of Theralithe™ corresponding ~200 g of lithium carbonate. At the admission, ~19.5 h after ingestion, the patient was conscious with trembling limbs, intense thirst, profuse sweats and vomiting and lithium serum concentration was 14.2 mmol/L. Toxicological screenings performed in urine and serum, were negative. Patient was treated with continuous extrarenal epuration by continue veno-venous hemodiafiltration starting (CCVHDF) 24 h post-admission and was carried on until 64 h. After 11 days in ICU, the patient was dismissed to the service without sequelae, and transferred to a psychiatric unit. To follow lithium concentrations in serum, urines and dialysates, we developed a simple, rapid and reliable method by capillary zone electrophoresis (CZE). Separation was achieved in 7 min. The method was linear between 0.14 and 1.44 mmol/L for serum samples, and between 0.07 and to 1.44 mmol/L for urines and dialysates. Limits of quantification were 0.15 mmol/L and 0.07 mmol/L for serum and others fluids, respectively. Intra- and inter-day precisions expressed as CV were systematically inferior to 12.1% for serum and 8.2% for other fluids. Results obtained regarding precision, accuracy, recovery and stability were satisfying, with recoveries ranging from 91.0 to 102.0%. Serum, urine and dialysate samples were measured using CZE and flame photometry. We observed a strong correlation between both methods as assessed by linear regression and Bland-Altman analysis. For the intoxicated patient, the assay was successfully applied to serum, urine and dialysates to determine the amount of lithium present in circulation and excreted. Lithium amounts in dialysates were estimated to correspond to 89% of total lithium excreted during CCVHF session while urine excretion account only for 11%.


Assuntos
Antidepressivos/envenenamento , Eletroforese Capilar/métodos , Carbonato de Lítio/envenenamento , Lítio , Doença Aguda , Adulto , Calibragem , Humanos , Lítio/sangue , Lítio/urina , Masculino , Reprodutibilidade dos Testes , Espectrofotometria Atômica
18.
Anal Chem ; 91(4): 2561-2569, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30638359

RESUMO

We describe how 4-dimensional in vivo biochemical analysis can be performed using photoacoustic contrast nanoagents that have been designed to probe both structural and chemical information in vivo, enabling noninvasive, real time, spatially resolved chemical imaging. Early chemical imaging of a patient's tumor can inform the decision of effective treatment, regarding choices of chemotherapy, radiation, or immunotherapy.


Assuntos
Técnicas de Química Analítica/métodos , Neoplasias/química , Técnicas Fotoacústicas/métodos , Animais , Humanos , Concentração de Íons de Hidrogênio , Lítio/sangue , Camundongos , Imagem Óptica/métodos , Oxigênio/sangue , Potássio/análise , Microambiente Tumoral/fisiologia
19.
Acta Physiol (Oxf) ; 225(2): e13191, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30257062

RESUMO

AIM: Therapeutic use of lithium in bipolar disorder is limited by the development of nephrogenic diabetes insipidus (NDI). We reported that pharmacological blockade of P2Y12 receptor (R) with clopidogrel or prasugrel significantly ameliorated lithium-induced NDI in rodents. Using mice genetically lacking P2Y12 -R we evaluated whether the observed amelioration is mediated through P2Y12 -R METHODS: P2ry12-/- mouse line (C57/BL6) was rederived from cryopreserved embryos of the knockout (KO) mice generated by Deltagen Inc. Syngeneic wild type (WT) mice obtained by heterozygous crossing were inbred. Groups of adult WT and KO mice were fed lithium-added (40 mmol LiCl/kg food) or regular diet, and euthanized after 2 or 4 weeks. Twenty-four hour urine samples and terminal blood and kidney samples were analyzed. RESULTS: At both time points, lithium-induced polyuria and decrease in aquaporin-2 (AQP2) protein abundance in the kidney medulla were less marked in KO vs WT mice. Immunofluorescence microscopy revealed that lithium-induced alterations in the cellular disposition of AQP2 protein in the medullary collecting ducts of WT mice were blunted in KO mice. Serum lithium, sodium and osmolality were similar in both genotypes after lithium treatment. After 2 weeks, lithium induced marked increases in urinary excretion of Na, K, and arginine vasopressin in WT mice but not in KO mice. CONCLUSION: Taken together, our data show that similar to pharmacological blockade, deletion of P2Y12 -R significantly ameliorates lithium-induced NDI, without reducing serum lithium levels. Hence, targeting P2Y12 -R with currently available drugs in the market offers a novel and safer method for treating NDI.


Assuntos
Diabetes Insípido Nefrogênico/induzido quimicamente , Lítio/toxicidade , Receptores Purinérgicos P2Y12/fisiologia , Animais , Aquaporina 2/metabolismo , Arginina Vasopressina/urina , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/metabolismo , Diabetes Insípido Nefrogênico/prevenção & controle , Dinoprostona/urina , Feminino , Lítio/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Natriurese/efeitos dos fármacos , Potássio/urina , Receptores Purinérgicos P2Y12/genética
20.
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
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