RESUMO
Boron neutron capture therapy is a perspective selective technology for the destruction of cancer cells, while the use of lithium instead of boron may represent a new and promising vector for the development of neutron capture therapy (NCT). The aim of the study was a comparative assessment of the cytotoxicity of various lithium salts, as well as an analysis of the accumulation of lithium in tumor cells in vitro to determine the possibility of using lithium in NCT. The cytotoxicity of lithium salts was determined using MTT-test and colony forming assay on human fibroblasts BJ-5ta, human skin melanoma SK-Mel-28, and mouse skin melanoma B16 cell lines. An assessment of lithium concentration in cells was performed using inductively coupled plasma atomic emission spectrometry. Our results showed that three different lithium salts at a concentration of 40 µg/ml are not toxic for both tumor and normal cells. The highest uptake values were obtained on murine melanoma B16 cells when exposed to lithium carbonate (0.8 µg/106 cells); however, human melanoma SK-Mel-28 cells effectively accumulated both lithium carbonate and lithium citrate (about 0.46 µg/106 cells for two salts). Thus, our results demonstrate a range of non-toxic doses of lithium salts and a high uptake of lithium by tumor cells, which indicates the possibility to use the lithium in NCT.
Assuntos
Terapia por Captura de Nêutron de Boro , Melanoma , Camundongos , Humanos , Animais , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Lítio/toxicidade , Sais , Carbonato de Lítio/toxicidade , Terapia por Captura de Nêutron de Boro/métodosRESUMO
Toxic products generated in the process of tumor growth and as a result of treatment may cause damage to organs distant from the tumor growth, including kidneys. The aim of the work was to identify ultrastructural changes in the components of kidney filtration barrier in conditions of distant tumor growth and lithium carbonate treatment. Tumor growth was induced by the inoculation of hepatocellular carcinoma-29 cells into the right thigh muscle of CBA mice. Lithium carbonate was injected along the periphery of the tumor. Ultrastructural analysis of podocytes and endotheliocytes of glomerular capillaries in the dynamics of tumor growth and lithium carbonate treatment was carried out. Under conditions of distant tumor growth, ultrastructural changes of the kidney filtration barrier were noted. Podocyte hypertrophy was detected, the width of foot process and glomerular membrane were increased. The number of fenestrae was decreased and cell hypertrophy was developed in the structure endothelium of glomerular capillary. Lithium carbonate had some protective effect on podocytes, but caused a significant hypertrophy of endotheliocytes leading to glomerular capillary occlusion.
Assuntos
Carbonato de Lítio/toxicidade , Neoplasias Experimentais/patologia , Podócitos/efeitos dos fármacos , Podócitos/ultraestrutura , Animais , Células HT29 , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos CBA , Podócitos/patologiaRESUMO
Prolonged lithium treatment is associated with various renal side effects and is known to induce inner medullary collecting duct (IMCD) remodeling. In animals treated with lithium, the fraction of intercalated cells (ICs), which are responsible for acid-base homeostasis, increases compared with renal principal cells (PCs). To investigate the intricacies of lithium-induced IMCD remodeling, male Sprague-Dawley rats were fed a lithium-enriched diet for 0,1, 2, 3, 6, 9, or 12 wk. Urine osmolality was decreased at 1 wk, and from 2 to 12 wk, animals were severely polyuric. After 6 wk of lithium treatment, approximately one-quarter of the cells in the initial IMCD expressed vacuolar H+-ATPase, an IC marker. These cells were localized in portions of the inner medulla, where ICs are not normally found. Pendrin, a Cl-/[Formula: see text] exchanger, is normally expressed only in two IC subtypes found in the convoluted tubule, the cortical collecting duct, and the connecting tubule. At 6 wk of lithium treatment, we observed various patterns of pendrin localization and expression in the rat IMCD, including a novel phenotype wherein pendrin was coexpressed with aquaporin-4. These observations collectively suggest that renal IMCD cell plasticity may play an important role in lithium-induced IMCD remodeling.
Assuntos
Plasticidade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antiportadores de Cloreto-Bicarbonato/metabolismo , Túbulos Renais Coletores/efeitos dos fármacos , Carbonato de Lítio/toxicidade , Transportadores de Sulfato/metabolismo , Compostos de Amônio/urina , Animais , Aquaporina 4/metabolismo , Antiportadores de Cloreto-Bicarbonato/genética , Esquema de Medicação , Regulação da Expressão Gênica , Concentração de Íons de Hidrogênio , Túbulos Renais Coletores/metabolismo , Túbulos Renais Coletores/patologia , Masculino , Concentração Osmolar , Fenótipo , Poliúria/induzido quimicamente , Poliúria/patologia , Poliúria/urina , Ratos Sprague-Dawley , Transdução de Sinais , Transportadores de Sulfato/genética , Fatores de Tempo , ATPases Vacuolares Próton-Translocadoras/metabolismoRESUMO
Investigation of toxicological effect of various metals is the field of interest for toxicological scientists since four to five decades and especially the toxicological effect of those drugs containing metals and there use is common because there is no other choice except to use these metal containing drugs. Inorganic as well as organic salts of lithium are commonly used in prophylaxis and treatments of many psychiatric disorders. The aim of the present study was to see the difference between the effect of organic and inorganic salt of lithium commonly used in psychiatric disorders on the GSH of human blood plasma. It is the scientific fact that ionic dissociation of organic and inorganic salts of any metal is always quite different hence to prove this fact, the effect of lithium citrate (organic salt of lithium) and lithium carbonate (inorganic salt of lithium) was investigated on human blood plasma GSH to find the difference between the effect of two. Ellman's method was used for the quantification of glutathione contents in plasma. It was found that lithium citrate decrease plasma GSH contents less than lithium carbonate indicating that organic salts of lithium are safe than inorganic salts of lithium when are used in psychiatric disorders. Further to analyze the effect of organic and inorganic salt of lithium on blood plasma GSH with the increase in incubation time was also evaluated and was found that both concentration and time dependent effect of organic salt of lithium shows that this salt has decreased plasma GSH contents of human blood less than inorganic salt of lithium either by promoting oxidation of GSH into GSSG or by lithium glutathione complex formation. These results suggest the physicians that the use of organic lithium salts is much safer than inorganic salts of lithium in terms of depletion of blood plasma GSH contents.
Assuntos
Citratos/sangue , Glutationa/sangue , Carbonato de Lítio/sangue , Psicotrópicos/sangue , Biomarcadores/sangue , Citratos/toxicidade , Relação Dose-Resposta a Droga , Dissulfeto de Glutationa/sangue , Humanos , Carbonato de Lítio/toxicidade , Psicotrópicos/toxicidade , Medição de Risco , Fatores de TempoRESUMO
Lithium (Li) has been widely used to treat bipolar disorder, and industrial use of Li has been increasing; thus, environmental pollution and ecological impacts of Li have become a concern. This study was conducted to clarify the potential biological effects of LiCl and Li(2)CO(3) on a nematode, Caenorhabditis elegans as a model system for evaluating soil contaminated with Li. Exposure of C. elegans to LiCl and Li(2)CO(3) decreased growth/maturation and reproduction. The lowest observed effect concentrations for growth, maturation and reproduction were 1250, 313 and 10 000 µm, respectively, for LiCl and 750, 750 and 3000 µm, respectively, for Li(2)CO(3). We also investigated the physiological function of LiCl and LiCO(3) in C. elegans using DNA microarray analysis as an eco-toxicogenomic approach. Among approximately 300 unique genes, including metabolic genes, the exposure to 78 µm LiCl downregulated the expression of 36 cytochrome P450, 16 ABC transporter, 10 glutathione S-transferase, 16 lipid metabolism and two vitellogenin genes. On the other hand, exposure to 375 µm Li(2)CO(3) downregulated the expression of 11 cytochrome P450, 13 ABC transporter, 13 lipid metabolism and one vitellogenin genes. No gene was upregulated by LiCl or Li(2)CO(3). These results suggest that LiCl and Li(2)CO(3) potentially affect the biological and physiological function in C. elegans associated with alteration of the gene expression such as metabolic genes. Our data also provide experimental support for the utility of toxicogenomics by integrating gene expression profiling into a toxicological study of an environmentally important organism such as C. elegans.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Expressão Gênica/efeitos dos fármacos , Lítio/toxicidade , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Dose Letal Mediana , Carbonato de Lítio/toxicidade , Cloreto de Lítio/toxicidade , Análise de Sequência com Séries de Oligonucleotídeos , Reprodução/efeitos dos fármacosRESUMO
The increasing widespread use of lithium, which is preferred as an energy source in batteries produced for electric vehicles and in many electronic vehicles such as computers and mobile phones, has made it an important environmental pollutant. In this study, the toxicity profile of lithium carbonate (Li2CO3) was investigated with the Allium test, which is a bio-indicator test. Dose-related toxic effects were investigated using Li2CO3 at doses of 25 mg/L, 50 mg/L, and 100 mg/L. The toxicity profile was determined by examining physiological, cytotoxic, genotoxic, biochemical and anatomical effects. Physiological effects of Li2CO3 were determined by root length, injury rate, germination percentage and weight gain while cytotoxic effects were determined by mitotic index (MI) ratio and genotoxic effects were determined by micronucleus (MN) and chromosomal aberrations (CAs). The effect of Li2CO3 on antioxidant and oxidant dynamics was determined by examining glutathione (GSH), malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) levels, and anatomical changes were investigated in the sections of root meristematic tissues. As a result, Li2CO3 exhibited a dose-dependent regression in germination-related parameters. This regression is directly related to the MI and 100 mg/L Li2CO3 reduced MI by 38% compared to the control group. MN and CAs were observed at high rates in the groups treated with Li2CO3. Fragments were found with the highest rate among CAs. Other damages were bridge, unequal distribution of chromatin, sticky chromosome, vagrant chromosome, irregular mitosis, reverse polarization and multipolar anaphase. The genotoxic effects were associated with Li2CO3-DNA interactions determined by molecular docking. The toxic effects of Li2CO3 are directly related to the deterioration of the antioxidant/oxidant balance in the cells. While MDA, an indicator of lipid peroxidation, increased by 59.1% in the group administered 100 mg/L Li2CO3, GSH, which has an important role in cell defense, decreased by 60.8%. Significant changes were also detected in the activities of SOD and CAT, two important enzymes in antioxidant defense, compared to the control. These toxic effects, which developed in the cells belonging to the lithium-treated groups, were also reflected in the tissue anatomy, and anatomical changes such as epidermis cell damage, cortex cell damage, flattened cell nucleus, thickening of the cortex cell wall and unclear vascular tissue were observed in the anatomical sections. The frequency of these changes also increased depending on the Li2CO3 dose. As a result, Li2CO3, which is one of the lithium compounds, and has become an important contaminant in the environment with increasing technological developments, caused a combined and versatile toxicity in Allium cepa L. meristematic cells, especially by causing deterioration in antioxidant/oxidant dynamics.
Assuntos
Antioxidantes , Carbonato de Lítio , Antioxidantes/farmacologia , Dano ao DNA , Glutationa/farmacologia , Carbonato de Lítio/toxicidade , Simulação de Acoplamento Molecular , Cebolas , Oxidantes/farmacologia , Raízes de Plantas , Superóxido Dismutase/farmacologiaRESUMO
The current publication describes most recent so far unpublished (key) guideline and GLP compliant reproductive and developmental toxicity studies of lithium carbonate in rats, including their interpretation and conclusions in terms of human hazard assessment when compared to existing literature. Particular attention was paid to the target organs and dose response of lithium ion related effects to differentiate between a primary (pharmacokinetic/pharmacodynamic) action and secondary effects as a result of systemic and target organ toxicity. In the key two-generation reproduction toxicity (OECD TG 416) study in rats, doses of 5, 15 and 45 mg/kg bw/d (0.95, 2.9 and 8.6 mg Li+/kg bw/d) were given by oral gavage, resulting in clear NOAELs of 15 mg/kg bw/d (2.9 mg Li+/kg bw/d) for systemic parental toxicity and 45 mg/kg bw/d (8.6 mg Li+/kg bw/d) for reproductive toxicity and fetal toxicity. Target organ changes were consistently observed in liver (cytoplasmic rarefaction) and kidney (dilated tubuli). In the key developmental toxicity (OECD TG 414) study in rats, doses given by oral gavage were 10, 30 and 90 mg/kg bw/d (1.9, 5.7 and 17.1 mg Li+/kg bw/d) was investigated resulting in NO(A)ELs of 30 mg/kg bw/d (5.7 mg Li+/kg bw/d) (maternal toxicity) and 90 mg/kg bw/d (17 mg Li+/kg bw/d) (fetal toxicity and teratogenicity). The highest dose of 90 mg/kg bw/day resulted in clear signs of toxicity and peak plasma concentrations at the toxic range (>1.0 mEq lithium/L). Toxic effects of lithium carbonate were not seen in the reproductive and developmental organs. No adverse effects on sperm (total motility, progressive motility and morphology of testicular and cauda epididymal sperm) were observed in the two-generation rat reproduction toxicity study. There was also no impact on fertility indices or on litter sizes in this study, nor were there any fetal effects in the two-generation reproduction toxicity and developmental toxicity study at doses causing already systemic toxicity in the dams. Secondary effects such as decreased weight (gain) and food consumption were reported in the developmental toxicity study. The absence of any reproductive/developmental findings at dose levels causing clear systemic toxicity in the test animals in these key mammalian studies, does not suggest an immediate concern for possible human reproductive or developmental toxicity effects from exposure to lithium during drug use.
Assuntos
Antimaníacos/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Carbonato de Lítio/toxicidade , Reprodução/efeitos dos fármacos , Animais , Antimaníacos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Feto , Humanos , Carbonato de Lítio/administração & dosagem , Masculino , Nível de Efeito Adverso não Observado , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Projetos de PesquisaRESUMO
Ganoderma lucidum has received a lot of attention recently due to its medicinal potential activities. The aim of this designed experiment was to evaluate the beneficial effects of Ganoderma lucidum extract against lithium carbonate induced testicular toxicity and related lesions in mice testis. For this purpose, lithium carbonate at a dose of 30 mg/kg, followed by 75, 150 mg/kg Ganoderma lucidum extract orally were administered for 35 days. The results were obtained from Ganoderma lucidum extract analysis prove contained a large amount of polysaccharides, triterpenoids and poly phenols based on spectrophotometric assay. Also, DPPH assay for Ganoderma lucidum extract showed high level of radical scavenging activity. The hematoxylin & eosin cross section from lithium carbonate treated group exhibited significant alterations in seminiferous tubules. Moreover, lithium carbonate induced oxidative stress via lipid peroxidation and generate MDA (P < 0.001). In addition, lithium carbonate initiated germ cells apoptosis via increase Bax expression (p < 0.001) and reduce germ cells differentiation through down-regulation of c-Kit expression (p < 0.05). Results from CASA showed that sperm parameters like count, motility and viability significantly decreased in lithium treated group (p < 0.001). It is clear that lithium carbonate induce severe damage on male reproductive system and histopathological damages via generation oxidative stress but supplementation with Ganoderma lucidum extract exhibited prevention effects and repaired induced damages.
Assuntos
Regulação da Expressão Gênica , Carbonato de Lítio/toxicidade , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Reishi/química , Testículo/patologia , Proteína X Associada a bcl-2/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Etanol/química , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testículo/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
Lithium is one of the most powerful and commonly used medications for the treatment of various psychiatric diseases, especially bipolar disorder. However, it has a narrow therapeutic index with toxic effects on various organs. There are several case reports of lithium-induced arrhythmia and ischemia. The current work aimed to study the toxic effects of lithium on the heart of adult albino rats and its molecular mechanisms and the ameliorating effect of N-acetyl cysteine (NAC). Sixty adult male Wistar albino rats were classified into four groups; control, NAC-treated received NAC 500 mg/kg/week dissolved in 1 ml 0.9% sodium chloride intraperitoneal, lithium-treated received 52.5 mg/kg/day of lithium carbonate dissolved in 1 ml 0.9% sodium chloride orally by gavage, and lithium-and-NAC-treated (group IV) received lithium and NAC in the previous doses. After 12 weeks, the rats of group III showed a significant accumulation of ascites and a decrease in the mean arterial blood pressure and electrocardiographic (ECG) findings of ischemia and arrhythmia. In addition, there was an elevation in cardiac biomarkers creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and several histological lesions with a significant increase in the area % of Van Gieson, endothelial nitric oxide synthase (eNOS), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunoreaction. There was significant upregulation of microRNA-1, microRNA-21 (miRNA-21), and microRNA-29 (miRNA-29). MiRNA-21 was strongly positively correlated to the area % of 8-OHdG, while miRNA-29 was strongly positively correlated to the area % of Van Gieson staining. NAC significantly improved the cardiotoxic effects of lithium. Being a nontoxic and safe antioxidant, NAC can be used to ameliorate lithium-induced cardiac injury.
Assuntos
Acetilcisteína/uso terapêutico , Antimaníacos/toxicidade , Antioxidantes/uso terapêutico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/etiologia , Carbonato de Lítio/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Cardiotoxicidade/sangue , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/genética , Creatina Quinase Forma MB/sangue , Masculino , MicroRNAs , Miocárdio/patologia , Ratos Wistar , Troponina I/sangueRESUMO
INTRODUCTION: Lithium has been used in medicine for almost seventy years. Besides beneficial effects, its therapy may cause serious side-effects, with kidney and liver being the organs most vulnerable to its harmful influence. Therefore, research on protective agents against lithium toxicity has been continuing for some time. OBJECTIVE: The aim of the present study is to evaluate the influence of additional selenium supplementation on lithium content, as well as homeostasis of the essential microelements iron, zinc, copper and manganese in kidney and liver of rats undergoing lithium exposure. MATERIAL AND METHODS: The study was performed on 4 groups of male Wistar rats (6 animals each) treated with: control - saline; Li-group - Li2CO3 at a dose of 2.7 mg Li/kg b.w.; Se-group - Na2SeO3 at a dose of 0.5 mg Se/kg b.w.; Li+Se-group - both Li2CO3 and Na2SeO3 at doses of 2.7 mg Li/kg b.w. and of 0.5 mg Se/kg b.w., respectively, in the form of water solutions by stomach tube, once a day for 3 weeks. The content of the studied elements in the organ samples was determined using flame atomic absorption spectroscopy (FAAS). RESULTS: Lithium administered alone caused a significant increase in its content in liver and kidney. Additional supplementation with selenium reversed these effects, and did not markedly affect other studied microelements compared to control. CONCLUSIONS: The obtained results suggest that selenium could be regarded as an adjuvant into lithium therapy. However, considering the limitations of the present study (the short duration, using only one dose and form of selenium) the continuation of the research seems to be necessary to clarify the influence of selenium supplementation on basic microelements and lithium accumulation in organs during lithium exposure.
Assuntos
Carbonato de Lítio/toxicidade , Selênio/farmacologia , Oligoelementos/metabolismo , Animais , Homeostase/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Carbonato de Lítio/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Substâncias Protetoras/farmacologia , Ratos Wistar , Oligoelementos/antagonistas & inibidoresRESUMO
Aneugenic compounds are able to cause chromosome missegregation during mitosis which results in aneuploidy in cells that are able to survive. Aneuploidy is considered a key early condition in the progression from a normal cell into a cancerous cell. The possible toxicity of therapeutic lithium has raised concern because lithium salts are currently widely prescribed as an efficient treatment of manic-depressive disorders and numerous undesirable side effects of long-term treatment have been reported to date. We have observed a dose-dependent cytotoxic effect of both Li2CO3 and LiCl in AA8 CHO cells, while no genotoxic damage was detected. Mitotic abnormalities such as multipolar anaphases and lagging chromosomes leading to the presence of micronuclei in the next interphase were frequently observed after treatment with lithium salts. Thus, the effectiveness of both lithium salts to induce alterations in the normal segregation of chromosomes could be ascribed to interference with proteins involved in the organization and/or function of the mitotic apparatus.
Assuntos
Aneugênicos/toxicidade , Aneuploidia , Antimaníacos/toxicidade , Carbonato de Lítio/toxicidade , Cloreto de Lítio/toxicidade , Mitose/efeitos dos fármacos , Animais , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Dano ao DNA , Relação Dose-Resposta a Droga , Micronúcleos com Defeito Cromossômico/induzido quimicamenteRESUMO
A bipolar patient with renal angiosclerosis due to lithium intoxication showed convulsive crises for about four months after each haemodialysis session. Aetiological work up was not able to isolate a unique cause, but modifications in treatment relieved the symptoms.
Assuntos
Antimaníacos/toxicidade , Transtorno Bipolar/tratamento farmacológico , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/terapia , Falência Renal Crônica/induzido quimicamente , Falência Renal Crônica/terapia , Carbonato de Lítio/toxicidade , Diálise Renal , Convulsões/etiologia , Antimaníacos/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Diagnóstico Diferencial , Eletroencefalografia , Epilepsia Parcial Complexa/diagnóstico , Humanos , Hiponatremia/diagnóstico , Carbonato de Lítio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polissonografia , Apneia Obstrutiva do Sono/diagnósticoRESUMO
Effects of daily injections of lithium carbonate (20, 40 or 80 mg/kg body weight) during 14 and 28 days were investigated in Wistar mice. Attention was paid (1) to changes in concentrations of lithium, creatinine and urea in serum, (2) to level of oxidative stress by measuring lipids peroxidation level and catalase, superoxide-dismutase and glutathione-peroxidase activities, and (3) to changes in the histological structure of brain. The first intraperitoneal injection was followed by a transitory peak of lithium in the blood, reaching 0.25 mM and 1.1 mM and disappearing 6 and 12 h later for the 20 and 80 mg/kg doses, respectively. From the first to the last day of treatment, lithium concentrations in the blood, measured 12 h after the injections, increased from 0 to 0.11 mM (20 mg/kg dose) or 0.25 mM (80 mg/kg dose). The 80 mg/kg treatment induced a renal insufficiency evidenced by an increase of blood creatinine and urea levels. Lithium treatment was found to trigger an oxidative stress in kidney, but not in brain. In kidney, the lipid peroxidation level (TBARS) and the superoxide dismutase and catalase activities were increased. No change in glutathione peroxidase activity was detected. Histology of the brain cortex revealed interesting modifications: thicker neuronal cells and a denser network of dendrites, as compared to controls.
Assuntos
Nefropatias/induzido quimicamente , Carbonato de Lítio/administração & dosagem , Estresse Oxidativo , Animais , Encéfalo/patologia , Encefalopatias/induzido quimicamente , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Injeções Intraperitoneais , Rim/química , Rim/enzimologia , Rim/metabolismo , Peroxidação de Lipídeos , Lítio/sangue , Carbonato de Lítio/toxicidade , Masculino , Camundongos , Superóxido Dismutase/metabolismoRESUMO
Lithium carbonate has been recognized to induce several renal side effects, including the nephrotic syndrome. This is a report of an 11-year-old, prepubertal boy with a mood disorder treated with lithium who presented with edema, bilateral pulmonary effusions, proteinuria, and hypoalbuminemia. Renal biopsy revealed pathologic changes consistent with minimal change disease. These symptoms normalized after lithium discontinuation.
Assuntos
Antimaníacos/toxicidade , Carbonato de Lítio/toxicidade , Transtornos do Humor/tratamento farmacológico , Nefrose Lipoide/induzido quimicamente , Síndrome Nefrótica/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/diagnóstico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/tratamento farmacológico , Biópsia , Criança , Comorbidade , Quimioterapia Combinada , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Transtornos do Humor/diagnóstico , Nefrose Lipoide/patologia , Síndrome Nefrótica/patologiaRESUMO
Lithium carbonate is an effective drug against bipolar disorders. Direct use of lithium carbonate has been reported to result in lithium toxication and pulmonary complications. With chitosan micro and nanoparticles gaining attention for their protein absorption, drug targeting and improved dissolution rate of sparingly water-soluble drugs, this work has focused on chitosan loaded Li as a possible alternative to Li alone for cellular uptake. Well standardized ionic gelation technique employed in this study resulted in Li loaded chitosan nanoparticles with hydrodynamic diameter below 300â¯nm and zeta potential ofâ¯+â¯30â¯mV and oval morphology. Through various techniques electrostatic interaction as well as Claritin dependent endocytic pathway is suggested as facilitating 1.3 times increase in cell proliferation in lithium carbonate loaded chitosan nanoparticles treated PC12 cells. A controlled Li release to the extent of less than 50% in 48â¯h from the nanoparticle was observed. This observation has very high significance as it ensures that the lithium toxicity can be avoided. These results indicated that chitosan is a promising carrier for lithium carbonate and may improve its therapeutic efficacy and also overcome toxicity during its use in the treatment of neuropsychiatric disorders.
Assuntos
Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Carbonato de Lítio/administração & dosagem , Nanopartículas/administração & dosagem , Animais , Transporte Biológico , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Carbonato de Lítio/química , Carbonato de Lítio/toxicidade , Nanopartículas/química , Células PC12 , RatosRESUMO
BACKGROUND: Selenium is an essential element which shows protective properties against diverse harmful factors. Lithium compounds are widely used in medicine, but, in spite of undoubted beneficial effects, treatment with these compounds may lead to severe side effects, including renal, gastrointestinal, neurological, endocrine and metabolic disorders. This study was aimed at evaluating the influence of selenium and/or lithium on lithium, iron, zinc and copper content in rats' erythrocytes as well as estimate the action of additional selenium on lithium exposure effects. METHODS: The experiment was performed on four groups of rats (six animals each): control - received saline; Li - received 2.7mg Li/kg b.w. as lithium carbonate; Se - received 0.5mg Se/kg b.w. as sodium selenite; Se+Li - received simultaneously 0.5mg Se/kg b.w. and 2.7mg Li/kg b.w. (sodium selenite and lithium carbonate). The administration was performed for three weeks, once a day by stomach tube, in form of water solutions. In erythrocytes the content of lithium, iron, zinc and copper was determined using flame atomic absorption spectroscopy. RESULTS: Lithium treatment insignificantly disturbed iron and zinc homeostasis as well as markedly increased lithium accumulation and copper content in rat erythrocytes. Selenium coadministration reversed those effects. CONCLUSIONS: The beneficial effect of selenium on disturbances of studied microelements homeostasis as well as on preventing lithium accumulation in erythrocytes in Li receiving animals allows suggesting that further research on selenium application as an adjuvant in lithium therapy is worth carrying on.
Assuntos
Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Homeostase/efeitos dos fármacos , Carbonato de Lítio/toxicidade , Selênio/farmacologia , Oligoelementos/metabolismo , Animais , Homeostase/fisiologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Oligoelementos/antagonistas & inibidoresRESUMO
Lithium is one of the classical drugs that have been widely used for treating bipolar disorder. However, several cardiac side effects including sick sinus syndrome, bundle branch block, ventricular tachycardia/fibrillation, non-specific T-wave abnormalities in addition to Brugada-type electrocardiographic changes have been noticed in patients who were given antidepressant, anticonvulsant, and/or antipsychotic drugs besides lithium. In this study, we assessed cardiohemodynamic and electrophysiological effects of lithium carbonate by itself to begin to analyze onset mechanisms of its cardiovascular side effects. Lithium carbonate in intravenous doses of 0.1, 1, and 10 mg/kg over 10 min was cumulatively administered with an interval of 20 min to the halothane-anesthetized beagle dogs (n = 4), which provided peak plasma Li+ concentrations of 0.02, 0.18, and 1.79 mEq/L, respectively, reflecting sub-therapeutic to toxic concentrations. The low and middle doses prolonged the ventricular effective refractory period at 30 min and for 5-30 min, respectively. The high dose decreased the heart rate for 45-60 min, delayed the intraventricular conduction for 15-20 min and the ventricular repolarization at 45 min, and prolonged the effective refractory period for 5-60 min. No significant change was detected in the other cardiovascular variables. Thus, lithium alone may have a wide safety margin against hemodynamic adverse events; however, it would directly and/or indirectly inhibit Na+ and K+ channels, which may synergistically increase the ventricular refractoriness from the sub-therapeutic concentration and decrease the heart rate at the supra-therapeutic one. These findings may partly explain its clinically observed various types of arrhythmias as well as electrocardiographic changes.
Assuntos
Anestesia Geral/métodos , Anestésicos Inalatórios/farmacologia , Antimaníacos/toxicidade , Arritmias Cardíacas/induzido quimicamente , Halotano/farmacologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Carbonato de Lítio/toxicidade , Potenciais de Ação/efeitos dos fármacos , Animais , Antimaníacos/administração & dosagem , Arritmias Cardíacas/fisiopatologia , Cães , Relação Dose-Resposta a Droga , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Infusões Intravenosas , Carbonato de Lítio/administração & dosagem , Modelos Animais , Período Refratário Eletrofisiológico/efeitos dos fármacos , Medição de Risco , Fatores de TempoRESUMO
BACKGROUND: Lithium salts are widely used for the treatment of mental disorders but cause thyroid dysfunctions while zinc is an essential trace element and is required for a broad range of biological activities. The present study was designed to explore the potential of zinc in regulating 131I biokinetics and thyroid functions following lithium therapy. METHODS: To carry out the investigations, 40 female sprague dawley rats weighing 110-140g were segregated into four groups viz. Group I animals served as untreated controls, group II animals were given lithium (Li2CO31.1 g/kg diet), group III animals were supplemented with zinc (227 mg ZnSO4/L drinking water) and animals in group IV were given a combined treatment of lithium and zinc. The treatments were given for durations of 1, 2 and 4 months. RESULTS: Following intraperitoneal administration of 0.37 MBq carrier- free-131I, a significant depression in the thyroidal 131I uptake both at 2 and 24 hrs was observed following lithium treatment for all the durations which however was brought to within normal levels following zinc supplementation. Lithium treatment caused a significant elevation in the thyroidal biological half lives of 131I which was appreciably attenuated following 2 and 4 months of zinc supplementation. Lithium administration for 2 and 4 months significantly decreased serum T3 and T4 levels which however were increased following zinc supplementation. Lithium treatment for 4 months caused a significant decrease in the thyroidal activities of Na+ K+ ATPase and monoamine oxidase which were brought to near normal levels by zinc. Further, lithium treatment for 4 months raised thyroidal levels of lipid peroxidation and catalase which however were normalized by zinc supplementation. On the contrary, thyroidal levels of reduced glutathione and glutathione S transferase decreased significantly following 2 and 4 months of lithium treatment but were significantly increased following zinc treatment. CONCLUSIONS: The present study concludes that zinc supplementation is helpful in attenuating the adverse effects caused by lithium on thyroid functions and can effectively regulate the biokinetics of 131I.
Assuntos
Antimaníacos/toxicidade , Carbonato de Lítio/toxicidade , Doenças da Glândula Tireoide/induzido quimicamente , Doenças da Glândula Tireoide/prevenção & controle , Sulfato de Zinco/uso terapêutico , Animais , Antioxidantes/metabolismo , Feminino , Ratos , Ratos Sprague-Dawley , Doenças da Glândula Tireoide/metabolismo , Testes de Função TireóideaRESUMO
Clinical and experimental studies have shown that lithium carbonate causes a number of clinical manifestations such as hyperparathyroidism, hypothyroidism, renal toxicity, and diabetes insipidus. The effect of this drug on the bone biology of experimental animals has not been studied to date. Therefore, the aim of the present experimental work was to study the effect of lithium on bone tissue in healthy sexually mature Wistar rats. Ten female Wistar rats, aged 312-412 months, 210-220 g body weight, were assigned to one of the following groups: untreated control group and experimental group receiving 45 mg/kg body weight/day of lithium carbonate in their drinking water during 3 months. Prior to euthanasia, blood samples were obtained in order to determine plasma phosphorus, calcium alkaline phosphatase, and lithium. After sacrifice, the tibiae were resected, processed, and embedded in paraffin. The following histomorphometric parameters were determined on digital photographs of the histologic sections: BV/TV (%), bone volume; Tb.Th (microm), trabecular thickness; Tb.N (mm(-2)/mm), trabecular number; Tb.Sp (microm), trabecular separation; Ob.S/BS (%), osteoblast surface; ES/BS (%), total erosive surface; Lc.S (%), lining cells surface; and GPC.Th (microm), thickness of growth plate cartilage. The results showed that administration of lithium carbonate cause bone loss in healthy sexually mature Wistar rats. Although the mechanism involved in bone toxicity remains to be clarified, the results obtained in the present study suggest that patients under long-term lithium therapy should be thoroughly evaluated, particularly those presenting other risk factors of osteopenia, such as menopause, low calcium intake, alcohol consumption, and glucocorticoid therapy.
Assuntos
Osso e Ossos/efeitos dos fármacos , Carbonato de Lítio/toxicidade , Animais , Osso e Ossos/patologia , Feminino , Osteoporose/induzido quimicamente , Ratos , Ratos WistarRESUMO
Chronic neurotoxicity caused by lithium salts can be reversible or irreversible and may appear after years of treatment, even at serum levels considered within the usual therapeutic range. The authors present the case of a patient with bipolar disorder who developed dementia at the age of 54 after being treated with lithium carbonate at therapeutic levels for 4 years. Nevertheless, lithium treatment was continued. At age 56, the patient presented with an acute encephalopathy caused by toxic lithium levels, which resolved only after lithium carbonate was discontinued. Full recovery from the dementia, which had started 2 years earlier, occurred only after cessation of lithium. The authors conclude that when patients treated with lithium develop subacute cognitive impairment, the possibility of lithium toxicity should be considered, even if the serum levels are considered within the therapeutic range. A long duration of neurotoxicity associated with lithium treatment does not necessarily indicate an irreversible prognosis.