Lithium salts cytotoxicity and accumulation in melanoma cells in vitro.

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.

Dose-dependent toxicity profile and genotoxicity mechanism of lithium carbonate.

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.

Lithium carbonate: Updated reproductive and developmental toxicity assessment using scientific literature and guideline compliant studies.

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.

The association between testicular toxicity induced by Li2Co3 and protective effect of Ganoderma lucidum: Alteration of Bax & c-Kit genes expression.

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.

Ultrastructure of the kidney filtration barrier in conditions of distant tumor growth and lithium treatment.

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.

Selenium prevents lithium accumulation and does not disturb basic microelement homeostasis in liver and kidney of rats exposed to lithium.

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.

The molecular mechanisms of lithium-induced cardiotoxicity in male rats and its amelioration by N-acetyl cysteine.

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.

Lithium disturbs homeostasis of essential microelements in erythrocytes of rats: Selenium as a protective agent?

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.

Lithium entrapped chitosan nanoparticles to reduce toxicity and increase cellular uptake of lithium.

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 300 nm and zeta potential of + 30 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 48 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.

Analysis of Safety Margin of Lithium Carbonate Against Cardiovascular Adverse Events Assessed in the Halothane-Anesthetized Dogs.

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.

Chronic lithium treatment induces novel patterns of pendrin localization and expression.

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.

A new insight on the role of zinc in the regulation of altered thyroid functions during lithium treatment.

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.

Effect of organo and inorganic lithium salt on human blood plasma glutathione- A comparative study.

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.

A case with reversible neurotoxicity after 2 years of dementia secondary to maintenance lithium treatment.

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.

Effects of lithium on growth, maturation, reproduction and gene expression in the nematode Caenorhabditis elegans.

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.

Study of blood and brain lithium pharmacokinetics in the rat according to three different modalities of poisoning.

Lithium-induced neurotoxicity may be life threatening. Three patterns have been described, including acute, acute-on-chronic, and chronic poisoning, with unexplained discrepancies in the relationship between clinical features and plasma lithium concentrations. Our objective was to investigate differences in plasma, erythrocyte, cerebrospinal fluid, and brain lithium pharmacokinetics using a multicompartmental approach in rat models mimicking the three human intoxication patterns. We developed acute (intraperitoneal administration of 185 mg/kg Li2CO3 in naive rats), acute-on-chronic (intraperitoneal administration of 185 mg/kg Li2CO3 in rats receiving 800 mg/l Li2CO3 in water during 28 days), and chronic poisoning models (intraperitoneal administration of 74 mg/kg Li2CO3 during 5 days in rats with 15 mg/kg K2Cr2O7-induced renal failure). Delayed absorption (4.03 vs 0.31 h), increased plasma elimination (0.65 vs 0.37 l/kg/h) and shorter half-life (1.75 vs 2.68 h) were observed in acute-on-chronically compared with acutely poisoned rats. Erythrocyte and cerebrospinal fluid kinetics paralleled plasma kinetics in both models. Brain lithium distribution was rapid (as early as 15 min), inhomogeneous and with delayed elimination (over 78 h). However, brain lithium accumulation was more marked in acute-on-chronically than acutely poisoned rats [area-under-the-curve of brain concentrations (379 ± 41 vs 295 ± 26, P < .05) and brain-to-plasma ratio (45 ± 10 vs 8 ± 2, P < .0001) at 54 h]. Moreover, brain lithium distribution was increased in chronically compared with acute-on-chronically poisoned rats (brain-to-plasma ratio: 9 ± 1 vs 3 ± 0, P < .01). In conclusion, prolonged rat exposure results in brain lithium accumulation, which is more marked in the presence of renal failure. Our data suggest that differences in plasma and brain kinetics may at least partially explain the observed variability between human intoxication patterns.

Lithium carbonate teratogenic effects in chick cardiomyocyte micromass system and mouse embryonic stem cell derived cardiomyocyte--possible protective role of myo-inositol.

The drug lithium carbonate (Li2CO3) use during pregnancy increases the possibility of cardiovascular anomalies. The earlier studies confirm its phosphatidylinositol cycle (PI) inhibition and Wnt pathways mimicking properties, which might contribute to its teratogenic effects. In this study the toxic effects of Li2CO3 in chick embryonic cardiomyocyte micromass system (MM) and embryonic stem cell derived cardiomyocyte (ESDC) were evaluated, with possible protective role of myo-inositol. In MM system the Li2CO3 did not alter the toxicity estimation endpoints, whereas in ESDC system the cardiomyocytes contractile activity stopped at 1500 µM and above with significant increase in total cellular protein contents. In ESDC system when myo-inositol was added along with Li2CO3 to continue PI cycle, the contractile activity was recovered with decreased protein content. The lithium toxic effects depend on the role of PI cycle at particular stage of cardiogenesis, while relation between myo-inositol and reduced cellular protein contents remains unknown.

Hemodialysis treatment of monomorphic ventricular tachycardia associated with chronic lithium toxicity.

INTRODUCTION: A patient with chronic lithium toxicity developed a life-threatening ventricular arrhythmia that resolved during removal of lithium by hemodialysis. Chronic lithium toxicity commonly results from diminished elimination and can produce neurotoxicity. Cardiovascular complications have been reported and generally affect the sinoatrial node and produce bradyarrhythmias. The majority of these arrhythmias require no emergent intervention. Ventricular arrhythmias associated with lithium toxicity are occasionally mentioned in the literature, but actual cases are rarely reported. CASE REPORT: A 74-year-old man was brought into the emergency department with a 3-day history of progressive encephalopathy, tremor, and weakness. The lithium level was elevated at 2.2 mmol/L, with a normal serum potassium. Electrocardiography revealed nonsustained monomorphic ventricular tachycardia (120-130 beats/min) lasting up to 1 min, alternating with sinus bradycardia and wandering atrial pacemaker. Episodes of monomorphic ventricular tachycardia recurred >100 times. The patient required a norepinephrine infusion for hypotension. Emergent hemodialysis was initiated to remove lithium and to treat the monomorphic ventricular tachycardia, which was felt to be secondary to lithium toxicity. Episodes of monomorphic ventricular tachycardia abated as hemodialysis progressed. The episodes resolved completely within 4 h of initiating hemodialysis. The patient was discharged home in sinus rhythm on day 5. Lithium was not reinstated. CONCLUSION: Monomorphic ventricular tachycardia associated with chronic lithium toxicity is exceptionally rare. Hemodialysis is a treatment option.

Lithium-induced hypothyroidism: oxidative stress and osmotic fragility status in rats.

The present study was conducted to explore the possible effects of different doses of lithium carbonate on thyroid functions, erythrocyte oxidant-antioxidant status, and osmotic fragility. Twenty-four Wistar-type male rats were equally divided into three groups: groups I and II received 0.1 and0.2 % lithium carbonate in their drinking water, respectively, for 30 days. The rats in group III served as controls, drinking tap water without added lithium. At the end of the experimental period, the erythrocyte osmotic fragility and the levels of triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were measured in blood samples. Compared to controls, there was a statistically significant increase of TSH but decreases of the T3 and T4 levels in group II. Both experimental groups showed a statistically significant increase of the maximum osmotic fragility limit. The minimum osmotic fragility values of the animals in group II were statistically higher than those of controls. The standard hemolytic increment curve of both experimental groups was shifted to the right when compared to the curve obtained from the controls. Also, relative to controls, the activities of MDA and SOD were significantly higher and the GSH level lower in group II, but not so in group I. The results of the present study show that treatment with lithium carbonate may result in thyroid function abnormalities, increased oxidative damage, and possible compromise of the erythrocyte membrane integrity resulting from increased osmotic fragility.

Lipid peroxidation, antioxidant activities and stress protein (HSP72/73, GRP94) expression in kidney and liver of rats under lithium treatment.

The present work was aimed at studying the effects of a subchronic lithium treatment on rat liver and kidneys, paying attention to the relationship between lithium toxicity, oxidative stress, and stress protein expression. Male rats were submitted to lithium treatment by adding 2 g of lithium carbonate/kg of food for different durations up to 1 month. This treatment led to serum concentrations ranging from 0.5 mM (day 7) to 1.34 mM (day 28) and renal insufficiency highlighted by an increase of blood creatinine and urea levels and a decrease of urea excretion. Lithium treatment was found to trigger an oxidative stress both in kidney and liver, leading to an increase of lipid peroxidation level (TBARS) and of superoxide dismutase and catalase activities. Conversely, glutathione peroxidase activity was reduced. Constitutive HSP73 (heat shock protein 73) expression was not modified by lithium treatment, whereas inducible HSP72 was down-regulated in kidney. GRP94 (glucose regulated protein 94) appeared as two isoforms of 92 and 98 kDa: the 98-kDa protein being overexpressed in kidney by lithium treatment whereas 92-kDa protein was underexpressed both in kidney and liver.