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The current publication describes most recent so far unpublished (key) guideline and GLP compliant reproductive and developmental toxicity studies of lithium carbonate in rats, including their interpretation and conclusions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.

High dose lithium chloride causes colitis through activating F4/80 positive macrophages and inhibiting expression of Pigr and Claudin-15 in the colon of mice.

OBJECTIVE: Lithium chloride (LiCl) was a mood stabilizer for bipolar affective disorders and it could activate Wnt/ß-catenin signaling pathway both in vivo and in vitro. Colon is one of a very susceptible tissues to Wnt signaling pathway, and so it would be very essential to explore the toxic effect of a high dose of LiCl on colon. METHODS: C57BL/6 mice were injected intraperitoneally with 200 mg/kg LiCl one dose a day for 5 days to activate Wnt signal pathway in intestines. H&E staining was used to assess the colonic tissues of mice treated with high dose of LiCl. The expression of inflammation-associated genes and tight junction-associated genes in colons was measured using qPCR, Western blot and immunostaining methods. The gut microbiome was tested through 16S rDNA gene analysis. RESULTS: The differentiation of enteroendocrine cells in colon was inhibited by treatment of 200 mg/kg LiCl. The F4/80 positive macrophages in colon were activated by high dose of LiCl, and migrated from the submucosa to the lamina propria. The expression of pro-inflammatory genes TNFα and IL-1ß was increased in the colon of high dose of LiCl treated mice. Clostridium_sp_k4410MGS_306 and Prevotellaceae_UCG_001 were specific and predominant for the high dose of LiCl treated mice. The expression of IgA coding genes, Pigr and Claudin-15 was significantly decreased in the colon tissues of the high dose of LiCl treated mice. CONCLUSION: 200 mg/kg LiCl might cause the inflammation in colon of mice through activating F4/80 positive macrophages and inhibiting the expression of IgA coding genes in plasma cells and the expression of Pigr and Claudin-15 in colonic epithelial cells, providing evidences for the toxic effects of high dose of LiCl on colon.

Valproic acid alters nitric oxide status in neurulating mouse embryos.

The molecular bases of the teratogenic effects elicited by valproic acid (VPA) are not fully defined. It was previously shown that inhibition of nitric oxide (NO) synthesis is associated with an enhancement of the teratogenic effects of VPA, while amplification of NO signal by sildenafil prompted a dose-dependent reduction of VPA-induced neural tube defects. In this study, for the first time, the effect of VPA on the NO synthesis was evaluated in mouse embryos during early organogenesis. On gestation day 8, ICR-CD1 mice received 600 mg/kg of VPA. Eight and 24 h later embryos were collected and analyzed for NO synthase (NOS) isoform expression, and for molecular mechanisms involved in their modulation. As main finding, in utero embryonic exposure to VPA determined a time-dependent shift of NOS isoforms expression, with a down regulated expression and activity of constitutive NOS (cNOS) and an increased expression and activity of inducible NOS (iNOS). The teratological relevance of this information remains to be established.

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.

In vitro effects of antidepressants and mood-stabilizing drugs on cell energy metabolism.

The evaluation of drug-induced mitochondrial impairment may be important in drug development as well as in the comprehension of molecular mechanisms of the therapeutic and adverse effects of drugs. The primary aim of this study was to investigate the effects of four drugs for treatment of depression (bupropion, fluoxetine, amitriptyline, and imipramine) and five drugs for bipolar disorder treatment (lithium, valproate, valpromide, lamotrigine, and carbamazepine) on cell energy metabolism. The in vitro effects of the selected psychopharmaca were measured in isolated pig brain mitochondria; the activities of citrate synthase (CS) and electron transport chain (ETC) complexes (I, II + III, and IV) and mitochondrial respiration rates linked to complex I and complex II were measured. Complex I was significantly inhibited by lithium, carbamazepine, fluoxetine, amitriptyline, and imipramine. The activity of complex IV was decreased after exposure to carbamazepine. The activities of complex II + III and CS were not affected by any tested drug. Complex I-linked respiration was significantly inhibited by bupropion, fluoxetine, amitriptyline, imipramine, valpromide, carbamazepine, and lamotrigine. Significant inhibition of complex II-linked respiration was observed after mitochondria were exposed to amitriptyline, fluoxetine, and carbamazepine. Our outcomes confirm the need to investigate the effects of drugs on both the total respiration rate and the activities of individual enzymes of the ETC to reveal the risk of adverse effects as well as to understand the molecular mechanisms leading to drug-induced changes in the respiratory rate. Our approach can be further replicated to study the mechanisms of action of newly developed drugs.

Use of meropenem to treat valproic acid overdose.

Overdose of valproic acid (VPA) or its derivatives can cause significant toxicities such as hyperammonemia or altered mental status. While levocarnitine has been used historically to manage VPA-associated hyperammonemia, no standard of therapy exists to manage VPA toxicity. We present a case of VPA overdose managed with meropenem in addition to levocarnitine. A 38-year old female presented to the emergency department after intentionally ingesting 20 tablets of extended release divalproex sodium. She received a 4-gram loading dose of levocarnitine. She developed altered mental status, and a repeat VPA level yielded a result of 278 µg/mL. She was given 1 g of meropenem and her subsequent VPA level was 193 µg/mL. Approximately 8 h after the initial dose, another 1 g of meropenem was administered. Additionally, she received 1 g of levocarnitine every 4 h for a total of six doses. A repeat VPA level returned at 62 µg/mL. The patient was transferred to the intensive care unit for further management. Carbapenem antibiotics inhibit acylpeptide hydrolase in the gastrointestinal tract. Inhibition of this enzyme prevents the reabsorption of metabolized VPA and therefore causes increased elimination. Our patient demonstrated a rapid lowering of VPA levels after administration of meropenem.

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.

Risk Factors for Utilization of Acute Care Services for Lithium Toxicity.

OBJECTIVE: This study evaluated risk factors for utilization of acute care services (ACS) (hospitalization or emergency department or urgent care visit) for lithium toxicity and the prevalence of lithium toxicity in a large, ambulatory population. METHODS: A nested case-control study compared lithium users with ACS utilization for lithium toxicity (case group) to lithium users without toxicity (control group) by using data from Kaiser Permanente Colorado for patients with at least one lithium prescription purchase. Patients in the case group were matched 1:5 with patients in the control group who had purchased lithium within 39 days of the ACS encounter. Possible lithium toxicity, identified by lithium level or diagnosis, was confirmed by chart review. Multivariable, conditional logistic regression analysis was used to identify patient and prescription characteristics associated with ACS utilization for lithium toxicity. The prevalence of lithium toxicity was determined. RESULTS: Of 3,115 individuals who took lithium, 70 experienced lithium toxicity, with or without ACS utilization, for a prevalence of 2.2%. Identified risk factors for ACS utilization for lithium toxicity included a newly initiated potentially interacting medication (odds ratio [OR]=30.30, 95% confidence interval [CI]=2.32-394.95), a higher number of treated chronic diseases (OR=1.28, CI=1.12-1.45), older age (OR=1.05, CI=1.02-1.09), and higher total daily lithium dose (OR=1.00, CI=1.00-1.00). CONCLUSIONS: Newly initiated, potentially interacting medications are a major preventable driver of ACS use for lithium toxicity, whereas age, chronic disease, and total daily lithium dose are small but significant factors. Clinicians should use extra caution when initiating a potentially interacting medication.

Clay eating attenuates lithium-based taste aversion learning in rats: A remedial effect of kaolin on nausea.

Kaolin clay eating has been considered as a marker of nausea in rats, because a variety of treatments, which evoke nausea in humans, generate consumption of kaolin clay in rats. The present study with two experiments replicated kaolin clay ingestion induced by an injection of emetic lithium chloride (LiCl). The LiCl injection, however, did not generate eating of wooden objects in rats. The present study also provides a new finding that consumption of kaolin clay alleviates rats' taste aversion learning caused by an LiCl injection. This finding is congruent with the contention that consumption of kaolin clay is not only a useful index of, but also an effective remedy for, drug-induced nausea in rats.

Lithium induces aerobic glycolysis and glutaminolysis in collecting duct principal cells.

Lithium, given to bipolar disorder patients, causes nephrogenic diabetes insipidus (Li-NDI), a urinary-concentrating defect. Li-NDI occurs due to downregulation of principal cell AQP2 expression, which coincides with principal cell proliferation. The metabolic effect of lithium on principal cells, however, is unknown and investigated here. In earlier studies, we showed that the carbonic anhydrase (CA) inhibitor acetazolamide attenuated Li-induced downregulation in mouse-collecting duct (mpkCCD) cells. Of the eight CAs present in mpkCCD cells, siRNA and drug treatments showed that downregulation of CA9 and to some extent CA12 attenuated Li-induced AQP2 downregulation. Moreover, lithium induced cell proliferation and increased the secretion of lactate. Lithium also increased urinary lactate levels in wild-type mice that developed Li-NDI but not in lithium-treated mice lacking ENaC, the principal cell entry site for lithium. Inhibition of aerobic glycolysis with 2-deoxyglucose (2DG) attenuated lithium-induced AQP2 downregulation in mpkCCD cells but did not attenuate Li-NDI in mice. Interestingly, NMR analysis demonstrated that lithium also increased the urinary succinate, fumarate, citrate, and NH4+ levels, which were, in contrast to lactate, not decreased by 2DG. Together, our data reveal that lithium induces aerobic glycolysis and glutaminolysis in principal cells and that inhibition of aerobic glycolysis, but not the glutaminolysis, does not attenuate Li-NDI.

The soluble (Pro) renin receptor does not influence lithium-induced diabetes insipidus but does provoke beiging of white adipose tissue in mice.

Earlier we reported that the recombinant soluble (pro) renin receptor sPRR-His upregulates renal aquoporin-2 (AQP2) expression, and attenuates polyuria associated with nephrogenic diabetes insipidus (NDI) induced by vasopressin type 2 receptor (V2R) antagonism. Patients that receive lithium therapy develop polyuria associated NDI that might be secondary to downregulation of renal AQP2. We hypothesized that sPRR-His attenuates indices of NDI associated with lithium treatment. Eight-week-old male C57/BL6 mice consumed chow supplemented with LiCl (40 mmol/kg diets) for 14 days. For the last 7 days mice received either sPRR-His [30 µg/(kg day), i.v.; sPRR] or vehicle (Veh) via minipump. Control (Con) mice consumed standard chow for 14 days. Compared to Con mice, 14-d LiCl treatment elevated water intake and urine volume, and decreased urine osmolality, regardless of sPRR-His or Veh administration. These data indicate that sPRR-His treatment does not attenuate indices of NDI evoked by lithium. Unexpectedly, epididymal fat mass was lower, adipocyte UCP1 mRNA and protein expression were higher, and multilocular lipid morphology was enhanced, in LiCl-fed mice treated with sPRR-His versus vehicle. The beiging of white adipose tissue is a novel metabolic benefit of manipulating the sPRR in the context of lithium-induced NDI.

Valproic Acid Overdose Review of a Case With Electrocardiographic Changes.

BACKGROUND: Valproic acid (VPA) is increasingly used to treat a variety of medical disorders, such as seizures, psychiatric disorders, and headaches. Therefore, accidental and intentional ingestions with valproic acid are increasing. OBJECTIVES: A case is presented in an adolescent with ischemic electrocardiographic changes after an acute overdose with VPA. DISCUSSION: Major features of a valproic acid overdose include respiratory depression, progressive coma, hepatotoxicity, thrombocytopenia, and hemodynamic instability. Electrocardiographic abnormalities usually consist of tachycardia and nonspecific changes. Supportive care is indicated in most overdoses and involves the monitoring and correction of electrolyte abnormalities, coagulopathies, and acid-base imbalances. Treatment may include activated charcoal, naloxone, l-carnitine, and extracorporeal detoxification. CONCLUSIONS: Valproic acid overdose is a relatively rare and electrocardiographic changes usually consist of tachycardia and nonspecific changes, but ischemic changes may occur and usually transient and require only recognition.

Comparative efficacy of alpha-linolenic acid and gamma-linolenic acid to attenuate valproic acid-induced autism-like features

The present study was undertaken to elucidate the effect of alpha-linolenic acid (ALA, 18:3, ω-3) and gamma-linolenic acid (GLA, 18:3, ω-6) on experimental autism features induced by early prenatal exposure to valproic acid (VPA) in albino wistar pups. The pups were scrutinized on the accounts of behavioral, biochemical, and inflammatory markers, and the results suggested that the GLA can impart significant protection in comparison to ALA against VPA-induced autism features. When scrutinized histopathologically, the cerebellum of the GLA-treated animals was evident for more marked protection toward neuronal degeneration and neuronal loss in comparison to ALA. Concomitant administration of ALA and GLA with VPA demonstrated a marked cutdown in the Pgp 9.5 expression with GLA having more pronounced effect. Henceforth, it can be concluded that ALA and GLA can impart favorable protection against the VPA-induced autism-like features with GLA having pronounced effect (AU)

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Electroencephalographic patterns of lithium poisoning: a study of the effect/concentration relationships in the rat.

OBJECTIVES: Lithium overdose may result in encephalopathy and electroencephalographic abnormalities. Three poisoning patterns have been identified based on the ingested dose, previous treatment duration and renal function. Whether the severity of lithium-induced encephalopathy depends on the poisoning pattern has not been established. We designed a rat study to investigate lithium-induced encephalopathy and correlate its severity to plasma, erythrocyte, cerebrospinal fluid and brain lithium concentrations previously determined in rat models mimicking human poisoning patterns. METHODS: Lithium-induced encephalopathy was assessed and scored using continuous electroencephalography. RESULTS: We demonstrated that lithium overdose was consistently responsible for encephalopathy, the severity of which depended on the poisoning pattern. Acutely poisoned rats developed rapid-onset encephalopathy which reached a maximal grade of 2/5 at 6 h and disappeared at 24 h post-injection. Acute-on-chronically poisoned rats developed persistent and slightly fluctuating encephalopathy which reached a maximal grade of 3/5. Chronically poisoned rats developed rapid-onset but gradually increasing life-threatening encephalopathy which reached a maximal grade of 4/5. None of the acutely, 20% of the acute-on-chronically and 57% of the chronically lithium-poisoned rats developed seizures. The relationships between encephalopathy severity and lithium concentrations fitted a sigmoidal Emax model based on cerebrospinal fluid concentrations in acute poisoning and brain concentrations in acute-on-chronic poisoning. In chronic poisoning, worsening of encephalopathy paralleled the increase in plasma lithium concentrations. CONCLUSIONS: The severity of lithium-induced encephalopathy is dependent on the poisoning pattern, which was previously shown to determine lithium accumulation in the brain. Our data support the proposition that electroencephalography is a sensitive tool for scoring lithium-related neurotoxicity.

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.

Comparative efficacy of alpha-linolenic acid and gamma-linolenic acid to attenuate valproic acid-induced autism-like features.

The present study was undertaken to elucidate the effect of alpha-linolenic acid (ALA, 18:3, ω-3) and gamma-linolenic acid (GLA, 18:3, ω-6) on experimental autism features induced by early prenatal exposure to valproic acid (VPA) in albino wistar pups. The pups were scrutinized on the accounts of behavioral, biochemical, and inflammatory markers, and the results suggested that the GLA can impart significant protection in comparison to ALA against VPA-induced autism features. When scrutinized histopathologically, the cerebellum of the GLA-treated animals was evident for more marked protection toward neuronal degeneration and neuronal loss in comparison to ALA. Concomitant administration of ALA and GLA with VPA demonstrated a marked cutdown in the Pgp 9.5 expression with GLA having more pronounced effect. Henceforth, it can be concluded that ALA and GLA can impart favorable protection against the VPA-induced autism-like features with GLA having pronounced effect.