Enantioselective Effect of Flurbiprofen on Lithium Disposition in Rats.

AIMS: Lithium is administered for treating bipolar disorders and is mainly excreted into urine. Nonsteroidal anti-inflammatory drugs inhibit this process. In this study, we examined the enantioselective effect of flurbiprofen on the disposition of lithium in rats. METHODS: Pharmacokinetic experiments with lithium were performed. RESULTS: Until 60 min after the intravenous administration of lithium chloride at 30 mg/kg as a bolus, 17.8% of lithium injected was recovered into the urine. Its renal clearance was calculated to be 1.62 mL/min/kg. Neither creatinine clearance (Ccr) nor pharmacokinetics of lithium was affected by the simultaneous injection of (R)-flurbiprofen at 20 mg/kg. (S)-flurbiprofen impaired the renal function and interfered with the urinary excretion of lithium. The ratio of renal clearance of lithium to Ccr was decreased by the (S)-enantiomer. CONCLUSION: This study clarified that the (S)-flurbiprofen but not (R)-flurbiprofen inhibited the renal excretion of lithium in rats.

Temporal association as a prerequisite factor of valsartan-induced lithium toxicity.

OBJECTIVES: Lithium is often the mood stabilizer of choice for the treatment of type I bipolar disorder. However, side effects as well as the narrow therapeutic dosing range often complicate its use. Lithium toxicity can be fatal and its serum level needs to be closely monitored, especially at the time of introduction and titration, or whenever combined with potentially interacting drugs, such as inhibitors of angiotensin-converting enzyme (ACE-I) or angiotensin receptor 1 (AT1 ) blockers. ACE-I and AT1 blockers can increase serum lithium levels, leading to acute lithium toxicity upon their introduction or titration. METHODS: Here, we report a case of lithium toxicity during concomitant treatment with valsartan, an AT1 blocker, in a patient who previously displayed a stable serum lithium level. The patient was observed for a few weeks and the serum lithium concentration was measured regularly. RESULTS: In contrast to previous reports, the toxicity in our patient occurred not upon introduction or titration of lithium or valsartan but after subtle modifications in daily dosing schedule for lithium. Just before the onset of toxicity, lithium had been split into two doses, whereby half of the lithium daily dose was administrated concomitantly with valsartan. We presumed that this combination had led to simultaneous concentration peaks of valsartan and lithium, promoting lithium retention within a sharp time window. CONCLUSIONS: Our observation points to the need for caution not only during the introduction and titration of ACE-I/AT1 blockers in lithium-treated patients, but also whenever the temporal pattern of drug administration is modified.

Sodium-phosphate cotransporter mediates reabsorption of lithium in rat kidney.

Lithium, used for the treatment of bipolar disorders, is reabsorbed via sodium-transport system in the proximal tubule. This step causes intra-/inter-individual difference of lithium disposition, and it has not been unclear which transporter contributes. In this study, we examined effect of foscarnet and parathyroid hormone (PTH), inactivators for sodium-phosphate cotransporter, and phlorizin, a typical inhibitor for sodium-glucose cotransporter, on the disposition of lithium in rats. Their intravenous administration stimulated urinary excretion of phosphate or glucose. After the intravenous injection of lithium chloride as a bolus, plasma concentration of lithium decreased time-dependently. The renal clearance of lithium was calculated to be 0.740 ml/min/kg in control rats, and this was 26.7% of creatinine clearance. Foscarnet and PTH significantly increased the renal clearance of lithium and its ratio to creatinine clearance, suggesting that they prevented the reabsorption of lithium. No effect of phlorizin on the renal handling of lithium was recognized. In control rats, the renal clearance of lithium showed a strong correlation with the renal excretion rate of phosphate, compared with creatinine clearance. These findings suggest that sodium-phosphate cotransporter reabsorbs lithium in the rat kidney. Furthermore, its contribution was estimated to be more than 65.9% in the lithium reabsorption. And, this study raised the possibility that therapeutic outcome of lithium is related with the functional expression of sodium-phosphate cotransporter in the kidney.

Voltage changes in the lithium dilution cardiac output sensor after exposure to blood from horses given xylazine.

BACKGROUND: In a previous in vitro study using saline medium, the authors showed that certain drugs changed the voltages of lithium dilution cardiac output (LiDCO) sensors and also influenced their accuracy in measuring lithium concentrations. These two parameters correlated and so we examined whether such drug-sensor interaction exists when LiDCO sensor was exposed to xylazine in blood. METHODS: Five healthy adult warm-blood horses were injected with 0.5 mg kg(-1) xylazine i.v. Physiological saline solution and venous blood were consecutively sampled through the same LiDCO sensor at 60, 45, 30, 15, and 0 min before and then 5, 15, 30, 45, and 60 min after xylazine injection. Sensor voltages were recorded and the differences between saline- and blood-exposed sensor voltages were compared at each time point. RESULTS: Saline-exposed sensor voltages continuously increased in a non-linear pattern during the experiment. Blood-exposed sensor voltages also increased in a similar pattern, but it was interrupted by an abrupt increase in voltage after xylazine injection. The differences between saline- and blood-exposed sensor voltages were 7 (6.1-8) mV [median (range)] before xylazine but decreased significantly at 5 and 15 min after xylazine treatment. The highest drug-induced voltage change was 3.4 (1.6-7) mV. CONCLUSIONS: This study showed that exposure of a LiDCO sensor to blood after a single clinically relevant dose of xylazine in horses changed the voltages of the sensors for 15 min. Comparison of saline- and blood-exposed sensor voltages could become a tool to detect drug-sensor interactions.

The association of the effect of lithium in the maintenance treatment of bipolar disorder with lithium plasma levels: a post hoc analysis of a double-blind study comparing switching to lithium or placebo in patients who responded to quetiapine (Trial 144).

OBJECTIVES: There is no robust proof that the efficacy of lithium in the prevention of manic and depressive episodes in bipolar disorder depends on its plasma level. This analysis aimed to compare the effect of lithium within the presumed therapeutic range of 0.6-1.2 mEq/L and below 0.6 mEq/L with that of placebo. METHODS: We carried out a post hoc analysis of a double-blind trial in which patients aged ≥18 years with bipolar I disorder (DSM-IV) who had achieved stabilization from a manic, depressive, or mixed episode during open-label treatment with quetiapine were randomized to continue quetiapine or to switch to lithium or placebo for up to 104 weeks. Of patients randomized to lithium, 201 obtained median lithium levels between 0.6 and 1.2 mEq/L, and 137 obtained median lithium levels <0.6 mEq/L. Their outcomes were compared with those of patients receiving placebo (n = 404). The primary outcome was time to recurrence of any mood event; additional outcomes included time to recurrence of a manic or depressive event. RESULTS: Times to recurrence of any mood event as well as a manic or depressive event were significantly longer for the lithium 0.6-1.2 mEq/L group versus placebo and versus lithium <0.6 mEq/L, with no differences between lithium <0.6 mEq/L and placebo. CONCLUSIONS: The results support and expand previous findings that lithium should be dosed high enough to achieve plasma levels ≥0.6 mEq/L in order to achieve an effect in the prevention of both manic and depressive recurrences of bipolar I disorder. A major limitation is that the composition of the two lithium groups was not based on randomization.

Effect of carrageenan-induced acute peripheral inflammation on the electrolyte disposition to cerebrospinal fluid in rats.

To clarify whether peripheral inflammation has a remote effect on the central nervous system, the electrolyte disposition between the circulating blood and central nervous system was evaluated in rats with carrageenan-induced acute peripheral inflammation (API). λ-Carrageenan was subcutaneously injected in the hind paw of the rat, and lithium was utilized as a surrogate marker of sodium. When the plasma and cerebrospinal fluid (CSF) concentrations of lithium were examined following lithium being intravenously administered, it was revealed that the CSF concentration of lithium in API rats is reduced compared to that in normal rats, while the plasma concentration profile of lithium in API rats is indistinguishable from that in normal rats. The pharmacokinetic analysis showed that the lithium disposition from the plasma to CSF markedly decreased by 35.8% in API rats compared to that in normal rats. On the other hand, when lithium was immediately administered into the lateral ventricle, its elimination profiles in CSF were not different between normal and API rats. It is therefore probable that the lithium disposition from the plasma to CSF alters in API rats, reflecting the entry process of electrolytes from the circulating blood to brain tissue being suppressed in response to peripheral inflammation.

Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion.

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms including inhibition of glycogen synthase kinase-3 (GSK-3), a major tau kinase. Recently, it has been shown that, in various neurodegenerative proteinopathies, lithium could induce autophagy. To analyze how lithium is therapeutically beneficial in tauopathies, transgenic mice overexpressing human mutant tau (P301L) were treated with oral lithium chloride (LiCl) for 4 months starting at the age of 5 months. At first, we examined the effects of treatment on behavior (using a battery of behavioral tests), tau phosphorylation (by biochemical assays), and number of neurofibrillary tangles (NFTs) (by immunohistopathology). In comparison with control mice, LiCl-treated mice showed a significantly better score in the sensory motor tasks, as well as decreases in tau phosphorylation, soluble tau level, and number of NFTs. Next, we examined lithium effects on autophagy using an antibody against microtubule-associated protein 1 light chain 3 (LC3) as an autophagosome marker. The number of LC3-positive autophagosome-like puncta was increased in neurons of LiCl-treated mice. Neurons containing NFTs were completely LC3-negative, whereas LC3-positive autophagosome-like puncta contained phosphorylated-tau (p-tau). The protein level of p62 was decreased in LiCl-treated mice. These data suggested that oral long-term lithium treatment could attenuate p-tau-induced motor disturbance not only by inhibiting GSK-3 but also by enhancing autophagy in tauopathy model mice.

Lamotrigine as add-on treatment to lithium and divalproex: lessons learned from a double-blind, placebo-controlled trial in rapid-cycling bipolar disorder.

OBJECTIVES: A substantial portion of the morbidity associated with rapid-cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add-on therapy for rapid-cycling bipolar depression non-responsive to the combination of lithium plus divalproex. METHODS: During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18-65 years with DSM-IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double-blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed-models analysis. RESULTS: During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non-adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double-blind adjunctive treatment phase, mean ± standard error change from baseline on the MADRS total score was -8.5 ± 1.7 points for lamotrigine and -9.1 ± 1.5 points for placebo (p = not significant; mixed-models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo. CONCLUSIONS: The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double-blind treatment.

Effects of alpha-lipoic acid in an animal model of mania induced by D-amphetamine.

OBJECTIVES: Oxidative stress and neurotrophic factors are involved in the pathophysiology of bipolar disorder (BD). Alpha-lipoic acid (ALA) is a naturally occurring compound with strong antioxidant properties. The present study investigated ALA effects in an amphetamine-induced model of mania. METHODS: In the reversal protocol, adult mice were first given d-amphetamine (AMPH) 2 mg/kg, intraperitoneally (i.p.) or saline for 14 days. Between days 8 and 14, the animals received ALA 50 or 100 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention paradigm, mice were pretreated with ALA, Li, or saline prior to AMPH. Locomotor activity was assessed in the open-field task. Superoxide dismutase (SOD) activity, reduced glutathione (GSH), and thiobarbituric acid-reactive substance (TBARS) levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). Brain-derived neurotrophic factor (BDNF) levels were measured in the HC. RESULTS: ALA and Li prevented and reversed the AMPH-induced increase in locomotor activity. PREVENTION MODEL: ALA and Li co-administration with AMPH prevented the decrease in SOD activity induced by AMPH in the HC and ST, respectively; ALA and Li prevented GSH alteration in the HC and TBARS formation in all brain areas studied. REVERSAL MODEL: ALA reversed the decrease in SOD activity in the ST. TBARS formation was reversed by ALA and Li in all brain areas. Furthermore, ALA reversed AMPH-induced decreases in BDNF and GSH in the HC. CONCLUSIONS: Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA's possible antimanic effect.

Lithium dilution, pulse power analysis, and continuous thermodilution cardiac output measurements compared with bolus thermodilution in anaesthetized ponies.

BACKGROUND: This study compares cardiac output (CO) measurements obtained by lithium dilution (LiDCO), pulse power analysis (PulseCO), and continuous thermodilution (CTD) with bolus thermodilution (BTD) in ponies. METHODS: Eight isoflurane-anaesthetized Shetland ponies received xylazine, ketamine, and midazolam infusions (0.3, 1.2, and 0.018 mg kg(-1) h(-1), respectively). CO was measured with BTD, CTD, LiDCO, and PulseCO. Lithium was injected into the jugular vein and blood was sampled from the facial artery for lithium detection and this artery was also used for PulseCO. Measurements were obtained during four stable haemodynamic conditions in the following order: isoflurane 1% (end-tidal concentration), isoflurane 2%, isoflurane 1%, and isoflurane 1%+dobutamine 5 µg kg(-1) min(-1). RESULTS: The bias (2 sd) was 2.5 (2.1) and 0.5 (2.9) litre min(-1) for LiDCO-BTD and for CTD-BTD comparisons, respectively. The limits of agreement were wider than ±30%; therefore, interchangeability was rejected for both comparisons. A possible error in LiDCO might explain the bias observed because CTD-BTD comparison showed less bias. Changes in PulseCO did not correlate with those of BTD and a weak correlation (r(2)=0.23; P=0.018) and concordance (Pc=0.42) was found between CTD and BTD. CONCLUSIONS: This is the first study to show a large bias for LiDCO-BTD comparison in animals receiving xylazine, ketamine, and midazolam infusions. The trending abilities of neither PulseCO nor CTD were reliable. Further studies are needed to elucidate possible influences of drugs on the accuracy of the LiDCOplus system.

[Techniques available for hemodynamic monitoring. Advantages and limitations]. / Técnicas disponibles de monitorización hemodinámica. Ventajas y limitaciones.

The pulmonary artery catheter has been a key tool for monitoring hemodynamic status in the intensive care unit for nearly 40 years. During this period of time, it has been the hemodynamic monitoring technique most commonly used for the diagnosis of many clinical situations, allowing clinicians to understand the underlying cardiovascular physiopathology, and helping to guide treatment interventions. However, in recent years, the usefulness of pulmonary artery catheterization has been questioned. Technological advances have introduced new and less invasive hemodynamic monitoring techniques. This review provides a systematic update on the hemodynamic variables offered by cardiac output monitoring devices, taking into consideration their clinical usefulness and their inherent limitations, with a view to using the supplied information in an efficient way.

The lithiumeter: a measured approach.

BACKGROUND: Lithium has long been recognised for its mood-stabilizing effects in the management of bipolar disorder (BD) but in practice its use has been limited because of real and 'imagined' concerns. This article addresses the need for lithium to be measured with respect to its clinical and functional effects. It introduces a visual scale, termed lithiumeter, which captures the optimal lithium plasma levels for the treatment of BD. METHODS: Key words pertaining to lithium's administration, dosing, and side effects as well as its efficacy in acute and long-term treatment of BD were used to conduct an electronic search of the literature. Relevant articles were identified by the authors and reviewed. RESULTS: This paper outlines the considerations necessary prior to initiating lithium therapy and provides a guide to monitoring lithium plasma levels. Current recommendations for optimal plasma lithium levels in the management of BD are then discussed with respect to indications for use in the acute phases of the illness and maintenance therapy. The risks associated with lithium treatment are also discussed. CONCLUSIONS: The lithiumeter provides a practical guide of optimal lithium levels for the clinical management of BD.

Lithium decreases VEGF mRNA expression in leukocytes of healthy subjects and patients with bipolar disorder.

OBJECTIVES: Vascular endothelial growth factor (VEGF) is thought to be involved in the pathophysiology of mood disorders and the target of antidepressants. The aim of this study was to elucidate molecular effects of lithium on VEGF expression by using leukocytes of healthy subjects and patients with bipolar disorder. METHODS: Eight healthy male subjects participated in the first study. Lithium was prescribed for 2 weeks, enough to reach therapeutic serum concentration. Leukocyte counts and serum lithium concentrations were determined at baseline, at 1- and 2-week medication, and at 2 weeks after stopping medication. VEGF mRNA levels were also examined in nine lithium-treated bipolar patients and healthy controls in the second study. RESULTS: In the first study, leukocyte counts were significantly increased at 2 weeks compared with those at baseline and were normalized after 2 weeks. VEGF mRNA levels were significantly decreased at 2 weeks and after 2 weeks compared with those at baseline. Consistent with the first study, VEGF mRNA levels were significantly decreased in the lithium-treated bipolar patients compared with healthy controls. CONCLUSIONS: Our investigation suggests that VEGF mRNA expression may be useful as a peripheral marker of the effects of lithium.

Lithium administered to pregnant, lactating and neonatal rats: entry into developing brain.

BACKGROUND: Little is known about the extent of drug entry into developing brain, when administered to pregnant and lactating women. Lithium is commonly prescribed for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic and postnatal animals as well as adults. METHODS: Lithium chloride in a clinically relevant dose (3.2 mg/kg body weight) was injected intraperitoneally into pregnant (E15-18) and lactating dams (birth-P16/17) or directly into postnatal pups (P0-P16/17). Acute treatment involved a single injection; long-term treatment involved twice daily injections for the duration of the experiment. Following terminal anaesthesia blood plasma, CSF and brains were collected. Lithium levels and brain distribution were measured using Laser Ablation Inductively Coupled Plasma-Mass Spectrometry and total lithium levels were confirmed by Inductively Coupled Plasma-Mass Spectrometry. RESULTS: Lithium was detected in blood, CSF and brain of all fetal and postnatal pups following lithium treatment of dams. Its concentration in pups' blood was consistently below that in maternal blood (30-35%) indicating significant protection by the placenta and breast tissue. However, much of the lithium that reached the fetus entered its brain. Levels of lithium in plasma fluctuated in different treatment groups but its concentration in CSF was stable at all ages, in agreement with known stable levels of endogenous ions in CSF. There was no significant increase of lithium transfer into CSF following application of Na+/K+ ATPase inhibitor (digoxin) in vivo, indicating that lithium transfer across choroid plexus epithelium is not likely to be via the Na+/K+ ATPase mechanism, at least early in development. Comparison with passive permeability markers suggested that in acute experiments lithium permeability was less than expected for diffusion but similar in long-term experiments at P2. CONCLUSIONS: Information obtained on the distribution of lithium in developing brain provides a basis for studying possible deleterious effects on brain development and behaviour in offspring of mothers undergoing lithium therapy.

Cooperative mechanisms of acute antidiuretic response to bendroflumethiazide in rats with lithium-induced nephrogenic diabetes insipidus.

The exact mechanism underlying thiazides-induced paradoxical antidiuresis in diabetes insipidus is still elusive, but it has been hypothesized that it is exerted either via Na+-depletion activating volume-homeostatic reflexes to decrease distal delivery, or direct stimulation of distal water reabsorption. This study examined how these two proposed mechanisms actually cooperate to induce an acute bendroflumethiazide (BFTZ)-antidiuretic effect in nephrogenic diabetes insipidus (NDI). Anaesthetized rats with lithium (Li)-induced NDI were prepared in order to measure their renal functional parameters, and in some of them, bilateral renal denervation (DNX) was induced. After a 30 min control clearance period, we infused either BFTZ into 2 groups, NDI+BFTZ and NDI/DNX+BFTZ, or its vehicle into a NDI+V group, and six 30 min experimental clearance periods were taken. During BFTZ infusion in the NDI+BFTZ group, transiently elevated Na+ excretion was associated with rapidly increased urinary osmolality and decreased free water clearance, but Li clearance and urine flow declined in the later periods. However, in the NDI/DNX+BFTZ group, there was persistently elevated Na+ excretion with unchanged Li clearance and urine flow during the experimental period, while alterations in free water clearance and urinary osmolality resembled those in the NDI+BFTZ group. In conclusion, BFTZ initially exerted two direct effects of natriuresis-diuresis and stimulating free water reabsorption at the distal nephron in NDI, which together elevated Na+ excretion and urinary osmolality but kept the urine volume unchanged in the first hour. Thereafter, the resultant sodium depletion led to the activation of neural reflexes that reduced distal fluid delivery to compensate for BFTZ-induced natriuresis-diuresis which, in cooperation with the direct distal BFTZ-antidiuretic effect, resulted in excretion of urine with a low volume, high osmolality, and normal sodium.

Altered electrolyte handling of the choroid plexus in rats with glycerol-induced acute renal failure.

The altered electrolyte handling of the choroid plexus was investigated in rats with acute renal failure (ARF) using lithium and rubidium as surrogate markers for sodium and potassium, respectively. Firstly, the transport of these two markers from the plasma to cerebrospinal fluid (CSF) was evaluated after they were concurrently injected into the femoral vein. As a result, their disposition from the plasma to CSF was shown to decrease in ARF rats, but the relationship profile between those two markers was not different from that observed in normal rats, indicating that the decreased disposition of lithium and rubidium occurs without affecting the stoichiometric balance. To clarify the mechanisms accounting for the decreased disposition, an inhibition study was then performed. When bumetanide, an inhibitor of the Na(+) /K(+) /2Cl(-) co-transporter, was directly introduced into the cerebroventricle prior to lithium and rubidium being intravenously administered, a marked increase in the markers' disposition was observed. However, such an increased disposition did not occur when bumetanide was injected into the femoral vein. Other inhibitors, such as amiloride for the Na(+) /H(+) exchanger and ouabain for Na(+) /K(+) -ATPase, did not show any effects on marker disposition regardless of the inhibitor being administered into either the cerebroventricle or femoral vein. These findings suggest that the decreased marker disposition in ARF rats is due to an increased efflux process of the choroid plexus mediated by the Na(+) /K(+) /2Cl(-) co-transporter. That is, electrolyte efflux from the CSF to plasma increases, and thereby the electrolyte influx from the plasma to CSF is counteracted.

Association between lithium serum level, mood state, and patient-reported adverse drug reactions during long-term lithium treatment: a naturalistic follow-up study.

OBJECTIVES: To assess the association between mood state and the prevalence and the severity of lithium adverse drug reactions (ADRs). METHODS: A 26-year follow-up study was conducted among patients > or =18 years treated at the outpatient lithium clinic of the University Medical Center Groningen, The Netherlands, between November 1973 and December 2000. At each monthly scheduled visit, patients were questioned by a research nurse in a standardized manner about the presence and the severity of nine specific ADRs that frequently occur as a consequence of lithium treatment and that can be identified by the patients themselves. In addition, lithium serum level was measured and mood state was rated at each visit. RESULTS: A total of 186 patients participated and the median duration of follow-up was 5.7 years (interquartile range 2.2-11.8 years). We observed an increased prevalence and severity of ADRs with increased lithium serum level (p < 0.05), also when adjusting for mood state. The prevalence and the severity of ADRs increased with decreasing mood state into the depressive range and decreased with mood state increasing into the manic range (p < 0.05), also when adjusting for lithium serum level. Taking into account the intraindividual dependency of the data resulted in a statistically significant (p < 0.001) association between, respectively, lithium serum level, mood state, and the prevalence and severity of ADRs. CONCLUSIONS: Both physicians and researchers need to be aware that lithium serum level and mood state are independently associated with patient reporting and severity scoring of ADRs, which may complicate objective assessment of ADRs.

Cardiac chronotropic hypo-responsiveness and atrial fibrosis in rats chronically treated with lithium.

Lithium is a widely used mood-stabilizing agent; however, it causes a variety of cardiovascular side effects including sinus node dysfunction. In this study we explored the potential adverse effects of lithium on cardiac chronotropic responsiveness, atrial tissue histology and gene expression in rats that were chronically treated with therapeutic doses of lithium. Male Wistar albino rats were given lithium chloride (2.5 g/kg) orally for 2 or 3 months. Following treatment, the atria were isolated and spontaneously beating rate and chronotropic responsiveness to ß-adrenergic stimulation was evaluated in an organ bath. Development of cardiac fibrosis was examined by histological methods. The expression of atrial Col1a1 (collagen I, alpha 1) and ß-arrestin2 was also assessed using quantitative RT-PCR. Treatment with lithium induced a significant hypo-responsiveness to adrenergic stimulation (P < 0.001) and caused fibrosis in the atrial tissue of treated rats. In addition, the expression of atrial Col1a1 mRNA was significantly increased in atrial tissues of lithium-treated animals, while ß-arrestin2 mRNA expression did not show a significant difference compared with control animals. Altogether, these findings indicate that cardiac chronotropic hypo responsiveness and associated cardiac fibrosis are side effects of chronic lithium treatment. Moreover, it seems that lithium treatment does not influence ß-arrestin2 mRNA expression.

Staying at the crossroads: assessment of the potential of serum lithium monitoring in predicting an ideal lithium dose.

OBJECTIVE: Lithium has been successfully employed to treat bipolar disorder for decades, and recently, was shown to attenuate the symptoms of other pathologies such as Alzheimer's disease, Down's syndrome, ischemic processes, and glutamate-mediated excitotoxicity. However, lithium's narrow therapeutic range limits its broader use. Therefore, the development of methods to better predict its dose becomes essential to an ideal therapy. METHOD: the performance of adult Wistar rats was evaluated at the open field and elevated plus maze after a six weeks treatment with chow supplemented with 0.255%, or 0.383% of lithium chloride, or normal feed. Thereafter, blood samples were collected to measure the serum lithium concentration. RESULTS: Animals fed with 0.255% lithium chloride supplemented chow presented a higher rearing frequency at the open field, and higher frequency of arms entrance at the elevated plus maze than animals fed with a 50% higher lithium dose presented. Nevertheless, both groups presented similar lithium plasmatic concentration. DISCUSSION: different behaviors induced by both lithium doses suggest that these animals had different lithium distribution in their brains that was not detected by lithium serum measurement. CONCLUSION: serum lithium concentration measurements do not seem to provide sufficient precision to support its use as predictive of behaviors.

Pharmacokinetics of intravenous lithium chloride and assessment of agreement between two methods of lithium concentration measurement in the horse.

BACKGROUND: Pharmacokinetics of lithium chloride (LiCl) administered as a bolus, once i.v. have not been determined in horses. There is no point-of-care test to measure lithium (Li+ ) concentrations in horses in order to monitor therapeutic levels and avoid toxicity. OBJECTIVES: To determine the pharmacokinetics of LiCl in healthy adult horses and to compare agreement between two methods of plasma Li+ concentration measurement: spectrophotometric enzymatic assay (SEA) and inductively coupled plasma mass spectrometry (ICP-MS). STUDY DESIGN: Nonrandomised, single exposure with repeated measures over time. METHODS: Lithium chloride was administered (0.15 mmol/kg bwt) as an i.v. bolus to eight healthy adult horses. Blood samples were collected pre-administration and at multiple times until 48 h post-administration. Samples were analysed by two methods (SEA and ICP-MS) to determine plasma Li+ concentrations. Pharmacokinetics were determined based on the reference ICP-MS data. RESULTS: Adverse side effects were not observed. The SEA showed linearity, R2 = 0.9752; intraday coefficient of variation, 2.5%; and recovery, 96.3%. Both noncompartmental and compartmental analyses (traditional two-stage and nonlinear mixed-effects [NLME] modelling) were performed. Geometric mean values of noncompartmental parameters were plasma Li+ concentration at time zero, 2.19 mmol/L; terminal elimination half-life, 25.68 h; area under the plasma concentration-time curve from time zero to the limit of quantification, 550 mmol/L min; clearance, 0.273 mL/min/kg; mean residence time, 31.22 h; and volume of distribution at steady state, 511 mL/kg. Results of the traditional two-stage analysis showed good agreement with the NLME modelling approach. Bland-Altman analyses demonstrated poor agreement between the SEA and ICP-MS methods (95% limits of agreement = 0.14 ± 0.13 mmol/L). MAIN LIMITATIONS: Clinical effects of LiCl have not been investigated. CONCLUSIONS: The LiCl i.v. bolus displayed pharmacokinetics similar to those reported in other species. The SEA displayed acceptable precision but did not agree well with the reference method (ICP-MS). The Summary is available in Spanish - see Supporting Information.