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Originally published online as doi:10.1189/jlb.0608388 on September 22, 2008

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(Journal of Leukocyte Biology. 2009;85:20-28.)
© 2009 by Society for Leukocyte Biology

Lithium and hematology: established and proposed uses

Daniele Focosi*,1,2, Antonio Azzarà*, Richard Eric Kast{dagger},1, Giovanni Carulli* and Mario Petrini*

* Division of Hematology, Azienda Ospedaliera Santa Chiara, University of Pisa, Pisa, Italy; and
{dagger} Department of Psychiatry, University of Vermont, Burlington, Vermont, USA

2 Correspondence: Division of Hematology, Azienda Ospedaliera Santa Chiara, University of Pisa, via Roma 56, 56100 Pisa, Italy. E-mail: dfocosi{at}tin.it


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ABSTRACT
 
Lithium (as lithium carbonate) is an unexpensive drug, widely used in psychiatry for over 50 years in treatment of mood instability (bipolar disorder) and as an adjunct to antidepressants. Hematological effects of neutrophilia and increased circulating CD34+ cells of marrow origin have long been known. Lithium was at the center of hematological investigations in the 1980s, but no definitive use in hematology has yet emerged. We review evidence that lithium increases G-CSF and augments G-CSF effects. We suggest possible therapeutic uses of lithium in neutropenia. In bone marrow transplantation, preharvest lithium-assisted hematopoietic stem cell mobilization may be useful as well.

Key Words: stem cell mobilization • stem cell transplantation • engraftment • CD34 • neutropenia


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INTRODUCTION
 
The monovalent cation lithium [in the chloride (LiCl) and carbonate (Li2CO3) forms] still represents the gold standard among treatments of bipolar disorder (manic-depression), 50 years after its introduction to common clinical practice. Lithium augmentation of antidepressant treatment in unipolar depression is also safe, effective, and common.


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PHARMACOKINETICS AND PHARMACODYNAMICS
 
Lithium ions are absorbed rapidly from the gastrointestinal tract, and plasma lithium peaks are reached 2–4 h after lithium administration. The distribution of lithium in the body approximates that of total body water, but its passage across the blood-brain barrier is slow, and at equilibration, the CSF lithium level reaches only approximately half of the plasma concentration. The elimination half-life of lithium averages 20–24 h. Half-life in geriatric patients and patients with impaired renal function is increased; 36 and 40–50 h have been reported, respectively. Lithium is excreted primarily in urine, and <1% is eliminated with the feces. Lithium is filtered by the glomeruli, and 80% of the filtered lithium is reabsorbed in the tubules, probably by the same mechanism responsible for sodium reabsorption. The renal clearance of lithium is proportional to its plasma concentration. About 50% of a single dose of lithium is excreted in 24 h. A low-salt intake, resulting in low tubular concentration of sodium, will increase lithium reabsorption and might result in retention or intoxication. Renal lithium clearance is under ordinary circumstances remarkably constant in the same individual but decreases with age and falls when sodium intake is lowered. The dose necessary to maintain a given concentration of serum lithium depends on the ability of the kidney to excrete lithium. However, renal lithium excretion may vary greatly between individuals, and lithium dosage must, therefore, be adjusted individually. In clinical reports, it has been noted that serum lithium may rise an average of 0.2–0.4 mmol/L after intake of 300 mg and 0.3–0.6 mmol/L after intake of 600 mg lithium carbonate. Glycogen synthase kinase-3 β (GSK-3β) is the known, primary lithium target. Although it is commonly stated that GSK-3β starts to get inhibited at the higher range (getting close to 2 mM), that common comment only refers to direct inhibition of the GSK-3β enzyme activity itself. In fact, at the usual blood levels, GSK-3 β inhibition is good via lithium-mediated, increased Akt phosphorylation of GSK-3. Akt-phosphorylated GSK-3 is enzymatically inactive and marked thereby for proteosomal degradation [1 ]. GSK-3β inhibition by this mood stabilizer leads to an up-regulation of β-catenin and subsequently, an increase of vascular endothelial growth factor (VEGF). In the hippocampus, increased VEGF results in increased neurogenesis and prevention of stress-induced reduction of VEGF [2 ].


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EFFECTS ON HEMATOPOIESIS
 
Lithium has been shown to be an effective agent, capable of modulating several aspects of hematopoiesis.

Effects on bone marrow hematopoietic stem cells (HSCs)
HSC transplantation is one of the few real cures available to hematological patients, and its uses are expanding continuously, ranging from regeneration of myocardium, stroke, and liver after ischemia. Currently, HSCs are routinely collected after stimulation by G-CSF.

Lithium protects HSCs following exposure to anticancer drugs and/or radiation at doses commonly used in the treatment of malignant disease. In 1998, Ballin et al [3] prospectively examined eight adult patients with bipolar disorder to find whether lithium carbonate increased their peripheral blood CD34+ HSCs. Following lithium therapy for 3–4 weeks, their neutrophil counts increased by a mean of 88% (from 4625±1350x109/l, mean±SD, pretreatment to a peak of 8300±3910x109/l). Concomitantly, there was a significant increment in their CD34+ cells (from 0.11±0.01% to a peak of 0.18±0.08%). There was a significant correlation between the rise in neutrophil count and that of the CD34+ cells (r=0.795; P=0.019). So, the authors [3] concluded that lithium therapy may be used to mobilize peripheral blood CD34+ cells for marrow transplantation (Fig. 1 ).


Figure 1
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  		Figure 1. Change in peripheral blood neutrophil and CD34+ cell counts following lithium carbonate therapy in eight patients. The bars represent weekly neutrophil counts, and the line segments demonstrate the change in CD34+ cell counts (modified with permission from Ballin et al. [3 ]).

In contrast to G-CSF, lithium is given orally and is much cheaper. Long-term lithium use does carry risks of thyroid and quite rarely renal function, but these side-effects are not seen in the short-term treatment that we envision here. Thus, it carries almost no hazard to normal donors of peripheral blood stem cells. It is known that not all patients on lithium therapy augment their neutrophil counts; why they don’t is unknown. Regarding the putative, deleterious effect that lithium might have on tumors in an autologous setting, the combined treatment of vinblastine (VB), bleomycin, and lithium to melanoma-bearing mice is more potent than chemotherapy alone [4 ].

Effects on neutrophils
Quantitative effects
The administration of lithium salts to hematologically normal subjects is associated with increased marrow neutrophil production [5 , 6 ] and enhanced release of G-CSF in vitro, followed by peripheral blood neutrophilia. The unsaturated vitamin B12-binding capacity, an indirect assessment of the total-body granulocyte pool, is elevated in patients taking lithium for manic-depressive psychosis [7 ]. This conclusion was later confirmed in kinetic studies with isotope-labeled granulocytes [8 ]. In man, oral lithium carbonate raises urinary levels of G-CSF [9 ] and augments production of G-CSF by PBMC [10 ]. This might suggest that the principal action of lithium in vivo is to enhance the production of a humoral stimulator of granulopoiesis. If lithium is given to gray collie dogs with cyclical neutropenia, a condition in which the defect is believed to lie in pluripotential stem cell and not in aberrant control mechanisms, the "cycling" of neutrophil, platelet, and reticulocyte numbers is eliminated [11 ]. Moreover, when Levitt and Quesenberry [12] studied the effects of adding lithium to a murine bone marrow liquid culture system, lithium substantially increased the number of granulocyte-committed progenitor cells and pluripotential stem cells. Lithium therefore seems to have at least two distinct actions in hematopoiesis: It enhances the production of G-CSF, and it directly stimulates the proliferation of pluripotential stem cells [12 ]. In 1978, Stein et al. [13] first formally showed that lithium-induced granulocytosis was not merely a redistribution of granulocytes that are marginated or are in the marrow reserves, supporting the hypothesis of increased granulocyte production [14 ]. Increased plasma levels of human neutrophil elastase occur during lithium therapy in humans [15 ] and dogs [16 ]. In mice given LiCl daily, an earlier and sustained increase of HSCs was detected beginning at Day 2 of lithium administration, despite that a portion of the stem cell pool is resistant to the proliferative effects of lithium [17 ].

Common and easily tolerated serum lithium levels in psychiatric patients are in range 0.3–1.0 mM. When lithium was injected i.p. at 0.5–5.0 mM, it increased the pluripotential stem cell population from normal mice. Significant increases were demonstrated in bone marrow colony-forming units (CFUs); bone marrow organ cellularity; and peripheral blood white blood cells (WBC). Marrow CFU increase was maximal at 4 days postlithium injection and greatest in the 1-mM group (P<0.001). Further increases in lithium concentration, i.e., 5 mM (levels not attainable in humans), effectively reduced CFU levels below normal, suggesting toxicity of the drug was apparent at this dose level [18 ]. In the presence of 1 mM lithium in vitro (high end of blood lithium level in psychiatric patients), marrow CFU-spleen (S) and CFU-culture (C) were increased. Marrow CFU-erythroid (E) and burst colony-forming units (BFU)-E were decreased at concentrations of lithium ≥0.5 mM. In vivo (0.5–5.0 mM i.p.), lithium produced similar results to those obtained in vitro with striking CFU-C enhancement. Serum from these lithium-treated mice contained increased G-CSF. In the Dexter continuous marrow culture system, lithium stimulates increased CFU-C production from the nonadherent fraction [19 ]. In the in vitro Dexter murine culture, lithium stimulates CFU-S and in vitro granulopoiesis by inducing production of GM-CSF in radio-resistant adherent stromal cells [13 14 15 16 ]. In facts, lithium increases CSF production by peripheral blood and bone marrow human mononuclear cells acting via phagocytes [20 ]. In the murine diffusion chamber granulopoiesis model, a mechanism not involving GM-CSF was suggested [21 , 22 ]. A lithium concentration of 4 mM gave the greatest enhancing effect on colony formation in CSF-stimulated cultures, and a concentration >1 mM inhibited de novo synthesis of CSF by monocytes [23 ]. We have tried to explain lithium-induced neutrophilia on the basis of the GSK-3/hypoxia-inducible factor-1 (HIF-1)/CXCL12 pathway [1 ], as depicted in Figure 2 . In summary, lithium inhibits GSK-3 function, thereby indirectly increasing the attractive CXCL12 gradient toward a hypoxic marrow trophic niche, where HSCs can thrive. This is reflected by increased marrow trophic niche function: peripheral neutrophilia, increased platelets, and increased CD34+ counts (Fig. 2) .


Figure 2
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  		Figure 2. A scheme of events linking lithium to neutrophilia (reproduced with permission from ref. [1 ]). DPP-4, Dipeptidyl peptidase-4; VHL, von Hippel-Lindau; p-HIF-1, phosphorylated HIF-1; meq, milliequivalent.

Qualitative effects
Perez et al. [24] first reported in 1980 that lithium carbonate was able to diminish polymorphonuclear neutrophil cAMP levels and restore normal chemotactic responsiveness in a 29-year-old woman with a long history of recurrent skin infections. Cohen et al. [25] initially reported normal random migration, chemotaxis, phagocytosis, and bactericidal ability of neutrophils from five patients receiving lithium carbonate (plasma levels of 0.7–1.7 mM). Other authors [25 26 27 28 ] proved that lithium-induced neutrophils show bactericidal defects at the Boyden’s chemotactic chamber as a result of excessive activation of the microtubular system.

In neutrophils from patients receiving VB, our group showed that in vivo lithium administration could correct chemotactic defects [29 ]. As a reverse proof, in donor (not lithium-induced) neutrophils, our group confirmed that lithium reduced chemotaxis as a result of excessive tubulin aggregation, an effect that could be antagonized by the microtubular-disaggregating agent vincristine [30 , 31 ] or by another cation, rubidium [32 ]; the latter could also increase bactericidal activity [32 ]. Accordingly, the potentiating effect of rubidium on cAMP is antagonized by the simultaneous addition of the two cations [33 ].

Other authors have reported a reduction of adherence after treatment of neutrophils with lithium [34 ].

Effects on megakaryocytes
In 1984, Joffe et al. [35 ] showed that lithium increases platelet counts, an effect that was confirmed by Balon et al. [36 ] in 1986. Lithium was then shown to increase megakaryocytopoiesis and thrombopoiesis [36 37 38 39 ]. Mice given LiCl daily show increased expansion of progenitor cells for CFU-megakaryocytes (Meg) and BFU-E and CFU-E and increased platelet counts [17 ]. Other authors have also investigated the effects of lithium carbonate on platelet function [28 ]. Although Ricevuti et al. [40 ] showed that platelet counts were not increased by lithium in thrombocytopenia induced by antineoplastic treatment, our group showed that this phenomenon occurred in some among a group of 19 patients affected by lymphomas and other neoplasias treated with lithium carbonate, 900 mg/day for 21 days [41 ].

Effects on cells of the reticuloendothelial system
Lithium has some effects on monocytes at concentrations far higher than those used to treat psychiatric patients. Monocytes of bipolar patients showed a mild hampering in their differentiation into fully active DC, showing a weak, residual expression of the monocyte marker CD14 and a relatively low potency to stimulate autologous T cells. Lithium treatment abolished this mild defect, and monocyte-derived dendritic cells (DC) of treated, bipolar patients showed signs of activation (i.e., an up-regulated potency to stimulate autologous T cells and a higher expression of the DC-specific marker CD1a). This activated phenotype contrasted with the suppressed phenotype of monocyte-derived DC exposed to lithium in vitro (10 mM) during culture [42 ]. Our group showed in 1986 that lithium carbonate induces an increase in monocyte and granulocyte cell lines in liquid culture [6 ].

Visca et al. [43] showed that monocytes of solid organ cancer patients showed a significant increase of monocyte–macrophage maturation from basal values after 14 days of lithium carbonate treatment and returned to basal values 14 days after withdrawal.

Effects on lymphocytes
Lithium is known to affect several aspects of lymphocyte function in vitro [28 ], including E-rosette formation, mitogen-induced thymidine incorporation, and reversal of cAMP-mediated plaque-forming cell (PFC) suppression [44 , 45 ]. Pretreatment of mice with lithium inhibits the PFC response to immunization with SRBC [46 ]. Weetman et al. [47] showed in 1982 that culture of pokeweed mitogen-stimnulated lymphocytes in the presence of lithium significantly increased IgG production at concentrations of 10–3–10–2 mM. Enhanced IgG and IgM synthesis was found in cultures with lithium alone at concentrations of 1–10 mM, levels within the therapeutic range. Accordingly, significantly higher numbers of spontaneous IgM PFCs were found in the peripheral blood of patients receiving lithium carbonate therapy than in normal controls [47 ]. Actually, excess infection or reduced postvaccination antibody titers are not systematically seen in bipolar patients.


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THERAPEUTIC USES IN HEMATOLOGY
 
Idiopathic neutropenia
Most lithium-treated psychiatric patients show a lithium-induced elevation of circulating neutrophils. Lithium has consequently been proposed for use in a wide set of idiopathic neutropenic disorders. Trial results have been mixed. Addition of lithium to culture of bone marrow from patients with a variety of neutropenic disorders and acute myeloid leukemia, in which normal or elevated serum and/or urinary G-CSF levels were present, did not enhance granulocyte-colony formation. Lithium administration appears to be most beneficial in neutropenic patients in whom it can be demonstrated that G-CSF production is reduced [48 ], such as the following.

Felty’s Syndrome
Increased urinary and serum G-CSF and absolute neutrophil counts (ANC) were observed in all eight patients receiving 900 mg lithium carbonate daily (a common and well-tolerated dose for most people) for 6 weeks [25 26 27 28 29 30 ]. In another study, all patients receiving 900 mg lithium carbonate daily, orally for 6 weeks showed statistically significant elevations in ANC during therapy. The effect was usually noted within 1 week and did not persist when the drug was withdrawn. The percentage increase in mean ANC varied between 138% and 617% of control value in different patients; the lower values were observed in those patients with basal serum lithium concentrations <0.5 mM [49 ]. It also reduces the number and duration of infections in these patients [50 ]. In a different work, lithium carbonate was administered to six patients with severe Felty’s syndrome, five of whom had problems with infection: Two patients had granulocyte increments that persisted after therapy was discontinued; in one of them, problems with infections resolved. In another patient, a transient ANC rise accompanied treatment. There was no response in three patients, although correlation to serum lithium levels was not provided. Granulocyte function was normal except for subnormal hexose monophosphate shunt activity in two of three patients. Although serum lithium levels were <1.5 mM, serious toxic effect occurred in one patient and significant side-effects in the other five [51 ].

Chronic benign neutropenia (CBN)
Our group showed that lithium was able to induce leukocytosis and to increase chemotaxis, marrow granulocyte reserve test, and phagocytosis in a 39-year-old woman with CBN. After lithium interruption, leukocyte functions returned to initial values [52 ].

A Number of childhood neutropenic disorders
Barrett et al. [53] first used lithium in 1977 to treat a child with congenital neutropenia, who showed a rise in neutrophil numbers and clearing of infection. In 1981, Chan et al. [54] similarly reported successful use of lithium in children with chronic neutropenia.

Cyclic hematopoiesis
This is a rare disease in man, in which severe neutropenia recurs at 21-day intervals with associated illness. As lithium carbonate therapy has been shown to eliminate cyclic hematopoiesis in gray collie dogs by inducing G-CSF [11 , 55 56 57 ], the effects of lithium treatment on five patients with this disease were examined. With lithium levels maintained between 0.5 and 1.0 mM, these patients showed no change in the fluctuations of their neutrophil counts [58 ]. A patient with previously documented cyclic neutropenia was followed for 48 days on no treatment. Blood counts obtained at 3-day intervals confirmed the presence of cyclic neutropenia with virtually complete disappearance of neutrophils at the nadir of cycles with a periodicity of 21 days. Lithium carbonate treatment was begun on Day 49. Serum lithium levels remained in the therapeutic range throughout the study interval of 58 days. Periodicity and depth of neutropenia were not diminished during the study period [59 ]. Similary, Ishii et al. [60] showed lithium efficacy in children with cyclic neutropenia.

Shwachman-Diamond Syndrome
Our group first showed in 1988 that neutrophils from an 11-month-old patient recovered from defective, stimulated migration in Boyden’s chemotactic chambers after exposure to 1 mM lithium; these in vitro findings [61 ] were confirmed later in vivo [62 , 63 ]. In this pediatric patient, auxology studies including periodic lithium challenges and dechallenges also showed that lithium could revert the growth delay (unpublished data).

Lithium treatment has failed to help a variety of neutropenic conditions including glycogenosis Ib, a disease characterized by neutropenia and impaired neutrophil migration [64 ]; in this setting, despite promising in vitro results [65 ], lithium carbonate has not proved useful [66 ].

Infectious neutropenia
The group of Gallicchio et al. [67] performed most of the experiments showing the effectiveness of lithium in accelerating hematopoietic recovery in the LP-BM5 murine leukemia virus infection model of murine AIDS (MAIDS), in which mice experience impaired hematopoeisis; in this setting, lithium improves blood cell formation and reduces lymphadenopathy and splenomegaly. MAIDS control and lithium-treated, virus-infected mice developed evidence of lymphoma; however, the involvement was much more massive at the gross and microscopic levels in the MAIDS control compared with the lithium-treated mice [68 ].

In this setting, antiretroviral drugs also contribute to impaired hematopoiesis. Zidovudine has some bone marrow toxicity, compensated by splenic-derived hematopoiesis, in particular, erythropoiesis. Overt toxicity develops when the spleen is unable to provide progenitors in response to continued zidovudine exposure in vivo [69 ]. In zidovudine-treated mice, lithium carbonate [70 ] and lithium chloride [71 ] reversed zidovudine toxicity, as measured by increases in peripheral WBC, platelets, and CFU-GM and CFU-Meg hematopoietic progenitors. This effect was optimal at a concentration of 1 mM (P<0.05); however, lithium was insufficient in reversing the reduction of erythropoiesis associated with zidovudine use in vivo [72 , 73 ].

Iatrogenic neutropenia
Lithium can enhance the recovery of peripheral blood neutrophil and pluripotential stem cell [CFU-S and CFU-mixed hematopoietic cell (Mix)] populations per femur from mice under different conditions.

Clozapine-induced granulocytopenia
Lithium has been shown to prevent [74 ] and treat [75 76 77 78 79 ] it, allowing clozapine rechallenge; extra vigilance may be required, however, to detect masked blood dyscrasias [80 ].

Carbamazepine (CBZ)-induced granulocytopenia
CBZ treatment inhibits murine and human bone marrow-derived GM (CFU-GM), erythroid (BFU-E), and CFU-Meg cells. The addition of lithium prior to and simultaneously with CBZ to marrow cultures was effective in reversing the CBZ-induced toxicity, only in the presence of an optimal lithium dose (1.0 mM) known to stimulate bone marrow function. However, when the addition of lithium was delayed 24 h to CBZ-treated cultures, no protective effect was observed for any marrow progenitor [81 ].

Antineoplastic drugs
Cyclophosphamide (CTX)
Beginning 2 h after CTX administration (200 mg/kg body weight) and on the following 2 days, mice received ultrapure Li2CO3 (35 µg/kg body weight) i.p. Control groups consisted of mice receiving CTX or PBS only; 24 h later and on Days 2–5, 7, 9, 12, 14, 16, 21, and 28, three mice from each group were serially killed. Peripheral blood was obtained and examined for their hematocrit, WBC, and differential values. Bone marrow was harvested and assayed in vivo for CFU-S and in vitro for CFU-Mix. In addition, cell-cycle status of regenerating marrow was evaluated in vitro by use of the hydroxyurea suicide technique. Mice receiving CTX plus lithium developed a significant elevation in the WBC count, which was demonstrated by an increase in the ANC when compared with CTX-administered controls. This enhanced hematopoietic activity was demonstrated further by an accelerated recovery of CFU-S and CFU-Mix compared with CTX controls. Cell kinetic studies demonstrated that a greater percentage of these HSCs obtained from lithium-treated animals was in active cell cycle [82 ].

VB
Twenty-four hours following i.v. VB (4 mg/kg/body weight), 72 male mice (144 BC3F1) received 35 µg m/animal ultrapure lithium carbonate i.p. Another 72 mice received VB or PBS as controls. Beginning 24 h later and continuing on Days 2, 5, 7, 9, 12, 21, and 28, three mice from each group were killed randomly and their hematological parameters analyzed. Bone marrow and splenic CFU-GM and CFU-Meg content was evaluated. Lithium was unable to prevent the onset of neutropenia or thrombocytopenia; however, lithium was successful in restoring normal WBC and platelet values earlier than the VB control group, thus, significantly reducing the period of drug-induced neutropenia and thrombocytopenia. This lithium-enhanced hematopoiesis was measured by an accelerated recovery in marrow and splenic CFU-GM and CFU-Meg compared with controls [83 ]. Lithium at concentrations ranging from 0.5 to 2.0 mEq/l proved to be capable of antagonizing the action of VB on the phagocytic capacity of human neutrophils, whereas the action of cytochalasin B was found to be unaffected by lithium [29 30 31 ].

Standard cytosine arabinoside and daunorubicin regimen (3+7) induction therapy for acute myelogenous leukemia
In 1977, Charron et al. [84] first attempted lithium use in this cohort of patients. In 1979, Charron and co-workers [85] showed in 22 patients that plasma lithium carbonate, 0.7–0.9 mM, markedly reduced the duration of neutropenia (10±4 days vs. 20±5 days) and thrombocytopenia and reduced the incidence of infection and the need for leukocyte transfusions. In the same year, Stein et al. [86] randomly assigned 27 patients to receive lithium carbonate, 300 mg twice/day (b.i.d.), or no lithium. Treatment groups were comparable with respect to age and baseline granulocyte counts. All patients developed granulocyte nadirs below 100/µl. By actuarial analysis, the median duration of granulocytopenia (ANC<1000/µl) was 16.0 days in the lithium group and 24.6 days in the no-lithium group (P=0.013). The median duration of ANC < 500/µl also favored the lithium group but only approached statistical significance (14.0 days vs. 20.5 days; P=0.054). Lithium levels between 0.5 and 1.0 mM were maintained easily in 11 of 12 patients receiving lithium (300 mg b.i.d.), and toxicity attributable directly to lithium was not observed. Despite the shortened duration of neutropenia, the incidence of infections and the rate of remission were not affected [86 ].

Chemotherapy for hematological malignancies
In a study on 33 patients with Hodgkin’s lymphoma (HL), non-HL, and multiple myeloma and in five patients with hypoplastic anemia (HA), administration of lithium carbonate led to a significant increase in the total WBC and neutrophil counts in all disease subsets but HA. The rise in ANC detected after 3 days suggests that lithium may exert a direct stimulant action on relatively mature myeloid cells (promyelocytes and even myelocytes) but not on the undifferentiated colony-forming cells. The exponential dependence was found between an increase in the ANC and duration of lithium intake, which permits forecasting the expected rise in the counts of these cells [87 ]. Lithium can also increase the platelet counts in solid organ neoplastic patients treated with polychemotherapy [41 ]. In a study on 45 patients with small-cell, bronchogenic carcinoma receiving combination chemotherapy and radiation therapy, 20 received lithium carbonate, and 25 received no additional therapy; control subjects experienced more days with neutropenia than the lithium-treated group (2.17 days per 100 patient days vs. 0.29), more severe febrile episodes (seven patients vs. one patient), more days hospitalized with fever and neutropenia (1.92 per 100 patient-days vs. 0.18), and more infection-related deaths (five vs. zero). Infection-free survival was significantly longer in the lithium-treated group than in controls (P<0.05). Delay in subsequent chemotherapy was longer (P<0.01), and the number of dose reductions was greater (P<0.01) in the control group. For leukocytes and neutrophils, the first cycle nadir, mean of all treatment nadirs, and the lowest nadir observed during treatment were significantly higher in the lithium group. Mean mid-cycle monocyte counts were greater in the lithium group (P<0.05) and correlated with concurrent serum lithium levels (r=0.74; P<0.05) [88 ].

Chemotherapy for solid organ cancer
In 1974, Tisman [89] first showed that lithium carbonate protected lymphosarcoma patients against drug-induced leukopenia. In 1976, Greco et al. [90] confirmed these preliminary results, but only in 1977, Catane et al. [91] reported the first randomized, placebo-controlled trial showing that lithium could ameliorate myelosuppression induced by chemotherapy for hormone-resistant prostatic cancer. Steinherz et al. [92] also confirmed these results in 1980. Lyman et al. [88] reported in 1980 that in patients treated with cytotoxic drugs for small cell carcinoma of the lung, the hematological benefits of lithium are associated with a significant reduction in the frequency of fever and infection.

Radiotherapy
Sixty-nine patients with HL experienced greater preservation of ANC with the use of lithium carbonate. At the same time, administration of lithium carbonate in the interval between the stages of anticancer treatment brought about an increase in ANC [93 ]. No appreciable effect of lithium carbonate administration in a dose of 900 mg/patient/day was recorded from 9 to 42 days after irradiation in 17 patients who received 0.5–5.7 Gy and suffered from acute radiation sickness (Degrees I–III of severity) as a result of the accident at the Chernobyl Nuclear Power Plant [94 ]. Lithium-stimulated recovery of granulopoiesis after sublethal irradiation is not mediated via increased levels of G-CSF but rather, via increased sensitivity of CFU-GM to CSF, thereby producing more CFU-GM, ultimately providing more circulating granulocytes [95 ]. In mice exposed to 2 Gy irradiation, lithium accelerates granulopoietic recovery by first providing for a completely reconstituted and functional hematopoietic, inductive microenvironment [96 ]. In mice administered lithium after receiving 200 rad whole-body irradiation, increased granulopoietic recovery was seen as measured by significant elevations in marrow and spleen-derived CFU-GM and elevation in the WBC, consisting mainly of neutrophils [97 ]. Accelerated, postirradiation recovery of hematopoietic marrow has been reported following treatment with lithium or vincristine. As these two agents appear to exert their effects on different, albeit overlapping, hematopoietic populations, it was felt that combining them might lead to a wider spectrum of enhanced, postirradiation marrow regeneration. Results demonstrated that an accelerated recovery, which appeared to be additive in nature, was observed in the marrow following combined vincristine-lithium/4.5 Gy total-body irradiation. The combined schedule significantly enhanced postirradiation recovery of WBC, 12-day CFU-S, BFU-E, and fibroblastic CFUs over radiation alone and recovery of marrow cellularity, multipotential CFUs [CFU-G, -E, -M, -Meg (GEMM)], and CFU-GM over radiation alone and either drug given singly with the 4.5 Gy. In addition, although data about the ability of regenerating stroma to support CFU-GM and CFU-GEMM did not suggest that vincristine was acting to enhance postirradiation marrow recovery by increasing stromal production of hematopoietic growth factors, lithium did appear to increase production of one or more of these factors, and this may be part of its mechanism of action [98 ].

Aplastic anemia
Blum [99] first treated an aplastic anemia patient with lithium in 1979. Pi and Dempsey [100 ] and Barrett [101 ] reported other cases, with little overall gain. Amano et al. [102] describe a 16-year-old female with severe aplastic anemia (refractory to two courses of a combined pulse corticosteroid and androgen and antilymphocyte globulins), who was then given lithium carbonate at a dose of 600 mg/day in combination with an androgen derivative. This had a dramatic effect on her peripheral blood smear. Within 3 weeks after the first course of this treatment, she no longer required RBC transfusions. Also, once the lithium carbonate dose was increased to 1200 mg/day, the patient no longer needed exogenous platelet transfusions. Approximately 6 months after the start of combination therapy, a peripheral blood smear showed entirely normal results. However, 2 months after lithium carbonate was discontinued (probably as a result of drug-induced liver dysfunction), leukocytopenia and thrombocytopenia reappeared. Therefore, lithium carbonate was readministered at a dose of 400 mg/day and later, at a dose of 800 mg/day. Again, the patient showed improvements in the three blood components without any adverse effects [102 ]. A 74-year-old woman was treated by lithium carbonate 3 x 300 mg/day for drug-induced aplastic anemia. After 8 days, she suddenly developed severe impairment of consciousness with myoclonias and hypertonia, which persisted during 10 days, despite lithium withdrawal and sodium chloride infusion. Mild electrolyte disorders, mild renal failure, and the patient’s age could have contributed to the development of intoxication. This case report shows that sometimes even short-term lithium administration may be life-threatening and should thus be prescribed cautiously [103 ].

Synergy between lithium carbonate (0.3 g thrice/day) and prednisolone (0.4 mg/kg/body weight/day) has been shown in the treatment of neutropenias [104 ].

Neurotoxicity
In 1976, Bhattacharyya et al. first showed that lithium ion in concentration of 0.2–1.0 mM promotes tubulin polymerization, provided small concentrations of Mg2+ are provided [105 ]; Li+ and Mg2+ protect microtubules against colchicine or VB, which act by inhibiting polymerization of tubulin. Accordingly, lithium was also shown in vivo able to antagonize neurotoxicity induced by vincristine (another alkaloid from Vinca spp.) [106 ].


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CONCERNS OF LITHIUM
 
Short-term treatment with the drug is usually free of any complications or side-effects, as long as serum levels of lithium are kept below 1 mM. Lithium toxicity is usually insidious in onset. A wide spectrum of signs and symptoms is possible, but the most common are tremor and diarrhea. Hypothyroidism is not rare with long-term treatment (years). Nephrogenic diabetes insipidus is rare. Symptoms vary from mild lethargy to seizures and coma. Although mild to moderate intoxication can be managed by simply withholding doses or dose reduction, more serious cases can be treated with i.v. saline. Life-threatening overdoses should be treated by hemodialysis. Some organ toxicities merit further discussion.

Thyroid toxicity
It is estimated that 4% of patients treated with lithium develop hypothyroidism per year of treatment. This is often handled by l-thyroxine supplementation or lithium discontinuation. Inhibition of thyroid hormone release is the critical mechanism in the development of hypothyroidism, goitre, and perhaps, changes in the texture of the gland, which are detected by ultrasonic scanning. Compensatory mechanisms operate and prevent the development of hypothyroidism in the majority of patients. When additional risk factors are present, environmental (such as iodine deficiency) or intrinsic (immunogenetic background), compensatory potential may be reduced, and clinically relevant consequences may derive. Hypothyroidism may develop in particular during the first years of lithium treatment, in middle-aged women, and in the presence of thyroid autoimmunity. Thyroid autoimmunity is found in excess among patients suffering from affective disorders, irrespective of lithium exposure. In patients who have been on lithium for several years, the outcome of hypothyroidism, goitre, and thyroid autoimmunity does not differ much from those observed in the general population. Hyperthyroidism and thyroid cancer are observed rarely during lithium treatment. Thyroid function tests (thyroid-stimulating hormone, free thyroid hormones, specific antibodies, and ultrasonic scanning) should be performed prior to starting lithium prophylaxis. A similar panel should be repeated at 1 year. Thyroid function abnormalities should not constitute an outright contraindication to lithium treatment, and lithium should not be stopped if a patient develops thyroid abnormalities. Decisions should be made, taking into account the evidence that lithium treatment is perhaps the only efficient means of reducing the excessive mortality that is otherwise associated with affective disorders [107 ]. Of interest, a relatively low dose of lithium (750 mg daily) offers a safe and effective, alternative means of controlling thyrotoxicosis in patients who cannot tolerate or do not respond to thionamides [108 ].

Teratogenicity
Despite over 50 years of use, the question remains unsettled of whether the effect is small. The main effects attributable to lithium are cardiac malformations and increased birth weight. In particular, lithium may be associated with Ebstein anomaly. Animal studies with lithium using doses comparable with human therapeutic serum levels have not reported any abnormalities. However, higher doses have produced anencephaly [109 ], exencephaly, skeletal and craniofacial defects, and abnormalities of blood vessel development. Experiments with other vertebrates have shown that lithium affects dorsoventral specification and inhibition of vasculogenesis. Both of these effects can be prevented by pretreatment with myoinositol, indicating that lithium interferes with the phosphatidylinositol cycle. More recent findings have shown that the effects of lithium on invertebrates may be mediated through inhibition of GSK-3β in the Wnt-GSK-3 pathway [110 ].

Leukemogenicity
Very rare cases of acute lymphocytic and acute myeloid leukemias [111 ] have been reported several months after starting lithium therapy. Gauwerky and Golde [112] actually reported in 1982 that lithium enhances the growth of human leukemia cells in vitro.

Drug interactions
Lithium Cmax, Kel, t1/2el, and AUC0-{alpha} were increased significantly during concurrent administration of nimesulide, rofecoxib, and celecoxib as compared with a control group [113 , 114 ], so that concurrent drug use should always be checked carefully.


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CONCLUSIONS
 
Apart from surprising effects in rare syndromes, the most promising use of lithium remains as an adjuvant for HSC mobilization in poor mobilizers.

On the basis of the available knowledge, we can advise further that lithium should be suspended before cytotoxic chemotherapy to prevent HSC damage. On the other hand, it has been proved that lithium could prevent neurotoxicity from vinca alkaloids so its use would remain advisable in patients receiving this drugs.


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FOOTNOTES
 
1 These authors contributed equally to this work. Back

Received June 28, 2008; revised June 28, 2008; accepted August 8, 2008.


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REFERENCES
 
    1
  1. Kast, R. E. (2008) How lithium treatment generates neutrophilia by enhancing phosphorylation of GSK-3, increasing HIF-1 levels and how this path is important during engraftment. Bone Marrow Transplant. 41
    2. 2
  2. Silva, R., Martins, L., Longatto-Filho, A., Almeida, O., Sousa, N. (2007) Lithium prevents stress-induced reduction of vascular endothelium growth factor levels Neurosci. Lett. 429,33-38[Medline]
    3. 3
  3. Ballin, A., Lehman, D., Sirota, P., Litvinjuk, U., Meytes, D. (1998) Increased number of peripheral blood CD34+ cells in lithium-treated patients Br. J. Haematol. 100,219-221[CrossRef][Medline]
    4. 4
  4. Ballin, A., Aladjem, M., Banyash, M., Boichis, H., Barzilay, Z., Gal, R., Witz, I. P. (1983) The effect of lithium chloride on tumor appearance and survival of melanoma-bearing mice Br. J. Cancer 48,83-87[Medline]
    5. 5
  5. Radomski, J., Fuyat, H., Nelson, A., Smith, P. (1950) The toxic effects, excretion and distribution of lithium chloride J. Pharmacol. Exp. Ther. 100,429-444[Free Full Text]
    6. 6
  6. Petrini, M., Vaglini, M., Carulli, G., Azzara, A., Ambrogi, F., Bertelli, A. (1986) Effects of lithium and rubidium on the differentiation of mononuclear cells Int. J. Tissue React. 8,391-392[Medline]
    7. 7
  7. Tisman, G., Herbert, V., Rosenblatt, S. (1973) Evidence that lithium induces human granulocyte proliferation: elevated serum vitamin B 12 binding capacity in vivo and granulocyte colony proliferation in vitro Br. J. Haematol. 24,767-771[CrossRef][Medline]
    8. 8
  8. Rothstein, G., Clarkson, D., Larsen, W., Grosser, B., Athens, J. (1978) Effect of lithium on neutrophil mass and production N. Engl. J. Med. 298,178-180[Abstract]
    9. 9
  9. Harker, W. G., Rothstein, G., Clarkson, D., Athens, J. W., Macfarlane, J. L. (1977) Enhancement of colony-stimulating activity production by lithium Blood 49,263-267[Abstract/Free Full Text]
    10. 10
  10. Turner, A., Allalunis, M. (1978) Mononuclear cell production of colony-stimulating activity in humans taking oral lithium carbonate Blood 52,234
    11. 11
  11. Hammond, W., Dale, D. (1980) Lithium therapy of canine cyclic hematopoiesis Blood 55,26-28[Abstract/Free Full Text]
    12. 12
  12. Levitt, L., Quesenberry, P. (1980) The effect of lithium on murine hematopoiesis in a liquid culture system N. Engl. J. Med. 302,713-719[Abstract]
    13. 13
  13. Stein, R. S., Hanson, G., Koethe, S., Hansen, R. (1978) Lithium-induced granulocytosis Ann. Intern. Med. 88,809-810[Abstract/Free Full Text]
    14. 14
  14. Stein, R., Hanson, G., Koethe, S. (1977) An in vivo evaluation of lithium induced granulocytosis Blood 50,161
    15. 15
  15. Capodicasa, E., Russano, A. M., Ciurnella, E., De Bellis, F., Rossi, R., Seuteri, A., Biondi, R. (2000) Neutrophil peripheral count and human leukocyte elastase during chronic lithium carbonate therapy Immunopharmacol. Immunotoxicol. 22,671-683[CrossRef][Medline]
    16. 16
  16. Rossof, A., Fehir, K. (1979) Lithium carbonate increases marrow granulocyte-committed colony-forming units and peripheral blood granulocytes in a canine model Exp. Hematol. 7,255-258[Medline]
    17. 17
  17. Joyce, R. (1984) Sequential effects of lithium on hematopoiesis Br. J. Haematol. 56,307-321[CrossRef][Medline]
    18. 18
  18. Gallicchio, V., Chen, M. (1980) Modulation of murine pluripotential stem cell proliferation in vivo by lithium carbonate Blood 56,1150-1152[Abstract/Free Full Text]
    19. 19
  19. Gallicchio, V., Chen, M. (1981) Influence of lithium on proliferation of hematopoietic stem cells Exp. Hematol. 9,804-810[Medline]
    20. 20
  20. Richman, C., Kinnealey, A., Hoffman, P. (1981) Granulopoietic effects of lithium on human bone marrow in vitro Exp. Hematol. 9,449-455[Medline]
    21. 21
  21. Ninane, J., Canon, J., Cornu, G., Rodhain, J., Stein, F., Symann, M. (1984) Effect of lithium on diffusion chamber granulopoiesis Int. J. Cell Cloning 2,216-226[Medline]
    22. 22
  22. Doukas, M., Shadduck, R., Waheed, A., Gass, C. (1989) Lithium stimulation of diffusion chamber colony growth is mediated by factors other than colony-stimulating factor Int. J. Cell Cloning 7,168-178[Medline]
    23. 23
  23. Morley, D. J., Galbraith, P. (1978) Effect of lithium on granulopoiesis in culture Can. Med. Assoc. J. 118,288-290[Abstract]
    24. 24
  24. Perez, H. D., Kaplan, H. B., Goldstein, I. M., Shenkman, L., Borkowsky, W. (1980) Reversal of an abnormality of polymorphonuclear leukocyte chemotaxis with lithium Clin. Immunol. Immunopathol. 16,308-315[CrossRef][Medline]
    25. 25
  25. Cohen, M., Zakhireh, B., Metcalf, J., Root, R. (1979) Granulocyte function during lithium therapy Blood 53,913-915[Abstract/Free Full Text]
    26. 26
  26. Friedenberg, W. R., Marx, J. J. (1980) The bactericidal defect of neutrophil function with lithium therapy Adv. Exp. Med. Biol. 127,389-399[Medline]
    27. 27
  27. Cohen, M., Zahkireh, B., Metcalf, J., Root, R. (1980) Granulocyte function in patients receiving lithium carbonate Adv. Exp. Med. Biol. 127,335-346[Medline]
    28. 28
  28. Friedenberg, W., Marx, J. (1980) The effect of lithium carbonate on lymphocyte, granulocyte and platelet function Cancer 45,91-97[CrossRef][Medline]
    29. 29
  29. Azzara, A., Caracciolo, F., Ruocco, L., Marini, A., Petrini, M., Ambrogi, F. (1986) Mauri, C. Sarge, R. eds. Human Neutrophil Microtubular System: In Vitro and In Vivo Evidence of Lithium Interference Harwood Academic Publishers Chur, Switzerland.
    30. 30
  30. Azzara, A., Carulli, G., Petrini, M., Ruocco, L., Marini, A., Grassi, B., Ambrogi, F. (1987) Effects of lithium on human leukocyte chemotaxis. Indirect evidence from the use of potassium and vinblastine concerning the modulation of microtubular system Haematologica 72,121-127[Medline]
    31. 31
  31. Carulli, G., Marini, A., Azzara, A., Petrini, M., Ruocco, L., Ambrogi, F. (1985) Modifications in the phagocytosis of human neutrophils induced by vinblastine and cytochalasin B: the effects of lithium Acta Haematol 74,81-85[CrossRef][Medline]
    32. 32
  32. Azzara, A., Petrini, M., Carulli, G. (1986) The effects of lithium and rubidium on human leukocyte functions Int. J. Immunother. 2,233
    33. 33
  33. Geisler, A., Klysner, R., Andersen, P. (1984) Opposite effects of lithium and rubidium neurohormone-stimulated cyclic AMP accumulation in rat brain. In Current Trends in Lithium and Rubidium Therapy (G. Corsini, ed.), Lancaster, PA, USA; Boston, MA, USA; The Hague, The Netherlands; Dordrecht, The Netherlands, MTP.
    34. 34
  34. MacGregor, R., Dyson, W. (1978) Effect of lithium on granulocyte adherence Clin. Res. 3,352
    35. 35
  35. Joffe, R. T., Kellner, C., Post, R., Unde, T. (1984) Lithium increases platelet count N. Engl. J. Med. 311,674-675[Medline]
    36. 36
  36. Balon, R., Berchou, R., Lycaki, H., Pohl, R. (1986) The effect of lithium on platelet count Acta Psychiatr. Scand. 74,474-478[CrossRef][Medline]
    37. 37
  37. Chatelain, C., Burstein, S., Harker, L. (1983) Lithium enhancement of megakaryocytopoiesis in culture: mediation via accessory marrow cells Blood 62,172-176[Abstract/Free Full Text]
    38. 38
  38. Gamba-Vitalo, C., Gallicchio, V. S., Watts, T. D., Chen, M. G. (1983) Lithium stimulated in vitro megakaryocytopoiesis Exp. Hematol. 11,382-388[Medline]
    39. 39
  39. Gallicchio, V., Gamba-Vitalo, C., Watts, T., Chen, M. (1986) In vivo and in vitro modulation of megakaryocytopoiesis and stromal colony formation by lithium J. Lab. Clin. Med. 108,199-205[Medline]
    40. 40
  40. Ricevuti, G., Mazzone, A., Rizzo, S. (1985) The effects of lithium on platelet count Acta Haematol 74,118-119[Medline]
    41. 41
  41. Carulli, G., Azzara, A., Marini, A., Petrini, M., Ambrogi, F. (1986) Effects of lithium on the platelet count in neoplastic patients treated with polychemotherapy Acta Haematol 75,242-243[Medline]
    42. 42
  42. Knijff, E. M., Ruwhof, C., de Wit, H. J., Kupka, R. W., Vonk, R., Akkerhuis, G. W., Nolen, W. A., Drexhage, H. A. (2006) Monocyte-derived dendritic cells in bipolar disorder Biol. Psychiatry 59,317-326[CrossRef][Medline]
    43. 43
  43. Visca, U., Giulivi, A., Ventura, M., Spina, M., Massari, A., Pomo, A., Santi, G. (1984) Effect of lithium carbonate on monocyte to macrophage maturation in cancer patients Boll. Ist. Sieroter. Milan. 63,154-159[Medline]
    44. 44
  44. Gelfand, E. W., Dosch, H. M., Hastings, B., Shore, A. (1979) Lithium: a modulator of cyclic AMP-dependent events in lymphocytes? Science 203,365-367[Abstract/Free Full Text]
    45. 45
  45. Hart, D. A. (1979) Modulation of concanavalin A stimulation of hamster lymphoid cells by lithium chloride Cell. Immunol. 43,113-122[CrossRef][Medline]
    46. 46
  46. Jankovic, B., Isakovic, K., Popeskovic, L. (1980) Negative immune deviation induced by lithium cation Immunol. Lett. 1,203[CrossRef]
    47. 47
  47. Weetman, A., McGregor, A., Lazarus, J., Rees Smith, B., Hall, R. (1982) The enhancement of immunoglobulin synthesis by human lymphocytes with lithium Clin. Immunol. Immunopathol. 22,400-407[CrossRef][Medline]
    48. 48
  48. Robinson, W. A. E. M., Huber, J., Gupta, R. (1980) In vivo and in vitro effects of lithium on granulopoiesis in human neutropenic disorders Adv. Exp. Med. Biol. 127,281-291[Medline]
    49. 49
  49. Gupta, R., Robinson, W., Smyth, C. (1975) Efficacy of lithium in rheumatoid arthritis with granulocytopenia (Felty’s syndrome). A preliminary report Arthritis Rheum. 18,179-184[CrossRef][Medline]
    50. 50
  50. Schapira, D. V., Gordon, P., Herbert, F. (1977) Reduction of infections in Felty’s syndrome through use of lithium Arthritis Rheum. 20,1556-1557[Medline]
    51. 51
  51. Mant, M., Akabutu, J., Herbert, F. (1986) Lithium carbonate therapy in severe Felty’s syndrome. Benefits, toxicity, and granulocyte function Arch. Intern. Med. 146,277-280[Abstract/Free Full Text]
    52. 52
  52. Carulli, G., Azzara, A., Polidori, R., Marini, A., Grassi, B., Ambrogi, F. (1984) Effects of lithium carbonate on leukocyte functions in chronic benign neutropenia Acta Haematol. 72,408-412[Medline]
    53. 53
  53. Barrett, A. J., Griscelli, C., Buriot, D., Faille, A. (1977) Lithium therapy in congenital neutropenia Lancet 2,1357-1358[Medline]
    54. 54
  54. Chan, H. S., Freedman, M. H., Saunders, E. F. (1981) Lithium therapy of children with chronic neutropenia Am. J. Med. 70,1073-1077[CrossRef][Medline]
    55. 55
  55. Hammond, W. P., Dale, D. C. (1980) Lithium treatment of cyclic hematopoiesis in the gray collie Adv. Exp. Med. Biol. 127,167-173[Medline]
    56. 56
  56. Hammond, W., Rodger, E., Dale, D. (1987) Lithium augments GM-CSA generation in canine cyclic hematopoiesis Blood 69,117-123[Abstract/Free Full Text]
    57. 57
  57. Hammond, W. P., Dale, D. C. (1982) Cyclic hematopoiesis: effects of lithium on colony-forming cells and colony-stimulating activity in grey collie dogs Blood 59,179-184[Abstract/Free Full Text]
    58. 58
  58. Hammond, W., Berman, B., Wright, D. D. (1983) DC lithium is an ineffective therapy for human cyclic hematopoiesis Blood 61,1024-1026[Abstract/Free Full Text]
    59. 59
  59. Williams, D., Jones, J. J. (1984) Lithium carbonate treatment in familial cyclic neutropenia Am. J. Clin. Pathol. 81,120-122[Medline]
    60. 60
  60. Ishii, E., Hara, T., Miyazaki, S., Fujiwara, T., Goya, N. (1983) Lithium therapy for cyclic neutropenia in children Scand. J. Haematol. 31,193-196[Medline]
    61. 61
  61. Azzara, A., Carulli, G., Polidori, R., Ceccarelli, M., Simoni, F., Ambrogi, F. (1988) In vitro restoration by lithium of defective chemotaxis in Shwachman-Diamond syndrome Br. J. Haematol. 70,502[CrossRef][Medline]
    62. 62
  62. Azzara, A., Carulli, G., Ceccarelli, M., Pucci, C., Raggio, R., Ambrogi, F. (1991) In vivo effectiveness of lithium on impaired neutrophil chemotaxis in Shwachman-Diamond syndrome Acta Haematol. 85,100-102[Medline]
    63. 63
  63. Azzara, A., Carulli, G., Petrini, M. (2003) Lithium effects on neutrophil motility in Shwachman-Diamond syndrome: evaluation by computer-assisted image analysis Br. J. Haematol. 123,369-370[CrossRef][Medline]
    64. 64
  64. Visser, G., Rake, J., Fernandes, J., Labrune, P., Leonard, J. V., Moses, S., Ullrich, K., Smit, G. P. (2000) Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European Study on Glycogen Storage Disease Type I J. Pediatr. 137,187-191[CrossRef][Medline]
    65. 65
  65. McCabe, E. R., Melvin, T., O'Brien, D., Montgomery, R. R., Robinson, W. A., Bhasker, C., Brown, B. I. (1980) Neutropenia in a patient with type Ib glycogen storage disease: in vitro response to lithium chloride J. Pediatr. 97,944-946[CrossRef][Medline]
    66. 66
  66. Mahoney, D. J., Ambruso, D., McCabe, E., Anderson, D., Leonard, J., Dunger, D. (1987) Lack of effect of lithium carbonate in patients with glycogenosis Ib Am. J. Dis. Child. 141,985-986[Abstract/Free Full Text]
    67. 67
  67. Gallicchio, V., Hughes, N., Tse, K., Ling, J., Birch, N. (1995) Effect of lithium in immunodeficiency: improved blood cell formation in mice with decreased hematopoiesis as the result of LP-BM5 MuLV infection Antiviral Res. 26,189-202[CrossRef][Medline]
    68. 68
  68. Gallicchio, V., Cibull, M., Hughes, N., Tse, K. (1993) Effect of lithium in murine immunodeficiency virus infected animals Pathobiology 61,216-221[Medline]
    69. 69
  69. Gallicchio, V., Hughes, N., Tse, K. (1993) Sustained zidovudine treatment on hematopoiesis in immunodeficient mice Int. J. Immunopharmacol. 15,673-681[CrossRef][Medline]
    70. 70
  70. Gallicchio, V., Hughes, N., Tse, K. (1993) Modulation of the hematopoietic toxicity associated with zidovudine in vivo with lithium carbonate J. Intern. Med. 233,259-268[Medline]
    71. 71
  71. Gallicchio, V., Hughes, N. (1992) Effective modulation of the hematopoietic toxicity associated with zidovudine exposure to murine and human hematopoietic progenitor stem cells in vitro with lithium chloride J. Intern. Med. 231,219-226[Medline]
    72. 72
  72. Gallicchio, V., Hughes, N., Hulette, B., Noblitt, L. (1991) Effect of interleukin-1, GM-CSF, erythropoietin, and lithium on the toxicity associated with 3'-azido-3'-deoxythymidine (AZT) in vitro on hematopoietic progenitors (CFU-GM, CFU-MEG, and BFU-E) using murine retrovirus-infected hematopoietic cells J. Leukoc. Biol. 50,580-586[Abstract]
    73. 73
  73. Kazim, S., Townsley, L., Hughes, N., Tse, K. F., Ling, J., Scott, K., Birch, N. J., Gallicchio, V. S. (1993) Lithium and anti-viral drug toxicity: II. Further studies on the ability of lithium to modulate the hematopoietic toxicity associated with the anti-viral drug zidovudine (AZT) Rom. J. Physiol. 30,231-239[Medline]
    74. 74
  74. Silverstone, P. (1998) Prevention of clozapine-induced neutropenia by pretreatment with lithium J. Clin. Psychopharmacol. 18,86-88[CrossRef][Medline]
    75. 75
  75. Papetti, F., Darcourt, G., Giordana, J., Spreux, A., Thauby, S., Feral, F., Pringuey, D. (2004) [Treatment of clozapine-induced granulocytopenia with lithium (two observations).] Encephale 30,578-582[Medline]
    76. 76
  76. Esposito, D., Hardy, P., Corruble, E. (2005) [Lithium treatment of clozapine induced neutropenia.] Encephale 31,520[Medline]
    77. 77
  77. Blier, P., Slater, S., Measham, T., Koch, M., Wiviott, G. (1998) Lithium and clozapine-induced neutropenia/agranulocytosis Int. Clin. Psychopharmacol. 13,137-140[Medline]
    78. 78
  78. Sporn, A., Gogtay, N., Ortiz-Aguayo, R., Alfaro, C., Tossell, J., Lenane, M., Gochman, P., Rapoport, J. L. (2003) Clozapine-induced neutropenia in children: management with lithium carbonate J. Child Adolesc. Psychopharmacol. 13,401-404[CrossRef][Medline]
    79. 79
  79. Adityanjee, (1995) Modification of clozapine-induced leukopenia and neutropenia with lithium carbonate Am. J. Psychiatry 152,648-649[Free Full Text]
    80. 80
  80. Kanaan, R., Kerwin, R. (2006) Lithium and clozapine rechallenge: a retrospective case analysis J. Clin. Psychiatry 67,756-760[Medline]
    81. 81
  81. Gallicchio, V., Hulette, B. (1989) In vitro effect of lithium on carbamazepine-induced inhibition of murine and human bone marrow-derived granulocyte-macrophage, erythroid, and megakaryocyte progenitor stem cells Proc. Soc. Exp. Biol. Med. 190,109-116[Abstract/Free Full Text]
    82. 82
  82. Gallicchio, V. (1986) Lithium and hematopoietic toxicity. I. Recovery in vivo of murine hematopoietic stem cells (CFU-S and CFU-Mix) after single-dose administration of cyclophosphamide Exp. Hematol. 14,395-400[Medline]
    83. 83
  83. Gallicchio, V. (1987) Lithium and hematopoietic toxicity. II. Acceleration in vivo of murine hematopoietic progenitor cells (CFU-GM and CFU-Meg) following treatment with vinblastine sulfate Int. J. Cell Cloning 5,122-133[Medline]
    84. 84
  84. Charron, D., Barrett, A. J., Faille, A., Alby, N., Schmitt, T., Degos, L. (1977) Lithium in acute myeloid leukemia Lancet 1,1307[Medline]
    85. 85
  85. Charron, D. J., Schmitt, T., Degos, L. (1979) Therapeutic complications in acute myelogeneous leukemia N. Engl. J. Med. 301,557-558[Medline]
    86. 86
  86. Stein, R., Flexner, J. M., Graber, S. E. (1979) Lithium and granulocytopenia during induction therapy of acute myelogenous leukemia Blood 54,636-641[Abstract/Free Full Text]
    87. 87
  87. Iavorkovskii, L. L., Gol'dshtein, I., Zile, M., Iavorkovskii, L. (1984) [Stimulating effect of lithium carbonate on neutropoiesis in iatrogenic neutropenia.] Ter. Arkh. 56,84-87[Medline]
    88. 88
  88. Lyman, G., Williams, C., Preston, D. (1980) The use of lithium carbonate to reduce infection and leukopenia during systemic chemotherapy N. Engl. J. Med. 302,257-260[Abstract]
    89. 89
  89. Tisman, G. (1974) Lithium carbonate protection against drug-induced leukopenia in lymphosarcoma patients Hematology (Am. Soc. Hematol. Educ. Program) 2,1509
    90. 90
  90. Greco, F., Brereton, H., Pomeroy, T. (1976) Lithium carbonate attenuation of neutropenia from cancer chemotherapy Proc. AACR Assoc. 17,250
    91. 91
  91. Catane, R., Kaufman, J., Mittelman, A., Murphy, G. (1977) Attenuation of myelosuppression with lithium N. Engl. J. Med. 297,452-453[Medline]
    92. 92
  92. Steinherz, P. G., Rosen, G., Ghavimi, F. (1980) Effect of lithium carbonate on leukopenia after chemotherapy J. Pediatr. 96,923-927[CrossRef][Medline]
    93. 93
  93. Il'in, N. V., Korytova, L., Filatova, A. (1986) [Correction of neutropenia with lithium carbonate during the radiation treatment of lymphogranulomatosis patients.] Ter. Arkh. 58,65-67[Medline]
    94. 94
  94. Konchalovskii, M. V., Shishkova, T., Chotii, V., Baranov, A. (1989) [Use of lithium carbonate as a leukocyte stimulant in acute radiation sickness in humans.] Gematol. Transfuziol. 34,16-23[Medline]
    95. 95
  95. Gallicchio, V., Chen, M., Watts, T. (1985) Lithium-stimulated recovery of granulopoiesis after sublethal irradiation is not mediated via increased levels of colony stimulating factor (CSF) Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 47,581-590[CrossRef][Medline]
    96. 96
  96. Gallicchio, V., Chen, M., Watts, T. (1984) Ability of lithium to accelerate the recovery of granulopoiesis after subacute radiation injury Acta Radiol. Oncol. 23,361-366[Medline]
    97. 97
  97. Gallicchio, V. S., Chen, M. G., Watts, T. D., Gamba-Vitalo, C. (1983) Lithium stimulates the recovery of granulopoiesis following acute radiation injury Exp. Hematol. 11,553-563[Medline]
    98. 98
  98. Johnke, R., Abernathy, R. (1991) Accelerated marrow recovery following total-body irradiation after treatment with vincristine, lithium or combined vincristine-lithium Int. J. Cell Cloning 9,78-88[Medline]
    99. 99
  99. Blum, S. F. (1979) Lithium therapy of aplastic anemia N. Engl. J. Med. 300,677[Medline]
    100. 100
  100. Pi, E. H., Dempsey, G. M. (1980) Lithium carbonate in aplastic anemia Arch. Gen. Psychiatry 37,720[Abstract/Free Full Text]
    101. 101
  101. Barrett, A. (1980) Hematological effects of lithium and its use in treatment of neutropenia Blut 40,1-6[CrossRef][Medline]
    102. 102
  102. Amano, I., Morii, T. Y., Yamanaka, T., Tsukaguchi, N., Nishikawa, K., Narita, N., Shimoyama, T. (1999) [Successful lithium carbonate therapy for a patient with intractable and severe aplastic anemia.] Rinsho Ketsueki 40,46-50[Medline]
    103. 103
  103. Efira, A., van Laethem, Y., Ectors, M., Unger, J. (1980) Lithium in hematology: a case of acute intoxication Acta Haematol 64,335-337[Medline]
    104. 104
  104. Iavorkovskii, L. L., Iavorkovskii, L. I. (1985) [Effectiveness of combined administration of lithium carbonate and prednisolone in neutropenias.] Ter. Arkh. 57,84-88[Medline]
    105. 105
  105. Bhattacharyya, B., Wolff, J. (1976) Stabilization of microtubules by lithium ion Biochem. Biophys. Res. Commun. 73,383-390[CrossRef][Medline]
    106. 106
  106. Petrini, M., Vaglini, F., Cervetti, G., Cavalletti, M., Sartucci, F., Murri, L., Corsini, G. U. (1999) Is lithium able to reverse neurological damage induced by vinca alkaloids? J. Neural Transm. 106,569-575[CrossRef][Medline]
    107. 107
  107. Bocchetta, A., Loviselli, A. (2006) Lithium treatment and thyroid abnormalities Clin. Pract. Epidemol Ment. Health 2,23[CrossRef][Medline]
    108. 108
  108. Ng, Y. W., Tiu, S. C., Choi, K. L., Chan, F. K., Choi, C. H., Kong, P. S., Ng, C. M., Shek, C. C. (2006) Use of lithium in the treatment of thyrotoxicosis Hong Kong Med. J. 12,254-259[Medline]
    109. 109
  109. Grover, S., Gupta, N. (2005) Lithium-associated anencephaly Can. J. Psychiatry 50,185-186[Medline]
    110. 110
  110. Giles, J., Bannigan, J. (2006) Teratogenic and developmental effects of lithium Curr. Pharm. Des. 12,1531-1541[CrossRef][Medline]
    111. 111
  111. Carulli, G., Azzara, A., Caracciolo, F., Margelli, M., Ambrogi, F., Grassi, B. (1983) Lithium and acute lymphocytic leukemia Haematologica 68,698[Medline]
    112. 112
  112. Gauwerky, C. E., Golde, D. (1982) Lithium enhances the growth of human leukemia cells in vitro Br. J. Haematol. 51,431-438[Medline]
    113. 113
  113. Sidhu, S., Kondal, A., Malhotra, S., Garg, S., Pandhi, P. (2004) Effect of nimesulide co-administration on pharmacokinetics of lithium Indian J. Exp. Biol. 42,1248-1250[Medline]
    114. 114
  114. Phelan, K. M., Mosholder, A. D., Lu, S. (2003) Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs J. Clin. Psychiatry 64,1328-1334[Medline]




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