Lithium therapy of canine cyclic hematopoiesis

Treatment of cyclic hematopoiesis in the grey collie dog with lithium carbonate eliminated the recurrent neutropenia and normalized the other blood cell counts. These findings suggest that human cyclic hematopoiesis may be successfully treated with lithium. The effects of lithium on the monocytes, platelets, and reticulocytes, as well as the neutrophils, suggest that lithium operates on basic regulatory mechanisms affecting the most primitive hematopoietic precursor cells.     

Cyclic hematopoiesis: effects of lithium on colony-forming cells and colony-stimulating activity in grey collie dogs

The cycling of blood cell counts in grey collie dogs with cyclic hematopoiesis can be eliminated by treatment with oral lithium carbonate. To explore the mechanism by which lithium alters this stem cell disorder, studies of bone marrow granulocyte-macrophage progenitor cells (CFU-C), neutrophil colony-forming cells (neutrophilic CFU-C), and colony-stimulating activity (CSA) were performed. In untreated dogs, the proportions of CFU-C were found to fluctuate cyclically, but the cyclic fluctuations in neutrophil colony-forming cells were even more marked, with numbers decreasing to undetectable levels during each period of neutrophilia. Dogs on lithium, however, did not cycle the numbers of total or neutrophilic CFU-C. Tritiated thymidine suicide rates were not altered by treatment with lithium. Serum CSA levels and bone marrow cell elaboration of CSA were not increased by lithium. These studies suggest that lithium corrects cyclic neutropenia by a direct effect on the differentiation and proliferation of CFU-C; normalization of the proportion of CFU-C that enter neutrophilopoiesis appears to be an important effect of the lithium therapy.     

The effect of lithium carbonate on chemotherapy-induced neutropenia and thrombocytopenia

Lithium carbonate ameliorates neutropenia associated with cancer chemotherapy. The effect of lithium on platelet suppression has not, however, been well established. In the present study, five patients with ovarian carcinoma received daily lithium during alternate cycles of treatment with hexamethylmelamine, cyclophosphamide, adriamycin, and cis-platinum. Analysis of myelosuppression was performed on 24 paired consecutive cycles given at identical doses, one with and one without lithium. During lithium cycles, nadir leukocyte, neutrophil, and platelet counts were significantly higher (P less than 0.01, less than 0.01, less than 0.05 respectively) and the interval between treatments was shorter (P less than 0.01). One patient who has received 11 cycles of chemotherapy continues to receive 100% doses owing to the beneficial effect of lithium on chemotherapy-induced thrombocytopenia. Lithium was poorly tolerated by some patients because of either tremor or nausea and vomiting, in spite of nontoxic serum lithium levels. The amelioration of drug-induced platelet suppression as well as neutrophil suppression noted in this study suggests that lithium's effect on hematopoiesis is not limited to stimulation of neutrophil production. The ability of lithium to decrease chemotherapy-induced myelosuppression suggests that lithium administration may facilitate escalation of chemotherapy doses in selected patients.     

Lithium augments GM-CSA generation in canine cyclic hematopoiesis

Cyclic hematopoiesis in gray collie dogs can be cured by lithium treatment. We examined the mechanism of lithium's effect by developing an assay for the canine equivalent of GM-CSF (called GM-CSA). Phytohemagglutinin (PHA)-stimulated canine blood mononuclear cells produce GM-CSA in a dose-dependent manner; this GM-CSA stimulates more neutrophil-containing colonies than does endotoxin-treated dog serum. Production of GM-CSA by PHA-stimulated normal dog cells was not altered by lithium. However, cells from gray collies during their neutrophilic period increased their GM-CSA when lithium (2 mEq/L) was added to low doses of PHA, whereas neutropenic gray collie cells did not. These data suggest that lithium could modulate cyclic hematopoiesis by increasing intramedullary GM-CSA at the time when marrow neutrophilic progenitor cells are at their nadir.     

Lithium does not inhibit the parathyroid hormone-mediated rise in urinary cyclic AMP and phosphate in humans.

To test the hypothesis that lithium is a general inhibitor of hormone-activated adenylate cyclase, we infuse parathyroid hormone (PTH) into human subjects prior to and during lithium carbonate administration. PTH infusion caused a significant increase in urinary cyclic AMP and urinary phosphate excretion. There was no significant difference in these responses in the lithium compared to the control period. In four patients with primary hyperparathyroidism, lithium had no significant effect on serum calcium or phosphate or on tubular reabsorption of phosphate. The data do not substantiate the hypothesis that lithium (at therapeutic concentrations) is a general inhibitor of hormonally-activated adenylate cyclase, nor do they support its potential clinical utility in primary hyperparthyroidism.     

不同抗甲状腺药物对^131Ⅰ治疗Graves病近期疗效的比较

目的探讨Graves病患者使用不同抗甲状腺药物后再行^131Ⅰ治疗的疗效比较。方法随访Graves病经抗甲状腺药物治疗后再行^131Ⅰ治疗的患者98例,按治疗前分别使用丙基硫氧嘧啶、他巴唑、碳酸锂分为3组,前两组在^131Ⅰ治疗前停用抗甲亢药物15天,碳酸锂组使用至治疗当日,采用个性化^131Ⅰ治疗后6个月复查并评价治疗效果。结果使用丙基硫氧嘧啶组在^131Ⅰ治疗6月后仍有38％患者甲状腺功能亢进,使用他巴唑组甲亢比例为23％,而碳酸锂组仅为9．6％,3组间比较均有显著性差异（α〈0．05）;3组间发生甲减例数比较无显著性差异（P〉0．05）。结论在^131Ⅰ治疗Graves病前使用丙基硫氧嘧啶会降低^131Ⅰ治疗甲亢的疗效,其影响高于他巴唑组及碳酸锂组,3组中碳酸锂组对^131Ⅰ治疗甲亢的疗效影响最小。     

Treatment of chronic secretory diarrhea of unknown origin by lithium carbonate

A 49-yr-old patient developed severe chronic secretory diarrhea associated with hypokalemia and gastric hypochlorhydria. Small bowel perfusion study revealed active proximal intestinal secretion. Despite thorough investigation, the cause of her secretory diarrhea was not elucidated. Her diarrhea was refractory to indomethacin, prednisone, and trifluoperazine therapy. The life-threatening profuse watery diarrhea responded, however, to oral lithium carbonate, an agent reported to inhibit cyclic adenosine monophosphate synthesis. Diarrhea stopped within 4 days of initiation of lithium chloride therapy. Discontinuation of lithium 2 wk later resulted in return of watery diarrhea. Lithium therapy was reinstituted and her diarrheal symptoms resolved completely. Three months later, lithium carbonate was discontinued. The patient continued to be well and remained asymptomatic 15 mo after discontinuation of therapy. Therefore, in patients with chronic secretory diarrhea in whom exhaustive tests fail to reveal an etiology, a trial of oral lithium therapy may be beneficial in ameliorating the disabling symptoms and could be life-saving.     

Hyperparathyroidism, hypothyroidism, and impaired renal function after 10 to 20 years of lithium treatment

Of 19 patients who had been receiving a therapeutic dosage of lithium carbonate for 10 to 20 years, 8 (42%) were found to have some laboratory evidence of hyperparathyroidism. Of the 3 who had parathyroid surgery, 2 had hyperplasia and 1 had a solitary adenoma, an unusually high incidence of hyperparathyroidism. Unusual features of lithium-induced hyperparathyroidism in this series include (1) low urinary calcium excretion and the absence of nephrolithiasis, (2) normal urinary cyclic adenosine monophosphate excretion, and (3) normal plasma inorganic phosphate. Eight patients (42%) required treatment for hypothyroidism. Three patients (16%) had impaired kidney function. While these observations do not contraindicate the continued use of lithium carbonate in manic depression, they strongly emphasize the need for close laboratory surveillance.     

Granulocyte function during lithium therapy.

Random migration, chemotaxis, phagocytosis, and bactericidal ability of neutrophils from 5 patients receiving lithium carbonate were compared with those of neutrophils from healthy donors. These cells functioned normally in all respects. Neither sera from patients receiving lithium carbonate nor the addition of lithium chloride to control cells in vitro significantly altered their functional capacity. These findings suggest that neutrophil function in patients receiving lithium therapy is preserved, and they support the potential utility of this drug as a leukopoietic agent in neutropenic states.     

Felty's syndrome: Effect of lithium on granulopoiesis

The effect of lithium carbonate upon granulopoiesis was studied in eight patients with Felty's syndrome. Absolute granulocyte counts increased in all patients receiving 900 mg lithium carbonate daily for six weeks. Increased urinary and serum granulocyte colony-stimulating activity was observed in all patients during lithium therapy. A causal relationship between increases in colony-stimulating activity and increased granulocytes is postulated.     

Short-term use of lithium carbonate in the treatment of thyrotoxicosis]

The examinations were performed on 3 groups of altogether 65 persons with thyreotoxicosis, the cause of which was either Basedow's disease or struma nodosa. The first group received metizol (thiamazol) in a daily dosage of 60 mg, the second group lithium carbonate (1.0 up to 1.5 g/a day), the third group metizol together with lithium carbonate. The groups were of the same value, concerning the degree of the symptoms of hyperthyroidism. The examinations showed that when lithium carbonate is used alone at the earliest a significant decrease of the serum T4 and T3 concentration as well as of the T3 binding index appears. After a treatment of seven days the therapeutic effects even up. Under the lithium therapy an essential improvement of the clinical findings was achieved. The combined therapy with lithium and metizol did not exhibit any advantages in this respect. The side-effects observed under the lithium therapy are no essential clinical problem.     

Lithium Therapy for Cyclic Neutropenia in Children

2 children with cyclic neutropenia were treated with lithium carbonate. In one patient, fever and stomatitis were ameliorated, but the duration of neutropenia was increased and parotitis occurred. In another patient, aphthous stomatitis disappeared but fever persisted. The duration of neutropenia was prolonged and submaxillaritis and sinusitis occurred. Thus, lithium administration may lead to complications when the duration of neutropenia is prolonged. We recommend discontinuation of the drug, even in the presence of amelioration of symptoms.     

Effect of lithium on stem cell and stromal cell proliferation in vitro

Lithium is recognized as a potent stimulator of hematopoiesis both in vivo and in vitro. Previous work has suggested that this stimulation is mediated as an indirect, humoral effect by the action of lithium upon the stromal cell population. In the present study, the effects of lithium on the stromal population were investigated using a long-term liquid marrow culture model. These findings indicate that exposure of in vitro cultures to lithium results in an increase in the total cellularity and in the number of various hematopoietic progenitor cells residing within the stromal layer. A distinct morphologically recognizable cell has not been identified as the target cell responsible for the indirect stimulation of hematopoiesis by lithium. However, two candidate radioresistant stromal cells believed to be active in the production of humoral mediators of hematopoiesis did proliferate in response to lithium exposure.     

Evidence that Lithium Induces Human Granulocyte Proliferation: Elevated Serum Vitamin B12 Binding Capacity in Vivo and Granulocyte Colony Proliferation in Vitro

S ummary . Concentrations of lithium similar to those present in the blood of patients receiving lithium carbonate therapy for manic-depressive psychosis cause leucocytosis in vivo and proliferation of human granulocyte colonies in vitro. These findings, plus the finding of elevated unsaturated vitamin B₁₂ binding capacity in patients with granulocytosis induced by lithium carbonate, suggests that such therapy produces a true increase in the body granulocyte pool. The possible value of lithium therapy in neutropenic states in man requires exploration.     

Effect of adenine nucleotides on granulopoiesis and lithium-induced granulocytosis in long-term bone marrow cultures

Studies were undertaken to evaluate the role of adenine nucleotides in regulating hematopoiesis using a long-term liquid culture system. In contrast to early investigations using clonogenic stem cell assays, where inhibitory effects were observed, adenosine and adenosine-5'-monophosphate (AMP) were found to stimulate myelopoiesis whereas the dibutyryl derivative of cyclic adenosine-3',5'-monophosphate (dcAMP) had either a modest inhibitory effect or no effect on long-term hematopoiesis. Dose effects for AMP enhancement of hematopoiesis were relatively narrow. When cultures were exposed to a broad range of concentrations (10 mM-10 nM), stimulation was only seen at a molar concentration of 1 X 10(-4) M. Stem cell assays revealed stimulation of multipotent stem cells (CFU-S), as well as committed progenitor cells (CFU-C). Lithium chloride has been shown to cause granulocytosis both in vivo and in vitro. Reductions in intracellular cAMP levels resulting from adenylate cyclase inhibition is a proposed mechanism for this stimulatory effect. However, lithium-induced granulocytosis in long-term cultures could not be blocked by the addition of dcAMP. Measurement of nucleotide levels on spent medium revealed rapid utilization and/or degradation of these reagents. This suggests that failure to abrogate the lithium effect with dcAMP may have been related to the inability to maintain constant intracellular concentrations. The varied observations regarding adenine nucleotide effects on hematopoiesis, as well as the reproducible stimulation by lithium, may be explained by our current appreciation of the complex adenylate cyclase system, which contains both inhibitory and stimulatory subunits for nucleotides and monovalent cations.     

Hyperparathyroidism induced by lithium. A new case

INTRODUCTION: Lithium salts, used for the first time in 1949, had proved to be a highly effective preventive measure in bipolar illness. The first report of lithium-induced hyperparathyroidism was suggested by Garfinkel et al. in 1973. About 40 cases have been reported since, suggesting an enhancement of occurrence of hyperparathyroidism in patients cured by lithium carbonate. We report here a new case discovered by a systematic measurement of calcemia after a surgical intervention for a hip joint prosthesis. EXEGESIS: Unusual metabolic features associated with this case of hyperparathyroidism include low urinary calcium excretion, normal cyclic AMP excretion and lack of calcic nephrolithiasis. The mechanism probably results from lithium linking with the calcium receptor on the parathyroid and then stimulating PTH secretion. In the same way it could enhance the tubular reabsorption of urinary calcium. Lithium withdrawal is often inefficient in clinical and laboratory test abnormalities and surgery is usually required. CONCLUSION: It is very important to recognise this particular secondary effect of lithium therapy because clinical symptoms of hypercalcemia can simulate a worsening of the bipolar illness.     

Efficacy of lithium in rheumatoid arthritis with granulocytopenia (felty's syndrome)

Lithium carbonate was given orally for 6 weeks in varying doses to 10 patients with Felty's syndrome. All patients receiving 900 mg of lithium daily showed statistically significant elevations in granulocyte count during therapy. The effect was usually noted within a week and did not persist when the drug was withdrawn. The percentage increase in mean absolute granulocyte count varied between 138% and 617% of control value in different patients; the lower values were observed in those patients with basal serum lithium concentrations less than 0.5 mEq/liter. It is concluded that a consistent rise in peripheral blood granulocytes was achieved by lithium carbonate in a dosage of 900 mg daily in patients with Felty's syndrome.     

Abnormal GM-CSA generation by lymphocytes in patients with cyclic hematopoiesis

Human cyclic hematopoiesis (CH) is a disease characterized by regular 21-day cyclic fluctuations of blood cell counts due to fluctuations in bone marrow cell production. The regular periodicity of the fluctuations suggests a defect in a regulatory feedback control loop. We examined the production of monocyte-derived recruiting activity (MRA) by monocytes and the response to MRA of lymphocytes from three patients with CH. MRA production was normal or increased in patients' monocytes, but granulocyte-macrophage colony-stimulating activity (GM-CSA) production in response to MRA was decreased in lymphocytes from patients with CH (p = 0.005). These data suggest that the regulatory defect in CH may involve defective lymphocyte generation of GM-CSA, resulting in deficient production of mature neutrophils.     

LITHIUM INHIBITS THE ACTION OF FLUDROCORTISONE ON THE KIDNEY

A patient with autoimmune Addison's disease treated with hydrocortisone and fludrocortisone became mineralocorticoid-deficient whilst taking lithium carbonate for a bipolar illness. During an in-patient metabolic balance study she required 1.0 mg fludrocortisone daily and dietary sodium supplementation to make plasma renin activity and serum potassium normal, and to abolish postural hypotension. We present data to suggest that lithium carbonate inhibits the action of fludrocortisone on the distal renal tubule.     

Effects of lithium carbonate on human calcium metabolism

Serum calcium and immunoreactive parathyroid hormone levels increase within the normal range in 80% of patients during the first four weeks of lithium carbonate administration and may rise above normal in 10% after long-term therapy. Since the lithium ion in vitro makes the parathyroid cell less sensitive to calcium, and since several lithium carbonate-treated patients with parathyroid adenomas have been described, it has been suggested that the lithium ion can stimulate parathyroid growth. The data are inconclusive, however, since the adenomas could be sporadic and there has been no direct proof of increased parathyroid mass or biologic activity. Based on the available studies, we have formulated a reasonable scheme for monitoring calcium metabolism during lithium carbonate treatment. Proper treatment of hypercalcemic lithium carbonate-treated patients remains uncertain, but we have outlined some tentative management guidelines.