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Lithium side effects in relation to dose and to levels and gradients of lithium in plasma.

The relation between lithium dose, lithium concentrations, and lithium gradients in plasma and the side effects tremor, nausea, abdominal pains, and loose bowels was studied in 19 subjects. Rapidly dissolving lithium carbonate tablets were used. Tremor was related to higher doses, to higher concentrations, and to higher gradients of lithium in plasma. Nausea was related to higher gradients. Abdominal pain and loose bowels showed no relation to doses, levels or gradients. Concentrations of lithium were dose-dependent, while gradients were relatively independent of dose.

Abdomen↗

Lithium effects: relation to lithium dose and to plasma peak levels.

In a 24-hour study, plasma peak lithium was determined in manic-melancholic patients who routinely had their entire lithium dose at night. A correlation analysis was undertaken of the relation of plasma peak level and the dose of lithium to a number of lithium induced changes: Increase in urine volume, weight gain, decrease in plasm phosphate, increase in plasma magnesium, decrease in plasma urea, increase in plasma alkaline phosphatase, increase in urinary pH. Only the changes in plasma phosphate and in urine pH were significantly correlated to the peak value of plasma lithium. The increase in urine volume was significantly correlated to the dose of lithium.

Adult↗

Mortality during initial and during later lithium treatment. A collaborative study by the International Group for the Study of Lithium-treated Patients.

We have previously shown that the mortality of patients with recurrent affective disorders in long-term lithium treatment is not higher than that of the general population. In the present study on 471 patients from Denmark and Germany, we examined mortality during the initial year of lithium treatment and during later lithium treatment. During initial lithium treatment, the total mortality was twice as high as in the general population (difference not significant) and the mortality due to suicide 16 times higher. During later lithium treatment, the mortality rates did not differ from those in the general population. Our results indicate that patients with frequent, often severe recurrences, those chosen for prophylactic lithium treatment, are at risk of high mortality, which then diminishes as the prophylactic action of the treatment takes effect.

Adult↗

Lithium neurotoxicity. I. The concentration of lithium in dopaminergic systems of rat brain determined by flameless atomic absorption spectrophotometry.

Severe neurotoxicity has been reported in patients receiving combinations of lithium and butyrophenones and halogenated phenothiazines and the suggestion has been made that lithium is preferentially concentrated in dopamine systems in brain. Conventional flame atomic absorption spectrophotometry does not allow analysis of sufficiently small samples of brain tissue to allow accurate association with specific transmitter systems, although previous reports have suggested that lithium is concentrated in the striatum. A method has been developed using flameless atomic absorption spectrophotometry to allow accurate measurement of lithium concentrations in 10--100 ng fresh weight of brain tissue. Using this technique in experiments where rats were fed lithium over a period of three weeks, we could not confirm a direct association of lithium with an area predominetly served by dopamine transmitters.

Animals↗

Clearance of endogenous lithium in humans: altered dietary salt intake and comparison with exogenous lithium clearance.

We compared endogenous with exogenous lithium clearance (CLi) and studied the effects of dietary salt intake on endogenous CLi in healthy volunteers. Lithium was detectable within a narrow fourfold range in serum and in urine in all 25 subjects studied [serum (n = 25), mean 0.27 +/- 0.02 mumol/l, range 0.13-0.55 mumol/l; urine (n = 20), range 1.49-7.32, mean 4.09 +/- 0.36 mumol/24 h]. Mean clearance and fractional excretion of endogenous lithium were lower (15.2 +/- 2.0 ml/min and 16.4 +/- 2.1%, respectively) compared with results obtained using the exogenous CLi technique (25.5 +/- 1.7 ml/min and 27.9 +/- 2.1%; P < 0.01 and P < 0.05, respectively; n = 17). In a separate group of six normal subjects, absolute (8.7 +/- 2.9 vs. 20.7 +/- 3.8 ml/min) and fractional excretion of lithium (8.3 +/- 2.9 vs. 18.0 +/- 5.1%) were significantly lower on 5 days of low (31 +/- 10 mmol/day) vs. high sodium intake (357 +/- 78 mmol/day; P < 0.05). Use of endogenous CLi precludes the need for lithium tablets. This could be a particular advantage in population studies and permits serial measurement of CLi on different days. Our results show that it is important to take dietary sodium intake into account in studies of endogenous CLi. Lower values for endogenous compared with exogenous CLi could reflect differences in renal handling depending on the plasma lithium concentration. This clearly requires further study.

Diet, Sodium-Restricted↗

Correlation between distal nephron enzyme activity, structure and function in rats during lithium and lithium plus neuroleptic treatment.

The histochemical activities of nonspecific acid and alkaline phosphatases, NADH- and NADPH-tetrazolium reductases, alpha-glycerophosphate dehydrogenase, succinate dehydrogenase, isocitrate dehydrogenase, lactate dehydrogenase and glucose-6-phosphate dehydrogenase were investigated in kidneys from rats treated with lithium and lithium plus neuroleptics. During the first 8 weeks of lithium treatment the activity of NADH-tetrazolium reductase, succinate dehydrogenase and alpha-glycerophosphate dehydrogenase activity in the collecting ducts increased. The other enzymes did not change. After 8 weeks of treatment no further changes in enzyme activity occurred. Withdrawal of lithium caused normalization of enzyme activity after 8 weeks. A decrease in concentration ability was found in parallel with the increase in enzyme activities (p less than 0.001). The changes in enzyme activity were not significantly correlated to morphological changes in the collecting ducts. Treatment with neuroleptics alone caused no change in enzyme activity. During combined lithium plus neuroleptic treatment the enzyme activities changed in a similar way as during lithium therapy, but the changes were less pronounced. In parallel, a less pronounced decrease in concentration ability was found during this treatment.

Animals↗

Problems of lithium prophylaxis: efficacy, serum lithium, selection of patients.

For safe and effective lithium prophylaxis the following points should be given attention: (1) selection of patients, (2) treatment management, (3) treatment monitoring, and (4) information and instruction. Indications for lithium treatment depend not only on diagnosis but also on factors predicting the extent to which the patient would be at risk of relapse without lithium. The criteria used for prophylactic trials seem too narrow, since they exclude patients who might benefit from the treatment. Treatment management involves gradual adjustment of doses and 12-hour serum lithium levels to values that for the individual patient give a maximum of prophylactic protection and a minimum of side effects. In some patients serum lithium may with advantage be maintained around 0.6-0.8 mmol/l instead of the usually recommended 0.8.-1.1 mmol/l. Patients, relatives and health personnel should be carefully instructed about the aims, the management, and the risks of lithium treatment.

Bipolar Disorder↗

Lithium effects on normal subjects. Relationships to plasma and RBC lithium levels.

15 normal subjects took lithium carbonate for 10 days in dosage sufficient to attain plasma lithium concentrations in the range of 0.7-1.4 mEg/l. Periodic blood specimens were analyzed for both plasma and RBC lithium. Subjects completed Profile of Mood States questionnaires every other day, and listed side effects. Just prior to beginning and ending the lithium trial, 10 subjects completed three tests of psychomotor function. Results indicate that such a course of lithium in normals induces dysphoric mood change and psychomotor slowing, without significant relationship to either plasma or RBC lithium concentrations.

Choice Behavior↗

Lithium-induced delirium with therapeutic serum lithium levels: a case report.

Lithium-induced delirium occurring in geriatric patients with serum lithium levels that are within the "therapeutic" range (less than 1.5 mEq/L) has been described in the literature. We present a case that illustrates three major issues regarding this syndrome: (1) differentiating lithium-induced delirium from a recurrence of a chronic psychiatric disorder; (2) the use of the electroencephalogram in supporting this diagnosis; and (3) factors that may increase a patient's vulnerability to delirium while on lithium. A brief review of the most relevant literature is then presented. We conclude that lithium-induced neurotoxicity should be suspected in any patient receiving lithium who develops delirium, regardless of the serum level, and that immediate discontinuation of the medication be considered.

Delirium↗

Inter-organ relation between salivary gland and kidney in lithium excretion. I. Effects of continuous stimulation of salivation on salivary, renal and systemic clearances of lithium in dog.

The effects of continuous stimulation of salivation on salivary, renal and systemic clearances of lithium were investigated following bolus intravenous administration of lithium chloride (0.145 meq/kg) in three beagle dogs. The salivation was frequently stimulated with citric acid solution, then parotid saliva and mandibular-sublingual saliva were collected separately by means of permanent fistulae. Although the continuous stimulation of salivation markedly increased the salivary clearance of lithium, no significant change was observed in plasma concentrations or systemic clearance of lithium. This was because the decrement in the renal clearance of lithium canceled out the effect of increased salivary clearance. It is suggested that the reabsorption of lithium in the renal tubule was enhanced under the continuous stimulation of salivation, and this seemed to be caused by loss of water or sodium through the salivary glands.

Animals↗

The relationship of lithium-potassium cotransport and the passive lithium leak to hypertension in Utah subjects.

Rate constants for lithium-potassium cotransport (kLPC) and the lithium efflux into MgCl2 with furosemide (passive lithium leak) along with sodium-lithium countertransport (SLC) were measured in erythrocytes from 351 normotensive adults age 18 and over, 220 youth under age 18 and in 27 hypertensives. The kLPC was significantly higher in the hypertensives than the adult normotensives with means and standard deviations of 13.9 +/- 9.2 vs. 8.7 +/- 5.9 10(-3)/hr (p less than 0.01). Adjusting for the significant weight (p = 0.014) and sex (p = 0.066, normotensive males higher than females) associations with kLPC in an analysis of covariance, increased the significant difference between the hypertensives and normotensives (p = 0.0004). The passive lithium leak rate constant was also higher in hypertensives than normotensives (20.2 +/- 7.6 vs. 15.5 +/- 5.3 10(-3)/hr, p less than 0.01). Weight (p=0.0003), but not sex, was related to the leak but did not account for the difference between hypertensives and normotensives (p = 0.0009). Mean blood pressure was positively associated with the lithium leak but not the kLPC or SLC values in a multivariate regression.

Adolescent↗

[Delirium syndrome as a side-effect of lithium in normal lithium levels].

Lithium is used with great success in the treatment of manic patients and for prophylaxis of bipolar disorders. There are only few reports about neuropsychiatric side effects at therapeutic serum levels. We report on a 38 year old woman with bipolar disorder who was treated with lithium for 20 years without side-effects. Subsequent to a manic episode, she became disoriented at night and showed marked memory deficits. The patient did not show any neurological or gastrointestinal signs of intoxication. Lithium serum-levels were in therapeutic range. The psychiatric symptoms disappeared when lithium was stopped. We interpret these symptoms as delirant syndrome with pseudo-dementia at therapeutic lithium serum levels. This side-effect must be taken into account even in patients on successful longtime lithium therapy.

Adult↗

Lithium and hematopoiesis: effective experimental use of lithium as an agent to improve bone marrow transplantation.

Bone marrow transplantation (BMT) has become a widely used procedure in the treatment of numerous hematological and non-hematological clinical disorders. The preparative regimen used for marrow recipients is not without risk as the immunodeficient recipient is susceptible to life-threatening infections due to the inability of the marrow to engraft properly. The monovalent cation lithium has been demonstrated to influence regenerating hematopoiesis following the use of several agents known to suppress hematopoiesis. The following report summarizes our studies which have been designed to determine the rate of hematopoietic reconstitution in lethally irradiated mice that were transplanted with bone marrow cells, harvested from either syngeneic or allogeneic donor animals, treated with lithium or phosphate buffered saline (PBS). Transplanted recipients receiving marrow cells from lithium treated donors were evaluated for their survival, peripheral blood indices and several classes of hematopoietic progenitors (granulocyte, erythroid, and megakaryocyte). Transplanted animals that received marrow cells from either syngeneic or allogeneic donors treated with lithium demonstrated greater survival, increased recovery of peripheral indices and hematopoietic progenitors compared to PBS-treated controls. These results indicate that the use of lithium to treat the donor may be an effective procedure to enhance hematopoietic recovery and engraftment in the transplanted recipient. Because of its wide-ranging effects, the use of lithium as a single agent, may be more efficacious than administering several hematopoietic growth factors in order to achieve a similar response.

Animals↗

Dissimilar effects of lithium and carbamazepine on erythrocyte lithium transport in vivo: clinical implications.

The effect of lithium (Li) and carbamazepine (CBZ) on erythrocyte lithium transport in vivo was investigated in 28 patients with affective or schizoaffective illness (14 given Li and 14 given CBZ). In 12 of them, Li or CBZ were added to current psychotropic treatment. The activities of erythrocyte lithium-sodium countertransport (LSC), lithium-potassium cotransport (LPC) and passive lithium diffusion (PLD) were assayed before and after 28 days of treatment. The administration of Li caused a significant decrease of LPC as well as PLD activity. The administration of CBZ resulted in a significant increase of the activity of LPC system. No systematic relationship was observed between Li or CBZ-induced alterations in erythrocyte transport and changes in clinical state of patients. The possible clinical implications of the dissimilar effect of Li and CBZ on erythrocyte lithium transport are discussed.

Adult↗

Saliva lithium levels for monitoring lithium prophylaxis of manic depressive psychosis.

The usefulness of salivary lithium values for monitoring long-term lithium prophylaxis was studied in 60 patients on lithium therapy. A total of 99 pairs of saliva and serum samples were obtained, and the correlation between serum and salivary lithium levels (r = 0.73) was found to be significant at the 1% level. The ratio of salivary serum levels to that of serum was found to range from 1.77 to 6.68. The ratio of 51% of the samples was between 3 and 3.99. It is therefore suggested that it is important to identify the subgroup of patients who show better correlation of salivary and serum lithium levels and use each individual's ratio to monitor only his lithium therapy.

Bipolar Disorder↗

[Lithium distribution in organs after lithium poisoning].

This paper describes the lithium distribution in the organs of two manic-depressive women who died following lithium intoxication. In both cases intoxication was observed during and after an acute phase of epidemic influenza accompanied by diarrhoea. The patients died from cerebral failure 5 and 7 days after receiving their last lithium dose. Death could not be prevented although NaCl infusions and haemodialyses were carried out. Only slight differences in lithium content were found when comparing extracerebral organs and serum. However, the brain accumulated considerable amounts of lithium ion. This reached toxic concentration in most of the brain areas of both patients. The highest values were found in the white matter, pointing to a lithium accumulation in lipid-enriched brain cells. The results were interpreted in connection with earlier findings of our group and other authors.

Brain↗

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).

Lithium is an agent capable of influencing many aspects of blood cell production, in particular, the formation of granulocytes. Because of this property, lithium has been demonstrated to be an effective agent whenever granulocyte production is either faulty or inadequate. The anti-viral drug zidovudine (AZT) has used been extensively in the treatment of acquired immune deficiency syndrome (AIDS). However, its effectiveness is limited because of the myelosuppression and bone marrow toxicity associated with its use. We have previously demonstrated that lithium, when combined with AZT in vitro with normal bone marrow cells or when administered in vivo to mice receiving dose-escalation AZT, reduced the myelosuppression and marrow toxicity of AZT significantly. We report here further studies designed to evaluate the extent of lithium's capacity to modulate AZT toxicity by investigating the ability of lithium to influence blood cell production when administered to normal mice during an initial exposure to AZT. C57BL6 were administered dose-escalation AZT (1.0 mg/ml and 2.5 mg/ml) for a period of 4-weeks in the presence or absence of lithium carbonate (1 mM). This was followed by an additional 4-week period during which mice received only AZT. Animals were analyzed on a weekly basis for their peripheral blood indices. Animals receiving dose-escalation AZT demonstrated anemia, thrombocytopenia, and neutropenia which was dose-related. During the period when animals received combination lithium/AZT, there was significantly less anemia, thrombocytopenia, and neutropenia as compared to the AZT controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Comparing oral lithium carbonate and intraperitoneal lithium chloride chronic administrations on rats' activity levels.

This study compares the effects produced by two modalities of lithium administration on rats' activity levels. Lithium was administered for 21 days either as carbonate in the diet (2 g in 2 liters of water and 1,500 g lab chow) or as chloride through single daily intraperitoneal injections (1 mEq/kg LiCl). Both treatments resulted in similar decreases in spontaneous activity and exploratory behavior, as recorded in an open field with a hole-board. Neither treatment influenced the amount of food consumed on a daily basis nor the rate of growth as manifested by weight gains over the period considered, suggesting that these treatments were not adversely affecting the animals' health. Both treatments increased water intake over control levels, this effect being most marked with the diet lithium carbonate administration, particularly during the second week of treatment. This latter modality of lithium administration, but not the injections of lithium chloride, significantly increased NaCl intake over control levels.

Administration, Oral↗