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PubMed1986

Effect of ibuprofen on lithium plasma and red blood cell concentrations.

The effect of ibuprofen on steady-state lithium plasma and red blood cell concentrations was studied in 11 normal volunteers. During the seven-day control phase, sustained-release lithium carbonate 450 mg was administered every 12 hours. Lithium plasma and red blood cell concentrations were determined on days 5, 6, and 7. During the treatment phase (days 7-15), ibuprofen 400 mg was administered four times a day concurrently with lithium. Lithium plasma and red blood cell concentrations were obtained on days 14, 15, and 16. Multiple blood samples were obtained over a 12-hour period on days 6 and 15. Urine samples were collected from six subjects. The mean minimum lithium concentration increased 15% when ibuprofen was added. Mean maximum lithium concentration, area under the curve, red blood cell concentrations, and the lithium red blood cell to plasma ratio were significantly higher during the treatment phase. Mean lithium total body and renal clearance values were significantly lower during the treatment with ibuprofen. The administration of ibuprofen can increase steady-state plasma lithium concentrations and decrease lithium clearance.

Adult↗
PubMed1981

Interaction of lithium and disulfiram in hexobarbital hypnosis: possible role of the 5-HT system.

The effects of lithium and disulfiram on the 5-hydroxytryptamine (5-HT) system and hexobarbital (HX)-induced hypnosis were studied. Treatment with lithium significantly prolonged HX hypnosis. Disulfiram, a potent inhibitor of brain aldehyde dehydrogenase, also produced a prolongation of HX hypnosis. A combination of lithium treatment for 3 days with disulfiram synergistically potentiated the HX hypnosis and reduced the brain HX levels on awakening. Furthermore, L-tryptophan loading significantly increased the HX sleeping time and reduced the brain HX level on awakening in lithium-pretreated rats, whereas it had not effect on HX hypnosis in controls rats. L-Tryptophan also potentiated HX hypnosis in disulfiram-treated rats. The combination of L-tryptophan, lithium and disulfiram caused the greatest prolongation of HX hypnosis. However, no synergism between lithium and disulfiram was observed in animals treated with lithium for 5 days. after 3 days of lithium treatment, the rate of synthesis of 5-HT was elevated, whereas it had returned to the control level after 5 days of lithium treatment. Tryptophan loading increased the rate of synthesis of 5-HT more than 2-fold in control animals. The increase in the rate of 5-HT synthesis caused by lithium was further potentiated by tryptophan loading. These results suggest that lithium and disulfiram exert their synergistic effect on HX hypnosis by acting on the 5-HT system and that an accumulation of 5-hydroxyindoleacetaldehyde, an active metabolite of 5-HT, may be responsible for the increase in the brain sensitivity to barbiturates caused by these drugs.

Animals↗
PubMed1995

Pharmacokinetic interactions between lithium and fluoxetine after single and repeated fluoxetine administration in young healthy volunteers.

Pharmacokinetic interactions following coadministration of fluoxetine and lithium were investigated in 10 young healthy subjects. Both drugs were administered orally in a non-blinded design with 3 consecutive treatment periods: single oral dose of lithium (32.4 mmol lithium as acetate, Quilonum; coadministration of single oral doses of lithium (32.4 mmol) and fluoxetine (Fluctin, 60 mg); and single oral dose of lithium after 7-day pretreatment with fluoxetine (20 mg t.i.d.). Periods 1 and 2 were separated by a 1-week washout phase, while period 3 followed on immediately after period 2. Lithium serum concentrations were practically identical in periods 1 and 3 (administration of lithium alone and after chronic fluoxetine dosing). However, in period 2, when the 2 drugs were coadministered as single oral doses, the lithium concentrations were lower in the first 4 hours after medication compared with treatment periods 1 and 3. Cmax was also significantly lower in period 2. The times to peak, however, were not significantly changed by any fluoxetine comedication. The parameters AUC0 --> infinity, t1/2, total clearance (Cltot) and renal clearance (Clren) determined after administration of lithium alone did not differ statistically from values determined after single or after repeated fluoxetine dosing. Coadministration of lithium and fluoxetine did not produce any clinically relevant changes in hemodynamics, ECGs or laboratory parameters. After single doses of both drugs the most frequently reported symptoms were gastrointestinal complaints, while mild sedative symptoms were predominant when lithium was given after repeated fluoxetine medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Association of maternal lithium exposure and premature delivery.

Lithium is widely used and the treatment of choice for patients with manic-depressive illness. For pregnant patients with manic-depressive illness, however, the use of lithium during the first trimester of pregnancy may present an increased risk for fetal maldevelopment. We have recently cared for several large-for-gestational-age, prematurely born infants whose mothers were treated with lithium throughout pregnancy. To determine whether maternal lithium use during pregnancy may predispose to the onset of premature labor and fetal macrosomia, we reviewed records from the International Register of Lithium Babies and from a cohort of manic-depressive pregnant women. More than one third (36%) of infants reported to the International Register were born prematurely, and 37% of the premature infants were large for gestational age; 15% of the term infants were born large for gestational age. In the cohort group, manic-depressive mothers who received lithium during pregnancy had a 2.5-fold higher incidence of premature births than manic-depressive pregnant patients who did not receive lithium treatment. The incidence of large-for-gestational-age births in lithium-treated women in the cohort was not different from that of the general population or from manic-depressive women not treated with lithium. In summary, an association between maternal lithium therapy and premature delivery is reported. We recommend that women receiving lithium therapy during pregnancy be closely monitored for the onset of premature labor.

Adult↗
PubMed1996

Controversies surrounding erythrocyte sodium-lithium countertransport.

BACKGROUND: Interest originally arose in ouabain-insensitive lithium transport across erythrocyte membranes when it was found that lithium could substitute for sodium, either undergoing 1:1 lithium exchange or 1:1 sodium-lithium countertransport in a manner that follows Michaelis-Menten kinetics. Elevation of the sodium-lithium countertransport activity in hypertension was first noted in 1980 and found to be a genetically linked phenomenon. This observation has since been confirmed on several occasions and associations with other diseases such as diabetes have been noted. Nevertheless, many unanswered questions remain about the clinical significance of disturbed sodium-lithium countertransport and its pathological basis. METHODS: Traditional methods for characterizing the sodium-lithium countertransporter have depended on determining differences between lithium fluxes into sodium-rich and sodium-free media. There have been inherent problems in deciding on suitable sodium substitutes. Of the available alternatives, choline has emerged as having advantages over magnesium. Reports in the literature have often failed to take into account varied assay conditions, making comparisons of data from different laboratories difficult. A further complexity has been the realization that sodium-lithium countertransport activity incorporates two key elements in the form of Vmax and k(m). Kinetic studies have shown independent variation in these two parameters with various disease states. RESULTS: Much of the published work to date has continued to rely on measurement of countertransport activity, with magnesium acting as the predominant sodium-substitute. This has occurred despite the undoubted benefits obtained from kinetic analysis. Where kinetics of the sodium-lithium countertransporter have been determined, there have emerged clear associations between Vmax and environmental influences such as plasma lipids with elevated values in dyslipidaemic states including diabetes. The affinity constant, k(m), is more clearly under genetic control and has independent associations with vascular disease. CONCLUSION: Study of the erythrocyte sodium-lithium countertransporter has revealed interesting relationships between altered behaviour of the transporter and specific disease states. Although still somewhat of an enigma, this transporter is emerging as an important membrane constituent whose further study may help us to understand the molecular mechanisms leading to vascular disease.

Animals↗
PubMed1982

Preferential accumulation of lithium in the dense bodies of human platelets.

From 50 to 73% of the lithium contained in platelets of patients receiving oral therapy with lithium carbonate was released by brief thrombin treatment. Similarly, about 50% of the lithium in platelets of normal volunteers incubated with lithium chloride was thrombin-releasable. The data indicate that an amount of lithium approximately equal to 10% of the calcium content was sequestered in the dense bodies (amine storage organelles) of human platelets. Electron microprobe analysis of dense bodies suggests that the addition of lithium did not change the phosphorus content but produced a loss of about 10% of the dense-body calcium. Nevertheless, synthetic solid analogues of the dense-body core incubated with lithium chloride did not sequester lithium preferentially over potassium and failed to exchange calcium for lithium. Thus, the mechanism responsible for the observed changes in platelet dense bodies may be related to selective membrane permeability properties rather than to binding of lithium to nucleotides or pyrophosphate in the dense-body core.

Blood Platelets↗
PubMed1982

Lithium: effects of short-term and chronic treatments in rats on the activity of dopamine-beta-hydroxylase (DBH) in the central versus peripheral nervous system.

The therapeutic usefulness of lithium in mania is now well-established. However, the precise neurochemical mechanisms by which lithium brings about its effects remain poorly understood. This report describes the effects of lithium on the central and peripheral levels of activity of dopamine-beta-hydroxylase (DBH), the enzyme that catalyzes the final step in the biosynthetic pathway to the formation of norepinephrine (NE) from dopamine. Since the neurotransmitter NE has been implicated in the mediation of lithium's action, what effects lithium may have on the activity of DBH was deemed worth investigating. Lithium chloride was administered intraperitoneally in rats on a short-term and chronic basis and the effects on DBH activities in the hypothalamus and serum were evaluated. A significant reduction in DBH activity occurred in the hypothalamus after short-term lithium but there was no change following chronic treatment. In contrast, serum DBH activity remained unchanged after both acute and chronic lithium injection. Since increased noradrenergic activity in the brain has been implicated in the etiology of mania, the lithium-induced decrease in hypothalamic DBH is suggestive of a neurochemical mechanism by which lithium may act in psychotic patients.

Animals↗
PubMed1990

Lithium-selective alteration of the function of brain versus cardiac Gs protein.

Lithium was recently demonstrated to inhibit the coupling of both muscarinic cholinergic receptors and beta-adrenergic receptors to pertussis toxin-sensitive and cholera toxin-sensitive G proteins, respectively, thus suggesting alteration of the function of G protein by lithium, as the single site for both the antimanic and antidepressant effects of this drug. One of the most puzzling aspects of the ability of lithium to ameliorate the manic-depressive condition, is its relatively selective action upon the central nervous system (CNS). In the present study, it was shown that lithium selectively attenuated the function of Gs proteins in the CNS, assessed through isoproterenol-induced increases in the binding of guanosine triphosphate (GTP) to these proteins. Therapeutic concentrations of lithium (1-1.5 mM in vitro) inhibited the function of Gs protein in the cerebral cortex of the rat, while 4- to 6-fold larger concentrations of lithium were required to alter the function of Gs protein equivalently in the cardiac ventricles of the rat. Chronic administration of lithium via rat chow, containing lithium carbonate, to rats totally abolished the effect of isoproterenol on the binding of GTP in the CNS but did not affect the function of peripheral cardiac Gs protein. The lithium-selective action on the function of Gs protein in the CNS may stem from the heterogeneity of the alpha s subunit proteins: in the heart, the major species is a 45 kDa molecule, while in the brain, a 52 kDa molecular weight species predominates. The heterogeneity in alpha s subunits may thus be the biochemical basis for the selective action of lithium on the CNS and for the scarcity of peripheral side effects.

Adenosine Diphosphate Ribose↗
PubMed1980

A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania.

Previous investigations of the treatment of mania have resulted in uncertainty about the efficacy of lithium versus a neuroleptic. In addition there have been reports of toxicity with a haloperidol--lithium combination. In order to determine the comparative efficacy of lithium vs haloperidol vs a combination of haloperidol--lithium, we studied 21 severely ill manic patients who all met rigorous criteria for bipolar illness and who required in hospital treatment. Subjects were randomly assigned to 3 groups: (A) Lithium plus placebo (B) Placebo plus haloperidol and (C) Lithium plus haloperidol. The study was conducted in double blind fashion for 3 weeks with the dosages of the medications varied according to clinical response or untoward effects. Subjects on haloperidol and placebo or the haloperidol--lithium combination were significantly improved after 7 days in comparison to the lithium-treated group. Groups B and C did not differ from each other, either in degree of improvement or in side effects. Inspite of the relatively small sample size the results suggest (1) that haloperidol is superior to lithium for treating severely ill acute mania and (2) that while a haloperidol--lithium combination does not result in a significant increase in side effects, it is not superior to haloperidol alone.

Adult↗
PubMed1987

Lithium and circadian patterns of melatonin in the retina, hypothalamus, pineal and serum.

Lithium, a widely used substance for treatment of manic-depressive illness has been reported to alter the phase relationship of a variety of circadian rhythms which have been implicated in the aetiology of depression and manic-depressive disorder. Although its mechanism of action is not understood, the theraputic action of lithium has been related to its ability to alter circadian rhythms. Chronic lithium administration to rats resulted in lithium levels comparable to the human theraputic range. These lithium levels affected a broad range of biological variables by significantly modifying their circadian pattern of variation, notably during the dark period of an alternating 12h light/12h dark schedule. These included water intake, body weight, retina weight and pineal, serum, retina and hypothalamic melatonin measures. Retinal lithium levels were significantly higher than serum lithium levels and retinal melatonin levels were reduced by lithium. The data are interpreted as suggesting that lithium may exert its theraputic effects by influencing melatonin levels at several locations along the retinal-hypothalamic-pineal pathway, resulting in a modulation of the potential cue value of this physiological stimulus for synchronization of circadian rhythms. Such an effect of lithium could have important chronobiological implications for circadian rhythms which use light and dark as a phase cue.

Animals↗
PubMed1990

Growth and morphological changes induced by lithium chloride treatment of HL-60 cells.

HL-60 cells were grown in culture and their proliferative behaviour and response to lithium were studied. Treatment of cells with lithium concentrations of up to 5 mM enhanced cell proliferation, however above 5 mM lithium, cell growth was inhibited. Cell viability remained above 90% with concentrations of lithium below 10 mM. With increasing concentrations of lithium cell death increased rapidly to about 70% after 3 days at 50 mM. DNA synthesis was also strongly inhibited by concentrations of lithium above 5 mM. At 50 mM lithium, [3H]-thymidine incorporation was 1%. Electron microscopy seems to indicate that the plasma membrane is the main target for lithium cytotoxicity, whilst lithium uptake studies suggest that cytotoxicity might be related to the accumulation of lithium within the cells.

Cell Division↗
PubMed1995

Effects of long-term lithium infusion on normal parathyroid tissue.

BACKGROUND: Approximately 10% of patients taking lithium for manic-depressive disorders become hypercalcemic. It remains unclear whether lithium initiates disease or promotes underlying hyperparathyroidism. We have previously demonstrated that at therapeutic concentrations lithium stimulates in vitro incorporation of both tritiated thymidine and bromodeoxyuridine into abnormal human parathyroid tissue, reflecting growth-promoting properties. Whether lithium has similar growth-promoting properties in normal parathyroid tissue remains unresolved. METHODS: We infused lithium (0 mmol/L, 3 mmol/L, or 10 mmol/L) through implantable subcutaneous pumps into normal rats for 3 months and measured levels of serum lithium, serum calcium, and serum parathyroid hormone (PTH) (with a radioimmunoassay specific for rat PTH 1-34.) On completion of the infusion, bromodeoxyuridine (30 mg/kg) was administered intraperitoneally. The parathyroid glands were removed and measured in two dimensions to calculate gland volume [V = (pi/6) x (d1) x (d2)2.] Parathyroid incorporation of bromodeoxyuridine was assessed by using immunocytochemistry. RESULTS: Serum lithium level was significantly (p < 0.05) different between groups and constant within groups. Levels of serum calcium and PTH were inversely related to each other; however, no significant differences were noted between groups with respect to level of serum calcium or serum PTH at any measurement. Similarly, no significant differences were noted between groups with respect to gland size or number of bromodeoxyuridine-positive cells. CONCLUSIONS: Long-term lithium infusion in rats for a period representing approximately 15% of their life span failed to evoke changes in parathyroid gland size or function. These data are consistent with (1) lithium as a promoter of hyperparathyroidism and (2) resection of abnormal parathyroid tissue and resumption of lithium for patients requiring long-term therapy.

Animals↗
PubMed1982

Lithium treatment: does the kidney prefer one daily dose instead of two?

Renal structure and function were investigated in two groups of long-term lithium treated patients. Lithium was administered in two different ways either in a one-dose per day schedule where the whole dose of lithium was given between 8 and 10 p.m. or in a schedule where the lithium dose was given, divided into two or three doses, during the day. Kidney biopsy was performed, and structural changes in the kidney tissue were determined together with 24-h urine volume in the individual patients. The functional as well as the structural changes were most pronounced in patients given their lithium in divided doses during the day. Lithium may be more harmful to the kidney when the lithium administration gives a relatively constant serum lithium level than when the administration causes greater variations including peak values and low minimum levels in serum lithium. The reason for this might be that a number of regenerative processes only occur in periods with low lithium concentrations.

Adult↗
PubMed1982

Lithium effects on calcium, magnesium and phosphate in man: effects on balance, bone mineral content, faecal and urinary excretion.

Calcium, magnesium and phosphate metabolism was studied in lithium-treated patients, using a metabolic balance technique. Two groups of patients participated in the study: 1) Patients who were to start on a prophylactic lithium treatment, and 2) Long-term lithium-treated patients whose treatment was to be terminated. Lithium treatment produced a positive balance in both calcium, phosphate and magnesium. By continuous lithium treatment the effect on magnesium wore off, whereas the effect on calcium and phosphate persisted. In urine, lithium induced a decrease in both calcium and phosphate excretion, whereas the excretion of magnesium was increased. Bone mineral content was measured by photon absorption, and lithium treatment resulted in a decrease in bone mineral content occurring within the first 6 months of lithium treatment. In the patients, bioavailability of the Li2CO3 preparation was found to be about 95%, and the patients contained about one 24-h dose of lithium just before the next dose of lithium was administered.

Biological Availability↗
PubMed1984

Glomerular filtration rate and PCO2 as determinants of lithium reabsorption.

To examine whether lithium reabsorption varies in proportion to the bicarbonate-dependent reabsorption of water and chloride, reabsorption was altered by varying PCO2 and glomerular filtration rate (GFR) in volume-expanded, anesthetized dogs during ethacrynic acid infusion. At constant GFR and plasma bicarbonate concentration, lithium, bicarbonate, chloride and water reabsorption were inversely related to plasma pH during variations in PCO2. Lithium and bicarbonate reabsorption varied by 9 +/- 1% and chloride reabsorption by 7 +/- 1% as plasma pH was altered by 0.1 unit from plasma pH 7.5. Calculation of reabsorbate concentrations indicated that lithium was reabsorbed as readily as water (reflection coefficient = 0). During mechanical constriction of the suprarenal aorta, GFR was reduced at constant plasma pH. Bicarbonate reabsorption fell more than chloride, water and lithium reabsorption. Lithium reabsorption was not significantly reduced until GFR was reduced by 35%. In stop-flow studies during ouabain infusion, urinary lithium concentrations were reduced below plasma concentrations. This is compatible with passive diffusion of lithium along a lumen-positive potential exceeding 10 mV in the diluting segment. Thus, lithium reabsorption behaved as expected for bicarbonate-dependent paracellular reabsorption during variations in PCO2; when GFR is reduced, an additional component of lithium reabsorption is disclosed.

Absorption↗
PubMed1982

Lithium pharmacokinetics, duration of therapy, and the adenylate cyclase system.

The elimination half-life of lithium carbonate in red blood cells, plasma, and urine was measured in 30 patients hospitalized for primary affective disorders. The duration of lithium treatment at the time of sampling was found to have a direct effect on lengthening time-course. Those on their initial course of lithium had the lowest half-lives (in days): 1.12 (urine), 1.28 (plasma), and 1.22 (red blood cells); those with less than 1 year of lithium had intermediate values: 1.85, 1.65, and 1.75, and those with more than 1 year of continuous lithium administration had the highest mean half-lives: 2.40, 2.43, and 2.24. The significance of these results for urine (p less than 0.01) and plasma (p less than 0.05) indicates further evidence that lithium may stimulate the production of an endogenous regulator of lithium efflux. 8 of these patients had lumbar punctures before lithium administration: those with previous treatment with lithium had higher mean cyclic adenosine monophosphate levels than those taking it for the first time. These results are discussed in the context of the possible mechanisms of lithium action.

Adenylyl Cyclases↗
PubMed1984

Lithium chloride: protective and antisecretory properties in rats.

Lithium chloride was evaluated as a potential protective agent against ethanol-induced hemorrhagic gastritis in rats. Rats received lithium chloride intragastrically (30, 60, or 90 mg/kg i.g.) or subcutaneously (3, 5, 10, 15, 20, 30, 60, or 90 mg/kg s.c.), or a placebo (H2O i.g. or 0.9% NaCl s.c.). Ninety minutes later 1 cm3 of 95% ethanol was administered intragastrically. After 30 min, the rats were killed and their stomachs were removed and visually scored for gross hemorrhagic gastritis. Lithium chloride at all doses less than 3 mg/kg significantly improved hemorrhagic gastritis when compared with the placebo. Moreover, rats treated with lithium chloride intragastrically had significantly less hemorrhagic gastritis than those treated subcutaneously even though serum lithium levels were similar. To determine if lithium's protective properties related to acid inhibition, pylorus-ligated and gastric fistula rats were studied. The median effective dose for lithium chloride was 20-30 mg/kg and the nonantisecretory dose was 3 mg/kg. No difference in hemorrhagic gastritis was noted between controls and animals receiving the nonantisecretory dose. However, at higher doses (LiCl 30, 60, and 90 mg/kg), lithium's protective properties persisted in spite of adding 150 mM HCl to the intragastrically administered ethanol (p less than 0.001). To determine further if lithium chloride stimulated endogenous prostaglandins, indomethacin, a prostaglandin inhibitor, was administered. Indomethacin did not alter lithium chloride's protective properties. In fact, when compared with exogenously administered 16,16-dimethyl prostaglandin E2 (5 and 500 micrograms/kg), high-dose LiCl (30, 60, or 90 mg/kg) resulted in significantly more protection against ethanol-induced injury (p less than 0.001). In contrast, when both nonantisecretory doses were compared, 16,16-dimethyl prostaglandin E2 (5 micrograms/kg) gave significantly better protection than LiCl (3 mg/kg). These data indicate that LiCl is a potent gastric antisecretory and protective agent. The protective properties of LiCl appear to be related to acid inhibition and be independent of endogenous prostaglandins, although other protective mechanisms may be present at higher LiCl doses. Additionally, this study indicates that LiCl may have clinical application in protecting the gastric mucosa against hemorrhagic gastritis.

Animals↗
PubMed1983

Lithium ion transport and affective disorders within families of bipolar patients. Identification of a major gene locus.

We have identified a genetic polymorphism in which one allele results in elevated RBC lithium ion ratios and also contributes to vulnerability to some forms of affective disorders. Interindividual variability in the lithium ion ratio (the ratio of the RBC to the plasma lithium ion concentration) is determined by variability in a lithium ion ratio (the ratio of the RBC to the plasma lithium ion concentration) is determined by variability in a lithium-sodium ion counterflow mechanism. Segregation analyses were conducted on lithium ion ratios in vitro in members of 120 normal families and on both the lithium ion ratio and the history of affective disorder in first-degree relatives of 31 bipolar patients. These analyses provided evidence for an autosomal major gene locus that influences the lithium ion ratio both in members of normal families and in relatives of bipolar patients. The allele at the major locus resulting in elevated lithium ion ratios was associated with an increased likelihood of psychiatric hospitalization among relatives of bipolar patients.

Alleles↗