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PubMed1995

Ramipril-induced decrease in renal lithium excretion in the rat.

1. The interaction of ramipril, an inhibitor of angiotensin I converting enzyme, with renal lithium handling was analysed in conscious normotensive Wistar rats and compared with the known increase in renal tubular lithium reabsorption induced by the non-steroidal anti-inflammatory drug, indomethacin. 2. The rats were treated for five days with ramipril (1 mg kg-1 day-1 orally), indomethacin (2.5 mg kg-1 day-1 intramuscularly) or their solvents. Lithium chloride (16.7 mg kg-1 intraperitonealy) was given as a single dose on the fifth day and renal functions were measured. 3. Ramipril induced a decrease in renal lithium clearance which was correlated with the decrease in the quantity of filtered lithium and the increase in the tubular fractional reabsorption of the metal. Ramipril also reduced the systolic blood pressure of the rats by about 15 mmHg. 4. In the absence of any effect on creatinine clearance or systolic blood pressure, indomethacin increased renal fractional lithium reabsorption and led to an increase in plasma lithium levels, as previously reported by our group. 5. In conclusions, our results indicate that ramipril decreases renal lithium excretion in Wistar rats, when given orally at a dose of 1 mg kg-1 day-1 over five days.

Angiotensin I↗

PubMed2005

Lithium-induced reduction in urinary concentrating ability and urinary aquaporin 2 (AQP2) excretion in healthy volunteers.

BACKGROUND: Lithium therapy is associated with the development of nephrogenic diabetes inspidus. Experimentally, lithium inhibits arginine vasopressin (AVP)-stimulated translocation of cytoplasmic aquaporin 2 (AQP2) to the apical membrane. Clinically, the actions of lithium on renal tubular function are less clearly established. This study examined the effects of four weeks of lithium therapy on desmopressin (dDAVP)-stimulated urinary concentrating ability in healthy volunteers. METHODS: Eleven healthy volunteers underwent baseline urinary concentrating ability studies which were repeated following 4 weeks therapy with lithium carbonate (250 mg twice a day). Urinary osmolality, urinary AQP2 and cyclic adenosine monophosphate (cAMP) levels were measured following overnight fluid deprivation and after the administration of 40 microg of dDAVP. Baseline values were compared with results after 4 weeks of lithium therapy. RESULTS: Four weeks of lithium therapy reduced dDAVP-stimulated urinary concentrating ability (996 +/- 27 to 945 +/- 26 mOsm/kg) (P < 0.05) and this was associated with significant reduction in urinary AQP2 excretion (99.2 +/- 10.0 to 77.8 +/- 7.4 fmol/micromol creatinine) (P < 0.05) and urinary cAMP excretion (3188 +/- 376 to 2212 +/- 378 units) (P < 0.01). CONCLUSION: Four weeks of lithium therapy in healthy volunteers produced a small but significant reduction in dDAVP-stimulated urinary concentrating ability, which appears to be mediated by the inhibition of AVP-stimulated translocation of cytoplasmic AQP2 to the collecting tubule apical membrane via inhibition of adenyl cyclase.

Adenylyl Cyclase Inhibitors↗

PubMed2004

Drug-induced lithium toxicity in the elderly: a population-based study.

OBJECTIVES: To study the association between hospital admission for lithium toxicity and the use of diuretics, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal antiinflammatory drugs (NSAIDs) in the elderly. DESIGN: Population-based nested case-control study. SETTING: Ontario, Canada. PARTICIPANTS: Ontario residents aged 66 and older treated with lithium. MEASUREMENTS: Estimated relative risk of hospital admission for lithium toxicity. RESULTS: From January 1992 to December 2001, 10,615 elderly patients continuously receiving lithium were identified, of whom 413 (3.9%) were admitted to the hospital at least once for lithium toxicity. After adjustment for potential confounders, a dramatically increased risk of lithium toxicity was seen within a month of initiating treatment with a loop diuretic (relative risk (RR)=5.5, 95% confidence interval (CI)=1.9-16.1) or an ACE inhibitor (RR=7.6, 95% CI=2.6-22.0). Conversely, neither thiazide diuretics nor NSAIDs were independently associated with a significantly increased risk of hospitalization for lithium toxicity. CONCLUSION: The use of loop diuretics or ACE inhibitors significantly increases the risk of hospitalization for lithium toxicity, particularly in naïve recipients.

Aged↗

PubMed1981

Flupenthixol decanoate in recurrent manic-depressive illness. A comparison with lithium.

The hypothesis that flupenthixol decanoate may serve as an alternative to prophylactically administered lithium in recurrent manic-depressive illness, bipolar and unipolar type, was tested in two groups of patients. In Group I the patients were allocated randomly to maintenance treatment with either lithium or flupenthixol decanoate. The patients in Group II had previously been given lithium and were switched to flupenthixol decanoate because of unsatisfactory prophylactic effect of lithium, doubtful tablet compliance, troublesome side effects, or fear of later harmful effects. The flupenthixol decanoate dosage was 20 mg every 2-3 weeks. The study was not blind. In Group I neither lithium treatment (14 patients) nor treatment with flupenthixol decanoate (19 patients) led to a significant fall of mean episode frequency or mean per cent time ill. The reasons for this lack of response are not clear, but prognostically negative selection of the patients presumably took place before and possibly also during the hospitalization. Since absent effects cannot be compared, this part of the trial remains inconclusive. In Group II (93 patients) treatment with flupenthixol decanoate was associated with significant falls of the frequency of manic episodes and per cent time ill in mania and with significant rises of the frequency of depressive episodes and per cent time ill in depression. Increase of depressive morbidity was seen only in patients who had been given lithium during the pre-trial period and was presumably a result of the discontinuation of lithium. It is not known whether flupenthixol decanoate is of value in the prophylactic treatment of recurrent manic-depressive illness, but the drug may be worth trying in patients whose disease is dominated more by manic than by depressive recurrences and who do not respond to lithium or do not tolerate it or do not take it.

Bipolar Disorder↗

PubMed1984

RBC-choline: changes by lithium and relation to prophylactic response.

Red blood cell (RBC)- and plasma-choline levels were measured in patients on lithium (n = 96), antidepressants (n = 32) and neuroleptics (n = 51), and in 25 healthy drug-free controls. Lithium patients exhibited highly increased RBC- and slightly increased plasma-choline levels compared with controls (P less than 0.001 and P less than 0.05, respectively); the choline ratio (RBC-/plasma-choline) was elevated almost to the same extent as RBC-choline (P less than 0.001). With antidepressants RBC-choline and choline ratios were slightly reduced (P less than 0.05), whereas neuroleptics showed no effect on choline levels. 79% of lithium patients were responders (reduction in hospitalizations with lithium), 21% were non-responders (no reduction or increase in hospitalizations). Choline ratio exhibited a significant relation to prophylactic lithium response, but lithium ratio did not. The percentage of non-responders was significantly higher in patients with a choline ratio exceeding 100 than in patients with a choline ratio below this cut-off (P less than 0.01). Thus, the increase of RBC-choline and choline ratios appears to be an effect specific for lithium and might be related to the outcome of lithium prophylaxis.

Age Factors↗

PubMed1989

Lithium-induced changes in the body mass index.

A total of 117 manic-depressives who had been on lithium for a mean duration of 4.7 years were examined before lithium therapy and subsequently at intervals. Information relating to pre-lithium height and weight and current weight were determined and used to calculate the body mass index (BMI) for each individual. Other relevant variables such as age, sex, cumulative lithium dose, duration of therapy, thyroid profile and serum lithium levels were recorded. The results indicated that, although there was a nonsignificant increase in BMI for the whole population, lithium and sex were not significant predictors of any increase in BMI. In nearly 27% of patients BMI actually slightly decreased during lithium therapy. The overall conclusions from this study are that, in the population studied, lithium may not have exerted any pharmacological effects to increase BMI.

Adult↗

PubMed1992

Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder.

A 12-month double-blind trial of carbamazepine vs lithium, given as sole treatment for the prophylaxis of bipolar affective disorder, was carried out in 31 patients. All were previously stable on lithium; 15 were switched over to carbamazepine and 16 remained on lithium. Although the overall relapse rate was similar in the 2 groups (6 on carbamazepine, 8 on lithium), nearly all the relapses in carbamazepine occurred in the first month, probably precipitated by lithium withdrawal. Two patients on carbamazepine developed a rash and were withdrawn. More side effects were noted during the early stages on carbamazepine. Patients on lithium tended to gain weight (+4 kg) compared with carbamazepine (-3.1 kg). It is concluded that carbamazepine is as effective as lithium in the prophylaxis of bipolar affective disorder; changeover from lithium to carbamazepine should be done slowly.

Adult↗

PubMed1993

Effect of lithium dosing schedule on urinary output.

Lithium has been reported to induce polyuria in up to 35% of patients receiving it. It has been suggested that polyuria may be reduced by using single rather than multiple daily dosing. However, this information is based on non-randomized studies, which used higher serum lithium levels than are currently used. In fact, the incidence of polyuria may be lower at currently used lithium levels, and the benefits of a single daily dose regimen on urine volume at these levels have not been assessed. We conducted a prospective randomized study to test the hypothesis that switching patients from multiple daily dose lithium to single daily dose lithium would significantly lower urine volume. Twenty-four patients previously stabilized on multiple daily dosing were randomly allocated to either single or multiple daily dose lithium. Twenty-four-hour urine volume, serum creatinine, creatinine clearance and serum lithium were measured at study entry and completion. Switching to single daily dose lithium did not significantly reduce the 24-h urine volume.

Adolescent↗

PubMed1979

Influence of lithium on cyclic AMP accumulation in isolated rat fat cells.

Lithium inhibits in vitro as well as in vivo several hormone-stimulated adenylate cyclases. The aim of this study was to investigate the mechanism by which lithium inhibits adenylate cyclase in vitro. It was found that lithium inhibited both the norepinephrine- and the glucagon-induced cAMP accumulation in rat fat cells at lithium concentrations above 10 mM. The basal cAMP content was unaffected even at 40 mM of lithium. The inhibitory action was time-dependent and reversible, indicating an intracellular site of action. Lithium inhibited both norepinephrine- and glucagon-stimulated cAMP accumulation in a mainly non-competitive way, but the inhibitory effect decreased with increasing hormone concentrations. In accordance, lithium and propranolol had a supraadditive effect on norepinephrine-induced cAMP accumulation. It is suggested that lithium affects both the hormone-receptor binding as well as the transfer of the hormonal stimulus by an intracellular site of action.

Adenylyl Cyclase Inhibitors↗

PubMed1980

Renal response to potassium infusion in rats given lithium for prolonged time.

The effects of infusion of potassium chloride was studied in Wistar rats given lithium by the food for more than 3 weeks. The animals were anaesthetized with amytal and three clearance periods were run. During periods 1 and 3 0.15 M NcCl was infused at a rate of 0.02 ml/min. for 60 min. and in period 2 0.5 M KCl was infused at the same rate for 90 min. Potassium infusion led to an increase of potassium excretion. Sodium excretion and urine flow were positive linear correlated to the potassium excretion but in rats given lithium the effect of potassium on sodium excretion was about eight times higher and the effect on urine flow about thirteen times higher than the effects on control rats not given lithium. The concentration of Na and K in the urine of the lithium-treated group were within a narrow range and almost unaffected by potassium infusion. Lithium clearance and the fractional excretion of lithium rose significantly during potassium infusion. Inulin clearance was almost unaffected by the potassium infusion. The results indicate that potassium infusion in rats given lithium for prolonged time leads to an increase of renal sodium, water and lithium excretion.

Animals↗

PubMed1981

A comparison between the natriuretic response to potassium in lithium- and amiloride-treated rats.

The effect of an increase of the potassium content of the food on the natriuretic and diuretic effects of lithium and amiloride was examined in Wistar rats pretreated with the respective drugs for a period of three weeks. Lithium (60 mmol/kg) or amiloride (200 mg/kg) was added to the food and the animals had access to water and a 0.46 M NaCl solution. An increase of the potassium content of the food resulted in a potassium dose-dependent increase of the natriuretic effect in both lithium-treated and amiloride-treated rats. The effect was temporary in lithium-treated rats but persistent in amiloride-treated rats. Lithium treatment resulted in a 10-fold increase of the water intake compared to control rats and amiloride-treated rats. An increase of the potassium intake reduced the water intake in the lithium-treated animals and modestly increased the water intake in amiloride-treated rats. The results show that the exaggerated natriuretic effect produced by administration of potassium to rats treated with lithium is not a specific phenomenon. It is suggested that a lowered ability of the kidneys to secrete potassium may be responsible for the exaggerated natriuretic response to potassium in amiloride- and lithium-treated rats.

Amiloride↗

PubMed1991

Lithium increases the alpha 1-adrenoceptor mediated inotropic effect in rat heart.

The intracellular mechanisms activated by stimulation of myocardial alpha 1-adrenoceptors are not known. As in several other tissues, however, activation of alpha 1-adrenoceptors in heart has been related to breakdown of phosphoinositides resulting in production of putative intracellular messengers: different inositol phosphates and diacylglycerol. Lithium has been shown to inhibit enzymes hydrolyzing inositol phosphates. In the present paper we report studies on the effect of lithium upon the alpha 1-adrenoceptor mediated inotropic response elicited in electrically driven rat papillary muscles. While there was no shift of the horizontal positioning of the dose-response curve to alpha 1-adrenergic stimulation in the presence of lithium, the alpha 1-adrenoceptor mediated inotropic effect was increased in a concentration dependent manner (0.25 to 3.0 mmol/l lithium). For comparison, the effect of lithium upon the beta-adrenoceptor mediated inotropic response was also studied. At 3.0 mmol/l lithium, the horizontal position of the dose-response curve to beta-adrenoceptor stimulation was shifted significantly to the right (to higher agonist concentrations) and the maximal beta-adrenoceptor mediated inotropic response was slightly although not significantly reduced. Thus the augmenting effect of lithium upon the alpha 1-adrenoceptor mediated response was specific for this receptor type. Although the effect of lithium may be complex, the data are compatible with the hypothesis that the inositol phosphates may be of functional importance during stimulation of myocardial alpha 1-adrenoceptors.

Animals↗

PubMed1992

Multiple-dose sodium polystyrene sulfonate in lithium intoxication: an animal model.

Previous work in our laboratory has demonstrated that sodium polystyrene sulfonate (SPS) significantly lowered serum lithium (Li) concentrations when administered in a single oral dose after an oral dose of lithium in a mouse model. The present study was designed to determine whether: 1) repetitive doses of SPS are effective in lowering serum lithium concentrations, 2) the effect of SPS on lithium concentration is dose related and 3) SPS enhances the elimination of lithium. Mice (N = 144) were given orogastric LiCl (250 mg/kg) and then divided into 4 groups: Controls received water 0, 30, 90, 180, and 360 min. after LiCl; the Full-Dose SPS Group received SPS (5 g/kg/dose) at equivalent times; the Half-Dose SPS Group received SPS (2.5 g/kg/dose) at the same times; and the Elimination Group received water at 0 and 30 min. after LiCl and SPS at 90, 180 and 360 min. after LiCl. Subgroups of each group were sacrificed at 1, 2, 4 and 8 hr post-treatment and serum analyzed for lithium concentrations. Statistical analyses revealed that, when compared to Controls: 1) SPS significantly lowered serum lithium concentrations; 2) this effect was dose-related; 3) repetitive dosing of SPS appears to enhance the elimination of lithium.

Animals↗

PubMed1984

Lithium induced interstitial nephropathy associated with chronic renal failure. Reversibility and correlation between functional and structural changes.

We have previously shown that administration of lithium to rats in the first weeks after birth results in a severe interstitial nephropathy. The aim of the present work was to study the relationship between functional impairment and structural lesions and to evaluate whether the nephropathy regresses after withdrawal of lithium. Three groups of animals were studied: 16 weeks-old controls (group A), rats treated with lithium for 16 weeks (group B) and rats treated for 8 weeks followed by 8 weeks without lithium (group C). Plasma urea and renal concentrating ability were determined and one kidney fixed by vascular perfusion with glutaraldehyde for light microscope morphometry. The results show a significant reduction in renal function after lithium treatment. There was a highly significant reduction in proximal tubular length and a pronounced increase in interstitial volume due to severe fibrosis. The total mass of glomerular tufts was also reduced, but not when this parameter was divided by the body weight. Sclerotic glomeruli were not observed. The structural and functional lithium-induced lesions are independent of sex and irreversible, since they persist 8 weeks after withdrawal of lithium. It is proposed that lithium-induced interstitial fibrosis is followed by proximal tubular atrophy with a reduction in the amount of functioning proximal tubules. This leads to a decrease in proximal tubular reabsorption of sodium and a disturbance in the glomerulo-tubular balance resulting in a decrease in glomerular filtration rate.

Animals↗

PubMed1985

Mechanism of inhibition by lithium of sodium transport in the toad bladder.

Lithium transport across the urinary bladder of Bufo marinus has been studied by means of the short-circuit current technique, as well as unidirectional ion flux measurements. Exposure to lithium of the epithelial (mucosal) surface of this preparation led to a slow, progressive decrease of ion transport, with increasing discrepancy between short-circuit current and lithium influx; in fact there was still an appreciable lithium influx across bladder exposed to amiloride even though short-circuit current was suppressed. Ohmic conductance and sodium efflux barely increased under these circumstances. Upon replacement of lithium by sodium on the epithelial side, the preparations recovered slowly indeed, and residual lithium could be detected in bladder tissue for more than 2 hr while the rate of sodium extrusion at the basal-lateral cell border was slowed down. Recovery from exposure to lithium was accelerated by vasopressin and amphotericin, both of which facilitate sodium entry at the apical border of the epithelium. Thus the lasting deleterious influence of lithium on sodium transport might result from the fact that this ion, once trapped in the cytoplasm, closes the sodium channels.

Amiloride↗

PubMed1995

A micropuncture study of renal tubular lithium reabsorption in sodium-depleted rats.

1. The marked reduction in fractional lithium excretion (FELi) which accompanies chronic sodium depletion was investigated using free-flow micropuncture in anaesthetized rats which had been maintained in a sodium-depleted state for 8-10 days. 2. Compared with previous values in sodium-replete rats, sodium depletion was associated with small reductions in total and superficial nephron glomerular filtration rate and enhanced fractional reabsorption of water, sodium and lithium in the proximal convoluted tubule. 3. In untreated (sodium-depleted) rats, fractional deliveries of lithium (FDLi) to the late proximal convoluted tubule, early distal tubule and late distal tubule were 0.41 +/- 0.02, 0.20 +/- 0.01 and 0.18 +/- 0.02 (means +/- S.E.M.), respectively. Fractional lithium excretion (0.08 +/- 0.01) was significantly lower than late distal FDLi (P < 0.001). 4. Treatment with amiloride did not affect segmental lithium handling up to the late distal tubule. Frusemide had no effect on lithium reabsorption in the proximal convoluted tubule, but early distal FDLi (0.30 +/- 0.01) was raised compared with the untreated group (P < 0.001). Both diuretics eliminated the difference between late distal FDLi and FELi, respective values being 0.17 +/- 0.02 and 0.15 +/- 0.01 (amiloride-treated rats) and 0.31 +/- 0.02 and 0.34 +/- 0.02 (frusemide-treated rats). 5. These data indicate that part of the reduction in FELi in chronic sodium depletion is due to enhanced fractional fluid (and lithium) reabsorption in the proximal convoluted tubule. In addition, however, they provide direct evidence for amiloride-sensitive lithium reabsorption in the collecting ducts.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

PubMed1974

Blood levels and management of lithium treatment.

The limited value of plasma measurements in the management of treatment with lithium is discussed in the light of the mechanisms of its therapeutic actions and toxic effects.The plasma level of lithium usually rises twofold or threefold in the three to five hours after ingestion of each dose of delayed-release tablets and then gradually falls. The precise shape and height of the lithium curve depend on gastric emptying, which can be slowed with propantheline or speeded with metoclopramide. Depressed or demented patients may be irregular in taking their tablets and variable in food intake. Both the time of the blood test and this behaviour must be considered before changing the prescribed dose of lithium salt because of a laboratory result. A lithium tolerance curve may be a safer guide to treatment than single measures.Mild intermittent thirst is a common early side effect, and severe persistent thirst with polyuria is an uncommon later effect of daily intakes of at least 1,500 mg lithium carbonate. This diabetes insipidus is reversible, non-progressive, unrelated to plasma level, and distinct in attack from lithium-induced hypothyroidism, which may occur at low dosage but is also usually of late onset and reversible or treatable with thyroxine while lithium is continued. Obesity is another occasional effect of large doses. These side effects and the antimanic and prophylactic effects may have different mechanisms.

Administration, Oral↗

PubMed1992

Lithium increases DNA replication, polyamine content, and insulin secretion by rat pancreatic beta-cells.

The impact of long-term lithium exposure on the replication, polyamine content, and insulin production of rat pancreatic beta-cells was examined. Fetal rat pancreatic islets enriched in beta-cells were isolated and cultured for 3 days in the presence of different concentrations of LiCl. It was found that lithium dose dependently stimulated beta-cell replication, evoking a 40% increase in beta-cell replication at 1 mM, which was further increased to 70% at 10 mM of the ion. In contrast, the islet contents of insulin mRNA and insulin and insulin biosynthesis rates remained unaltered. The long-term insulin accumulation in the culture medium was nevertheless increased in LiCl-treated groups. In addition, neither the mitogenic effect nor the increased insulin accumulation in the medium by lithium was further augmented by growth hormone, which itself stimulated these functions. Lithium was also found to elevate the islet content of polyamines. Treatment with enzymatic inhibitors of polyamine synthesis failed to preclude the mitogenic and secretagogic impact of lithium, suggesting that the increased contents of polyamines did not convey the lithium effect. We conclude that lithium treatment stimulates rat beta-cell replication and long-term insulin secretion in vitro. These direct effects of the ion on the beta-cell may contribute to the antidiabetic effect of lithium encountered in animal models and patients.

Animals↗