Influence of lithium carbonate on the effects of the natriuretic factor

It has been shown in rat experiments that administration of lithium carbonate for 3 days (100 mg/kg) enhances renal excretion of water and electrolytes following an increase in the volume of extracellular fluid. In this case renal excretion of natriuretic factor rises, whereas its concentration in blood plasma does not ascend. Lithium carbonate raises the sensitivity of the kidneys to natriuretic factor and reduces its effect on transport activity in the small intestine.     

Effects of caroxazone, a reversible monoamine oxidase inhibitor, on the pressor response to oral tyramine in man.

1 A double-blind, placebo-controlled study was carried out in order to investigate the effects of caroxazone, a new antidepressant drug endowed with a reversible short-lasting MAO-inhibitory activity in man, on the blood pressure response to tyramine administered by the oral route. 2 The study was carried out in 9 healthy volunteers who were randomly assigned to treatment with caroxazone 200 mg three times daily (7 subjects) or with indistinguishable placebo (2 subjects). 3 The sensitivity to tyramine was assessed in each subject both before and after the 7-9 days of treatment. 4. While placebo did not modify the pressor response to tyramine, the threshold dose of tyramine which induced a rise in systolic blood pressure was lowered by about four-fold in 6 out of the 7 subjects treated with caroxazone. In the seventh subject the observed potentiation of peroral tyramine was not quantitatively evaluable. 5 Challenges performed in three subjects after discontinuation of treatment with caroxazone show that the effects of the compound are short-lasting, since the sensitivity to tyramine seems to regain the baseline value within 1-2 days. 6 Even if caroxazone potentiates peroral tyramine to a relatively low degree, a tyramine poor diet is recommended for patients during caroxazone treatment. 7 The reversibility of the MAO-inhibitory action of caroxazone is confirmed by the rapid return to normal values in the response to tyramine after discontinuation of treatment. This property of caroxazone would allow patients to return to a free diet in much less time than the safety limit of 2 weeks recommended for the currently used irreversible MAO-inhibitors.     

Limited potentiation of blood pressure response to oral tyramine by brain-selective monoamine oxidase A-B inhibitor,TV-3326 in conscious rabbits

TV-3326 is a novel cholinesterase inhibitor that produces irreversible brain-selective inhibition of monoamine oxidase (MAO)-A and B and has antidepressant-like activity in rats after chronic oral administration. This study determined whether TV-3326 would cause less potentiation than other irreversible MAO-inhibitors of the blood pressure (BP) response to oral tyramine in conscious rabbits. Dose-response curves were established for the increase in BP induced by tyramine (5-200 mg/kg) administered orally via a naso-pharyngeal tube. From these, the dose that increased BP by 30 mmHg (ED(30)) was computed for each rabbit before and after oral administration of clorgyline, 1 mg/kg for one week, tranylcypromine 10 mg/kg, once, moclobemide, 20 mg/kg 3 times and TV-3326, 26 mg/kg for 2 weeks. Clorgyline, tranylcypromine and TV-3326 inhibited brain MAO-A by 90%; the former two inhibited intestinal MAO-A by 85-97% but TV-3326 had no effect. Tranylcypromine and clorgyline produced 6 and 20-fold increases in the pressor response to tyramine while TV-3326, like moclobemide, only potentiated it 2-fold. If TV-3326 is found to produce as little potentiation of the tyramine response in human subjects, it may be a potentially useful therapeutic agent for the treatment of Alzheimer's disease with depression.     

Suppression of Herpes Simplex Virus Infections with Oral Lithium Carbonate—A Possible Antiviral Activity

In vitro studies have shown an inhibitory effect of lithium salts on herpes simplex virus (HSV) replication by mechanisms that interfere with viral DNA synthesis. Moreover, clinical studies have shown that oral lithium carbonate and topical lithium succinate can suppress genital HSV infections in humans. We conducted a randomized, double-blind, placebo-controlled trial of oral lithium carbonate in 11 healthy subjects age 28–65 years (mean ± SD age 38 ± 11 years) who had at least four recurrent HSV infections in the year preceding the study. Six patients completed at least 5 months of, lithium therapy at a mean (± SD) average daily lithium dose of 437 ± 185 mg (range, 150–900mg) and an average serum lithium level of 0.56 ± 0.20 mmol/L. Overall, lithium treatment resulted in a consistent reduction in the mean number of episodes/month, the average duration of each episode, the total number of infection days/month, and the maximum symptom severity. In contrast, treatment with placebo resulted in an increase in three out of the four severity measures. Although the comparisons between the treatment groups did not achieve statistical significance due to the limited sample size, there was a clear “trend” for a reduction in the total monthly duration of all HSV infections with lithium (p = 0.08). Lithium treatment was well tolerated and produced no deleterious effects on renal or thyroid function. These observations lend support to prior observations of an antiviral activity of lithium, and suggest the possibility that oral lithium may represent a safe prophylactic agent in patients with recurrent HSV infections.     

Pressor response to oral tyramine during co-administration with safinamide in healthy volunteers

The aim of this study was to evaluate the pressor response to oral tyramine during repeated administration of oral safinamide in healthy volunteers. Twelve females and eight males aged 52.7 ± 4.9 years entered the study. An oral tyramine screening test was conducted to select subjects sensitive to the tyramine pressor effect on systolic blood pressure (SBP) in the dose range of 200–400 mg. Safinamide 300 mg was then administered once daily under fasting conditions. Starting on day 5 (safinamide pharmacokinetic steady state), single ascending doses of tyramine were co-administered daily: 50, 100 and 200 mg were administered on days 5, 6 and 7, respectively. Vital parameters were monitored by telemetry. No SBP increase ≥30 mmHg over baseline was observed when tyramine was co-administered with safinamide. Less than one third of the 400 mg responders reported SBP increases between 22 and 27 mmHg, which were below the threshold of 30 mmHg over baseline. SBP increases, as well as time interval to pressor response measured after co-treatment with safinamide and tyramine 200 mg, were not significantly different from those measured after administration of oral tyramine 200 mg alone. Safinamide 300 mg, administered o.d. under fasting conditions, does not change the tyramine pressor response as evaluated at steady state after 6–7 days of treatment as compared with the effect of tyramine administered alone. Safinamide, which inhibits monoamine oxidase (MAO)-B, does not affect oral tyramine metabolism mediated mostly by the intestinal MAO-A.     

Effect of moclobemide, a new reversible monoamine oxidase inhibitor, on absorption and pressor effect of tyramine

We determined in healthy subjects the pressor effect and the plasma level of free tyramine in response to intravenous and oral tyramine doses before and after therapeutic doses (3 X 100 mg/day) of moclobemide, a new reversible, preferential type A monoamine oxidase (MAO) inhibitor. In fasting subjects moclobemide increased the pressor effect of intravenously and orally administered tyramine; the tyramine dose-pressor curve was shifted to the left by factors of 2.4 and 4.1, respectively. No increase in systolic blood pressure occurred at free plasma tyramine concentrations lower than 70 ng/ml before, and 20 ng/ml after, moclobemide. Peak plasma tyramine concentrations increased dose-dependently after oral tyramine; after moclobemide similar peak plasma concentrations of tyramine were obtained with 2.6 times smaller doses of tyramine. Thus, the potentiation by moclobemide of the pressor effect of oral tyramine appears to be due to inhibition of tyramine first-pass metabolism, as well as to inhibition of tyramine catabolism by MAO within adrenergic nerve terminals. The peak concentrations of free tyramine in plasma and the concomitant increase of systolic blood pressure were significantly (p less than 0.01) smaller when tyramine was administered with a meal (before or after moclobemide) than when given with tap water. We conclude that at doses of 3 X 100 mg/day moclobemide induces only a mild potentiation of the pressor effect of tyramine. This potentiation is virtually absent under natural conditions when tyramine is given with a meal.     

Effect of oral linezolid on the pressor response to intravenous tyramine

AIMS: To investigate the effect of monoamine oxidase A inhibition from a single oral dose of linezolid on the pressor response to intravenous (i.v.) tyramine, using positive and negative controls to validate the methodology. METHODS: This placebo-controlled, three-period crossover study was conducted in 12 healthy male volunteers. Each volunteer received either one oral dose of moclobemide (300 mg), linezolid (600 mg), or placebo tablet followed by an i.v. tyramine pressor test until an increase in systolic blood pressure of at least 30 mmHg above baseline occurred. Each study day was separated by a 7-day washout period. The dose of tyramine required to raise the blood pressure by 30 mmHg (TYR30) was calculated for each oral treatment by linear interpolation between log-transformed doses of i.v. tyramine. The influence of body mass index (BMI) on TYR30 was also investigated. RESULTS: The tyramine sensitivity factor (ratio of the geometric least square mean TYR30 for placebo and active oral treatment) was 1.8 [90% confidence interval (CI) 1.6, 2.0, P < 0.0001] for linezolid and 2.1 (90% CI 1.8, 2.4, P < 0.0001) for the positive control moclobemide. BMI had a statistically significant effect on TYR30. CONCLUSIONS: There was a significant difference in the pressor response to i.v. tyramine between linezolid and placebo. Moclobemide (positive control) and linezolid have a similar pressor response to i.v. tyramine. The statistically significant effect of BMI on TYR30 underlines the advantage of within-individual comparisons of treatments in order to reduce variability and provide more accurate treatment estimates.     

Linezolid, a novel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine

The primary objective of this study was to compare the effects of oral linezolid with moclobemide and placebo on the pressor response to oral tyramine. Secondary objectives were to determine possible mechanisms of the effect based on changes in the pharmacokinetics of tyramine and to evaluate alternative methods for quantifying the pressor effect. Subjects received linezolid (625 mg bid orally), moclobemide (150 mg tid orally), or placebo for up to 7 days. Using the oral tyramine dose producing a >30 mmHg increase in systolic blood pressure (SBP) (PD>30), a positive pressor response was defined as a PD>30 index (pretreatment/treatment ratio of PD>30) of > or = 2. There were 8/10, 11/11, and 1/10 responders with linezolid, moclobemide, and placebo, respectively. Responses returned to baseline within 2 days of drug discontinuation. The ratio of mean greatest SBP and heart rate at the time of greatest SBP (GSBP/HR) increased linearly with tyramine dose both pretreatment and during treatment with linezolid and moclobemide. During treatment, responses to tyramine when subjects took linezolid or moclobemide were significantly different from placebo. Both drugs significantly decreased tyramine oral clearance compared with placebo. Urinary excretion of catecholamines and metabolites was consistent with MAOI activity of the drugs, but results were variable. The MAOI activity of linezolid is similar to that of moclobemide, a drug used clinically without food restrictions. Restrictions to normal dietary intake of tyramine-containing foods are not warranted when taking linezolid.     

Potentiation of the pressor effect of oral and intravenous tyramine during administration of the selective MAO-A inhibitor moclobemide in healthy volunteers

The interaction between tyramine and the new short-acting and reversible mono amine oxidase inhibitor moclobemide was investigated in a double-blind placebo-controlled study in six healthy volunteers. There were two consecutive study periods of 8 days during which the subjects received moclobemide three x 200 mg daily or placebo. On day 5 of each study period changes in systolic blood pressure (SBP) were determined after incremental intravenous bolus doses of tyramine and on days 6, 7 and 8 changes in SBP were determined after oral tyramine (100, 200 and 300 mg, respectively). Oral tyramine was administered together with a standard breakfast, before which moclobemide had been given. On days 5- 8 blood was taken for determination of blood drug levels. On days 6-8 blood samples were taken before and at 15, 30 and 45 min after tyramine administration for determination of plasma tyramine and plasma norepinephrine concentrations. When SBP had increased by approximately 30 mmHg no further doses of either intravenous or oral tyramine were given. Moclobemide was well tolerated by all subjects. Plasma trough levels of moclobemide were within the therapeutic range. The tyramine induced increases in SBP were greater during moclobemide than during placebo. After intravenous tyramine the dose-response curve for SBP was shifted to the right by a factor of approximately 3. When compared to placebo the pressor response to 100 mg tyramine orally was not significantly different, but the pressor response to the other two doses was enhanced during moclobemide.     

The effect of lithium on the renal response to the dopamine prodrug gludopa in normal man.

1. The effect of oral lithium on the renal response to gamma-L-glutamyl-L-dopa (gludopa, 25 micrograms kg-1 min-1) was investigated in seven normal males. 2. Gludopa at this dose produced an 800-fold increase in urine dopamine excretion. It was natriuretic and suppressed plasma renin activity without altering blood pressure and pulse. 3. Lithium alone increased sodium excretion and stimulated plasma renin activity. However, it abolished the natriuresis produced by gludopa. 4. Gludopa did not significantly affect lithium clearance. 5. This study suggests that lithium interacts with dopamine at the proximal tubule and that the lithium clearance method is not suitable for investigating dopaminergic mechanisms in the kidney.     

Effects of LM 5008, a selective inhibitor of 5-hydroxytryptamine uptake, on blood pressure and responses to sympathomimetic amines

LM 5008 (4-[2-(3-indolyl)ethyl]piperidine) (10, 20 and 50 mg kg-1) had no significant effect on pressor responses to noradrenaline or tyramine in rats anaesthetized with urethane. Desmethylimipramine (1 mg kg-1) blocked the response to tyramine but chlorimipramine (5 mg kg-1) had no significant effect on responses to noradrenaline or tyramine. In the rabbit, anaesthetized with chloralose, LM 5008 (5 mg kg-1) had no effect on pressor responses to noradrenaline, tyramine or angiotensin II, while desmethylimipramine (0.25 mg kg-1) inhibited responses to tyramine and potentiated those to noradrenaline. LM 5008 (10 mg kg-1) had no effect on resting blood pressure of conscious normotensive or DOCA-saline hypertensive rats. Tranylcypromine (5 mg kg-1) produced a fall in blood pressure in conscious normotensive and in DOCA hypertensive rats. Treatment with a combination of LM 5008 (10 mg kg-1) and tranylcypromine (5 mg kg-1) resulted in the appearance of a behavioural hyperactivity syndrome, but blood pressure was not different from that of animals treated with tranylcypromine alone. These results further demonstrate the selectivity of LM 5008 for 5-hydroxytryptamine as opposed to catecholamine uptake.     

Some biochemical aspects of the potential benefit of associating MD780515 with tricyclic antidepressants

In the rat, suitable oral doses of tricyclic antidepressants (amitriptyline 20 mg kg-1, imipramine, desipramine 2.5 mg kg-1) are able to antagonize the increase of cardiac levels of intravenous tyramine after a pharmacologically active dose (3.5 mg kg-1 orally) of a reversible and specific type A MAO inhibitor, MD780515 (3-[4-(3-cyanophenylmethoxy)phenyl]-5-(methoxymethyl)-2-oxazolidinone). MD780515, in oral doses up to 35 mg kg-1, does not alter the liver microsomal drug metabolizing enzymes in the rat. Therefore, when given with tricyclic antidepressants, it should not interfere with their metabolism.     

Blood pressure effects of monoamine oxidase inhibitors in response to orally administered tyramine in the rat

The reversible monoamine oxidase-A inhibitors BW 1370U87, BW 616U76, brofaromine, and moclobemide, and the irreversible nonselective monoamine oxidase inhibitor phenelzine were compared for potentiation of the pressor response to oral tyramine. Conscious rats were pretreated with doses of the monoamine oxidase inhibitors sufficient to produce 80% inhibition of brain monoamine oxidase, and then were challenged with orally administered tyramine. Blood pressure was monitored prior to and after tyramine, and peak pressor responses were compared. At a dose of 15 mg/kg tyramine, the pressor response of BW 1370U87 was statistically similar to the vehicle control response. BW 616U76, brofaromine, and moclobemide elicited mild tyramine pressor effects, whereas phenelzine resulted in a marked elevation of blood pressure. Higher doses of tyramine elicited blood pressure elevations from all of the monoamine oxidase inhibitors.     

Beta-blockade antagonism of tyramine-induced rise in blood pressure

Summary The effect -adrenoceptor blockade on the pressor response to tyramine has been investigated in 6 healthy volunteers, each submitted to an i.v. tyramine pressor test before and after 7 days of propranolol 40 mg b.d. or indenolol 60 mg o.d. Tyramine was given as i.v. boluses of 1–6 mg, alternating with saline, in a randomized, single blind fashion.Prior to treatment tyramine caused a temporary, dose-dependent increase in systolic and diastolic blood pressure, whilst the heart rate remained unaffected. Both propranolol and indenolol reduced the pressor response to tyramine, as shown by a significant increase in ED₁₅, i.e. the dose of tyramine required to increase systolic blood pressure by 15%.     

COMT inhibition with nitecapone does not affect the tyramine pressor response.

Nitecapone (OR-462) is a new selective COMT inhibitor with gastroprotective properties. The aim of the present study was to determine whether nitecapone potentiates the haemodynamic effects of a tyramine-induced increase in catecholamine release. The systolic blood pressure response to tyramine was studied in 11 healthy male volunteers (age 20-32 years). Tyramine was given i.v. as rapid bolus injections in increasing doses without drug intake and after oral intake of single doses of 25 mg and 100 mg of nitecapone. The tyramine dose required to increase systolic blood pressure by 30 mm Hg ('pressor dose') was 4.98 mg, 5.04 mg and 4.88 mg after no medication, and with 25 mg and 100 mg of nitecapone, respectively. There were also no differences in the systolic blood pressure response vs time curves between the three regimens. COMT inhibition with nitecapone did not potentiate the haemodynamic responses to tyramine-induced catecholamine release.     

Lithium carbonate as a potential pharmacological vehicle: intravenous kinetics of single-dose administration in healthy subjects

OBJECTIVE: We have been developing lithium carbonate solution as a vehicle for delivery of uric acid in a research setting. We wished to determine the pharmacokinetics of a single systemic administration of 500 mg lithium carbonate (13.5 mmol free Li(+)) in healthy subjects. METHODS: Ten healthy subjects received 500 ml of a 0.1% lithium carbonate and 4% dextrose solution intravenously over 1 h. Serum lithium concentrations were determined at baseline, 15, 30, 45, 60, 75, and 90 min, and 2, 3, 7, 24, and 48 h after the start of infusion for kinetic analysis. RESULTS: Administration led to a time-dependent increase in plasma concentration, followed by a rapid decay of serum lithium concentration. Kinetic analysis showed that the pattern best fit a two-compartment model, with rapid extravascular distribution, an elimination phase half-life of 7.8+/-1.7 h, and clearance of 5.3+/-1.1 l/h. CONCLUSIONS: In healthy subjects, lithium half-life is shorter and clearance is higher than suggested by previous reports in other groups. Administration of 500 ml 0.1% lithium carbonate and 4% dextrose over 1 h is safe, well tolerated, and possibly a suitable vehicle for other agents such as uric acid.     

An Assessment of Erythrocyte Lithium Concentrations as a Measure of Patient Compliance

Following oral administration of only one dose of lithium (e.g. just prior to a clinic blood test), plasma concentrations rise quickly and may appear to be in the therapeutic steady state range for several hours. At the clinic, therefore, noncompliance may go undetected. It has been suggested that measurements of erythrocyte lithium concentrations (Le) may be more useful than plasma lithium concentrations (Lp) in detecting patient non-compliance. This was investigated by comparing the pharmacokinetics of lithium in plasma and erythrocytes after a single 800 mg dose of lithium carbonate and during constant dosing around steady state. Twelve healthy male volunteers took part in the study and took 800 mg of lithium carbonate (Priadel) for 28 days. Le and Lp ranges were determined around steady state using data obtained from eight volunteers known to be compliant. Compliance was measured using electronic monitoring. Both erythrocyte and plasma lithium concentrations reached values comparable to steady state after a single oral dose. This suggests that Le measurements are no better than Lp measurements when attempting to identify noncompliant patients who only dose shortly before a blood test.     

Influence of food on the tyramine pressor effect during chronic moclobemide treatment of healthy volunteers

Summary An open study was carried out to examine the effect of moclobemide, a new antidepressant reversible inhibitor of MAO-A, on the pressor response induced by oral tyramine added to meals of different lipid and protein composition, and to correlate the blood pressure increase in the tyramine test with that obtained during an exercise test.Eight healthy volunteers of both sexes participated in the study. A tyramine sensitivity and an exercise test were performed beforehand. Subjects were included if, under fasting condition, their systolic blood pressure (SBP) increased by more than 30 mmHg after administration of 400 or 600 mg tyramine. Exercise tests were performed to determine the grade of effort that corresponded to a rise in SBP of 30 mmHg.Subjects received moclobemide 600 mg/d. Starting on Day 7, each subject consumed a standardized meal (52 g lipids, 43 g proteins, 86 g carbohydrates) just before taking moclobemide. Tyramine was added to these meals in daily increasing doses of 50, 100, 150 ... mg until an increase in SBP > 30 mmHg was obtained. On moclobemide treatment, an average dose of 250 mg tyramine (range 150-400 mg) increased SBP by 36.6 mmHg. The time to reach peak SBP was longer (175 min) than in the fasting condition before the trial (40.6 min).The administration of the same dose of tyramine both during a protein-rich (75 g proteins, 85 g lipids, 90 g carbohydrates) and lipid-rich (110 g lipids, 55 g proteins, 100 g carbohydrates) meal significantly reduced the average increase in SBP to 21 mmHg, but did not significantly modify the time of appearance of the peak SBPIn the exercise test, an increase in SBP of 30 mmHg was produced by the low load of about 100 W. During moclobemide treatment, oral doses of tyramine considerably larger than the amounts present in normal meals did not increase SBP by more than the effort exerted during every day life. Concomitant administration of a large quantity of lipids significantly reduced the pressor response.     

Subchronic supplementation of lithium carbonate induces reproductive system toxicity in male rat

Lithium is frequently used as an effective drug for the treatment of several psychiatric disorders in human. This alkali element and its salt, at its higher doses, may lead to various side effects or has several toxic effects after prolonged therapeutic use. To test this hypothesis, the present study was designed to investigate the adverse effect of subchronic exposure of lithium carbonate on reproductive organs of male rat. Rats were exposed to lithium carbonate at doses of 500, 800, 1100 mg/kg of diet for 90 days. The weight of reproductive organs, histology of testis, epididymis, seminal vesicle, prostate, testicular interstitial fluid volume (IFV), testosterone level, sperm morphology and fertility index were analyzed. Treatment with higher doses of lithium carbonate (i.e. 800, 1100 mg/kg diet) significantly reduced testes, epididymis and accessory sex organs weights, whereas, lower dose (500 mg/kg diet) did not show any untoward effect. Similarly, the sperm number from cauda epididymis and daily sperm production was significantly decreased with higher doses of lithium carbonate. The serum testosterone levels and IFVs were also reduced significantly. Seminal vesicle and prostate secretions were completely blocked and spermatozoa were not seen in the lumen of epididymis and vas deference. Histological studies have revealed that lithium carbonate (1100 mg/kg) caused degeneration of spermatogenic cells and vacuolization of sertoli cells cytoplasm in the testis. The sperm transit rate and production of abnormal spermatozoa were significantly (P<0.01) increased. When the lithium carbonate-treated males were mated with normal cyclic females, the fertility index declined to 50% even after 30 days of withdrawal of lithium carbonate treatment. These results clearly suggest that subchronic exposure of lithium carbonate promote reproductive system toxicity and reduces fertility of male rats.     

Pharmacokinetics of mirtazapine and lithium in healthy male subjects

A substantial proportion of patients diagnosed with depression and treated with antidepressants show no or insufficient response. In such patients, lithium is often added to the antidepressant for augmentation. The present study investigated the possible drug-drug interaction between mirtazapine and lithium in 12 healthy male subjects in a randomized, double-blind, placebo-controlled two-period cross-over design. Subjects meeting the inclusion and exclusion criteria were randomly assigned to one of two groups. After an overnight fast, they received either a single oral dose of 600 mg lithium carbonate (16 meq Li+) for 10 days at 08.00 h and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9 or the same number (n = 4) of placebo capsules and and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9. At pre-defined times, blood samples were drawn for the measurement of mirtazapine plasma concentrations and lithium serum concentrations. In addition, psychometric tests were performed and the safety and tolerability of the drugs were assessed. The results indicate that mirtazapine does not alter the pharmacokinetics of lithium and vice versa. In addition, the combination of mirtazapine and lithium appeared to be safe and well-tolerated. Extensive psychometric testing after the administration of mirtazapine did not reveal any differences on any tests in subjects on lithium and placebo, respectively.