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Biomedical subjects

A G Mallinger

Publications and source records attributed to A G Mallinger.

At least 55 records · Page 3Linked to original sources
PubMed1991

Cross-sectional and longitudinal relationship of sodium-lithium countertransport to insulin, obesity and blood pressure in healthy perimenopausal women.

The objectives of this study were to assess the possible role of insulin as a regulator of red blood cell sodium-lithium countertransport and to examine the relationship of countertransport activity to change over time in insulin, blood pressure, and other variables. At baseline, countertransport was measured, and at baseline and after 2-3 years of follow-up, blood pressure, body mass index (BMI), lipids, fasting and two-hour plasma insulin and glucose were measured in 144 white healthy, premenopausal women, age 42-50 years. At baseline, using high and low categories of fasting insulin, triglycerides and BMI, countertransport was independently related to fasting insulin (P = 0.017), and triglycerides (P = 0.001), but not to BMI by analysis of variance. In similar analyses with fasting insulin, BMI, and countertransport, diastolic blood pressure was independently related only to countertransport (P = 0.003). Among the 73 who remained premenopausal after 2-3 year follow-up, baseline countertransport was significantly correlated with increases in fasting and two-hour insulin (r = 0.37, 0.38, P = 0.003, respectively), and these relationships remained significant after adjustment for change in BMI. Among subjects with high baseline countertransport, systolic blood pressure increased 5.6 mmHg compared with -2.2 mmHg with low countertransport, P = 0.001 after adjusting for baseline and change in BMI, triglycerides, and fasting and two-hour insulin. The data are consistent with a role for insulin and lipids in the regulation of sodium transport which may, in turn, play a role in blood pressure regulation. A relatively short follow-up in this healthy population suggests a relationship of baseline countertransport to changes in insulin metabolism, and blood pressure.

Adult↗
PubMed1991

Pharmacokinetics of monoamine oxidase inhibitors.

Few studies on the pharmacokinetics and plasma drug levels of monoamine oxidase (MAO) inhibitors have been performed, despite several decades of clinical use. Older MAO inhibitors such as tranylcypromine produce neuronal accumulation of neurotransmitter amines as a consequence of functionally irreversible MAO inhibition. Typically, these agents are cleared from the body rapidly, so plasma drug levels are not correlated with MAO inhibition. However, recent research has demonstrated that tranylcypromine can produce direct and reversible pharmacologic effects, as well as clinical mood effects, that appear more closely related to transient plasma tranylcypromine levels than to the degree of MAO inhibition. In addition, a new generation of reversible MAO inhibitors is now being introduced. The antidepressant actions of these latter agents will almost certainly be directly influenced by pharmacokinetic factors. This review summarizes the existing pharmacokinetic literature on tranylcypromine, phenelzine, moclobemide, and selegiline. These drugs and others like them promise to become increasingly important in modern psychopharmacologic practice.

Humans↗
PubMed1990

Three-year outcomes for maintenance therapies in recurrent depression.

We conducted a randomized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy. A five-cell design was used to determine whether a maintenance form of interpersonal psychotherapy alone or in combination with medication could play a significant role in the prevention of recurrence. A second question was whether maintaining antidepressant medication at the dosage used to treat the acute episode rather than decreasing to a "maintenance" dosage would provide prophylaxis superior to that observed in earlier trials in which a maintenance dosage strategy was employed. Survival analysis demonstrated a highly significant prophylactic effect for active imipramine hydrochloride maintained at an average dose of 200 mg and a modest prophylactic effect for monthly interpersonal psychotherapy. We conclude that active imipramine hydrochloride maintained at an average dose of 200 mg is an effective means of preventing recurrence and that monthly interpersonal psychotherapy serves to lengthen the time between episodes in patients not receiving active medication.

Adult↗
PubMed1990

Plasma tranylcypromine: relationship to pharmacokinetic variables and clinical antidepressant actions.

Because the clinical actions of psychotherapeutic agents can be influenced by their pharmacokinetics, we investigated plasma tranylcypromine in relation to treatment outcome in 26 patients with bipolar depression. After oral administration of a tranylcypromine dose, plasma drug levels were measured hourly from 5-8 hours (N = 16) or 0-8 hours (N = 10) postdose, and pharmacokinetic parameters were calculated. Depressive symptoms were rated using the Hamilton Rating Scale for Depression (HAM-D), and subjects were categorized as responders, partial responders, or nonresponders, based on end-pair ratings. Twelve subjects were responders, seven were partial responders, and seven were nonresponders (mean scores = 3.2, 13.1, and 24.9, respectively); pretreatment HAM-D scores did not differ among the three groups. Tranylcypromine elimination (t1/2) was unrelated to clinical outcome. However, plasma tranylcypromine measured 5 hours postdose (5hTCP) was correlated with the end-pair HAM-D scores (r = 0.48, p less than 0.015) and was significantly higher in nonresponders than in responders (ANOVA, F = 4.7, p less than 0.02; Newman-Keuls test, p less than 0.05). For subjects who were studied from 0-8 hours postdose, the time to peak absorption (Tpeak), the area under the plasma tranylcypromine-versus-time curve, and the volume of distribution (Vd) were determined. Two subjects having delayed (3-4 hours) Tpeak also manifested elevated mean 5hTCP (63.9 vs. 34.1 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Sleep EEG and DST findings in anergic bipolar depression.

The authors report sleep EEG and dexamethasone suppression test (DST) findings for a homogeneous sample of anergic bipolar depressed outpatients (bipolar I, N = 7; bipolar II, N = 19) characterized by motor retardation, volitional inhibition, hypersomnia, or weight gain and sleep EEG findings for 26 age- and sex-matched normal control subjects. Sleep architecture was abnormal in bipolar depression, particularly with respect to little stage 1 sleep. The biological profile of an anergic episode of bipolar depression did not include a shorter than normal mean REM latency, poor sleep continuity, or abnormally low amounts of stages 3 and 4 sleep, and only three (13%) of 23 patients manifested cortisol nonsuppression.

Adult↗
PubMed1987

Stimulation of cell membrane sodium transport activity by lithium: possible relationship to therapeutic action.

Because lithium is extruded from cells by means of coupled exchange for external sodium (Na+-Li+ countertransport), we hypothesized that clinical treatment with this agent could lead to significant augmentation of net cellular sodium influx. We therefore directly measured sodium influx in vitro using erythrocytes (RBCs) from 27 depressed bipolar patients. When cells were loaded with sufficient lithium to maximally stimulate Na+-Li+ countertransport activity (5.1 mmoles/1 RBCs), there was a significant 44% increase in mean sodium influx. To approximate clinical conditions more closely, we also studied sodium influx in a subset of eight subjects after loading cells with 0, 0.40, 0.66, and 1.55 mmoles lithium/1 RBCs. Over this range of lithium concentrations, sodium influx increased progressively. In separate experiments, we found that RBC sodium content measured in eight subjects did not change significantly during a 4-week course of lithium treatment. Thus, excess cellular sodium during such treatment may be extruded by increased activity of the membrane Na+-K+ pump, which has electrogenic properties and thereby could augment the membrane potential. In the nervous system, such an effect could stabilize cell membranes electrophysiologically, and possibly affect processes, such as behavioral sensitization or kindling, proposed to have a role in the development of recurrent affective disorders.

Bipolar Disorder↗
PubMed1987

Red blood cell sodium-lithium countertransport and cardiovascular risk factors in black and white college students.

Whites with essential hypertension have high activity of cell membrane sodium-lithium (Na+-Li+) countertransport when compared with normotensives. To determine whether elevated Na+-Li+ countertransport is related to the twofold higher risk of hypertension in US blacks, maximal rates of red blood cell (RBC) Na+-Li+ countertransport were measured in 34 black and 21 white male college students. The race groups were similar in social and physical measurements. Mean Na+-Li+ countertransport activity (mmol Li/RBC per h) was significantly lower in blacks than in whites (0.214 +/- 0.083 versus 0.295 +/- 0.083, P less than 0.001). Countertransport activity was positively correlated with Type A behaviour among whites (r = 0.45, P = 0.039). Other within race correlations between Na+-Li+ countertransport activity and blood pressure and cardiovascular risk factors were generally positive though not significant in whites, whereas they were small or negative in blacks. If Na+-Li+ countertransport has a role in the aetiology of hypertension, it would appear to differ between blacks and whites.

Adolescent↗
PubMed1986

Pharmacokinetics of tranylcypromine in patients who are depressed: relationship to cardiovascular effects.

We investigated the pharmacokinetics of tranylcypromine, as well as the relationship between plasma levels of this agent and its effects on blood pressure and pulse rate. Tranylcypromine was absorbed rapidly after oral dosing, with the peak level being attained within 0.67 to 3.50 hours. Absorption was biphasic in seven of nine subjects. Elimination of tranylcypromine also was rapid, with a t 1/2 between 1.54 and 3.15 hours. From 2 to 7 hours after dosing, standing systolic and diastolic blood pressures were lowered and standing pulse was raised, compared with baseline. Onset of the effect on standing systolic blood pressure was correlated with the time of peak plasma tranylcypromine concentration. Maximum orthostatic drop of blood pressure and rise of pulse rate occurred 2 hours after dosing. Mean plasma tranylcypromine concentrations were correlated with mean orthostatic drop of systolic blood pressure and rise of pulse rate. Patients who have clinically significant hypotensive reactions to this agent may benefit from changes in their dose regimen aimed at minimizing peak tranylcypromine levels.

Administration, Oral↗
PubMed1985

A pharmacokinetic approach to the study of cell membrane lithium transport in vivo.

Although many previous investigations have focused on in vitro studies of lithium transport by erythrocytes (RBCs) of psychiatric patients, the extent to which such studies actually reflect the transport of this drug by other types of cells in vivo is unknown. To study lithium transport in vivo, pharmacokinetic analysis of plasma lithium concentration data was performed in four subjects who were given single oral doses of lithium carbonate (600 mg). The data were analyzed according to a two-compartment model, consisting of a central compartment (extracellular, including plasma) and a peripheral (intracellular) compartment. Rate constants for the transfer of lithium into (ki) and out of (ko) the intracellular compartment were calculated. In RBCs from the same subjects, lithium transport in vitro was also directly measured. Rate constants were determined for phloretin-sensitive transport (ks), which corresponds to Na+-Li+ countertransport activity, and residual passive "leak" diffusion (kr). In RBCs, these two pathways account for major components of lithium efflux and influx, respectively. To compare the in vivo and in vitro rate constant data, the ratios ko/ki and ks/kr were also calculated. There was a significant correlation between these two rate-constant ratios (r = 0.96, p less than 0.05), although the values observed in vitro were higher than those found in vivo. Because the in vivo rate constants reflect lithium transport by many types of cells in the peripheral compartment, this finding supports the idea that the RBC may provide a useful model for studying lithium transport processes that are also operative in other types of cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Membrane Permeability↗
PubMed1984

Erythrocyte choline transport in drug-free and lithium-treated individuals.

The choline (Ch) content of erythrocytes (RBCs) has been reported to be elevated in several psychiatric and neurologic disorders. The present investigation was conducted in order to examine the relationship between in vivo RBC Ch content and Ch flux across the RBC membrane (measured in vitro). To perform the in vitro studies, we measured the outward transport of endogenous Ch (DoCh efflux) and the concomitant inward transport of deuterated Ch (D4Ch influx), in RBCs that were incubated in physiologic media for 24 min at 17 degrees C. Transport of the Ch isotopes was linear during these incubations. In drug-free, psychiatrically normal control subjects, DoCh efflux was inversely correlated with the natural logarithm of in vivo RBC Ch content (r = -0.97, p less than 0.001), and there was a nearly significant correlation between D4Ch influx and in in vivo RBC Ch content (r = -0.81, p less than 0.06). In patients with bipolar affective disorder, lithium treatment both inhibited DoCh and D4Ch transport, and substantially elevated in vivo RBC Ch content. However, varying degrees of transport inhibition were produced by this drug in different subjects. Our findings suggest that membrane Ch transport may have a role in the regulation of endogenous RBC Ch content. Studies of membrane Ch transport in RBCs or other types of cells could potentially help to increase our understanding of cholinergic function in psychiatric or neurologic disorders.

Bipolar Disorder↗
PubMed1983

Essential hypertension and membrane lithium transport in depressed patients.

Na+-Li+ countertransport activity in erythrocytes has previously been reported to be decreased in certain patients with mood disorders, but increased in essential hypertensives and possibly their first-degree relatives. The present investigation examines specific parameters of Na+-Li+ countertransport in relation to both affective disorder and essential hypertension. Depressed patients having a personal or family history of essential hypertension had significantly higher Vmax and fractional lithium release values than did other patients or control subjects. Values of K 1/2 did not differ among the groups. Essential hypertension in experimental subjects or their families may complicate attempts to study human erythrocyte (RBC) lithium transport in depressed patients.

Adult↗
PubMed1983

Lithium treatment during pregnancy: a case study of erythrocyte choline content and lithium transport.

Lithium treatment can affect the transport of choline and lithium ions across cell membranes, but little is known about these effects during pregnancy. In a patient treated with lithium carbonate during the final month of pregnancy, maternal erythrocyte (RBC) lithium transport and the choline content of maternal and fetal blood were measured. Fetal RBC choline levels appeared to be substantially elevated by maternal lithium treatment, and cellular lithium transport in the mother was affected by pregnancy. These observations, although preliminary, suggest interactions of lithium with both fetal and maternal physiology during pregnancy.

Adult↗
PubMed1981

Anergic depression accompanied by increased intracellular sodium and lithium.

This report describes a patient who experienced chronic retarded depression punctuated by precipitous worsening of mood with hyperphagia or by intermittent euphoric episodes. Ratings of depressive symptom severity changed in close association with intracellular sodium content. Intracellular sodium was highly correlated with intracellular lithium. Difficulties that were encountered in the clinical management of this patient are discussed.

Adult↗
PubMed1980

Transmembrane distribution of lithium and sodium in erythrocytes of depressed patients.

In this investigation the intracellular: extracellular distribution of lithium across the erythrocyte membrane (RBC lithium distribution) was studied in vitro and in vivo. The in vitro studies were conducted by incubating cells from drug-free subjects in lithium-containing physiologic media. The in vivo studies consisted of measurements of plasma and erythrocyte (RBC) lithium and sodium concentrations during lithium carbonate treatment. Previous observations of a correlation between in vitro and in vivo RBC lithium distribution values were verified, and it was found that addition of 0.1 mM ouabain to the in vitro incubation media abolished this correlation. To examine the relationship between RBC lithium distribution and specific clinical features of depression, in vitro studies were conducted with RBCs from 20 depressed patients and 14 nondepressed control subjects. The patients were categorized as having bipolar (manic-depressive), unipolar, or secondary depressive disorders. After in vitro incubation with lithium for 48 h, the RBCs from bipolar patients had lithium distribution values that were similar to those observed in ouabain-treated cells. It appears that the lithium transport characteristics of RBCs of bipolar patients may differ from those of other depressed patients or nondepressed subjects.

Depression↗
PubMed1977

Adjustment of lithium dose during lithium-chlorothiazide therapy.

There has been a long-held belief that lithium salts cannot be used in the presence of thiazide diuretics. Recently, however, thiazides have been demonstrated to be not only safe, but actually indicated in two situations in which lithium salts are used. The first is in the treatment of lithium-induced nephrogenic diabetes insipidus and the second is in severe manic depressive illness in which high doses of lithium do not produce therapeutic serum or intraeythrocytic lithium concentrations. This new information now makes it possible for some manic depressive patients with serious medical illnesses (such as hypertension or congestive heart failure), in whom thiazide diuretics are routinely used, to be treated cautiously with lithium carbonate. This paper analyzes data from 13 patients taking lithium carbonate and varying doses of chlorothiazide in order to indicate the approximate magnitude of downward adjustment of daily lithium dose which the clinician must make to safely give 500, 750, and 1,000 mg/day of chlorothiazide.

Chlorothiazide↗