PubMed Health⌕ Search

Biomedical subjects

H L Meltzer

Publications and source records attributed to H L Meltzer.

At least 19 recordsLinked to original sources
PubMed1991

A pharmacokinetic analysis of long-term administration of rubidium chloride.

When a substance with a long biologic half-life is administered over an extended period with a varying dose schedule, many concerns about safety arise. In the case of rubidium chloride, which has been reported to have antidepressive activity, some of these concerns are related to the potential for unanticipated accumulation in the intracellular fluid, where replacement of more than 40% of the potassium ions is associated with toxicity in animals. A pharmacokinetic model of rubidium distribution, based on a three-compartment system, is in accord with the empirical data from previous human trials. By comparison of predicted with observed plasma rubidium levels, a sudden change in the ratio of intra- to extracellular distribution of rubidium can be detected, and availability of this warning signal of potentially toxic intracellular accumulation can be useful during extended administration.

Animals↗
PubMed1990

Lithium toxicity: when is hemodialysis necessary?

A case of severe lithium intoxication is presented in which the function of the lithium pump was monitored, and was found to improve as the signs of lithium toxicity abated. The status of the lithium pump may provide an index of the severity of lithium intoxication. Since the lithium pump regulates the extrusion of lithium from the intracellular to the extracellular space, it is argued that the activity of the lithium pump is an index of the severity of lithium intoxication and crucial to the process of detoxification.

Adult↗
PubMed1990

Mode of action of lithium in affective disorders. An influence on intracellular calcium functions.

The inference that lithium acts by altering intracellular calcium functions is supported by the three areas considered above. First, recent work in other laboratories has broadened the range of lithium actions on calcium-dependent physiological functions. Second, a theoretical analysis of the coupling of calcium transport to the triphosphoinositide response presents a plausible mechanism by which lithium could limit the damage caused by deficient calcium transport. Third, we have recently reported that there is a direct enhancement of the calmodulin-activated membrane-bound calcium pump in lithium-treated bipolar subjects.

Adenosine Triphosphatases↗
PubMed1989

Increased content of a minor ankyrin in erythrocyte membranes of bipolar subjects.

This preliminary study reports on the increased content of a structurally important protein in erythrocyte membranes of bipolar patients treated with lithium carbonate compared with control subjects. The external portion of the erythrocyte membrane is a lipid bilayer into which various integral proteins are inserted; some of these serve as ion channels or energy-dependent transport systems. Another group of proteins, including those termed "ankyrins," link the bilayer to an underlying network of cytoskeletal proteins, and maintain both cell shape and the arrangement of integral proteins within the bilayer. Structural changes resulting from the observed excess of one of the ankyrins in membranes from bipolar subjects could alter several aspects of membrane function. Ankyrins also occur in neurons, where a corresponding increase would alter central nervous system function.

Adult↗
PubMed1988

Calmodulin-activated calcium ATPase in bipolar illness.

Calmodulin-activated calcium ATPase is a transport enzyme which establishes the normal level of intracellular ionized calcium in most cells. We have determined values for three parameters of this enzyme: E-t, the concentration in the membrane; Vmax, the maximal velocity, and Ka, the binding affinity for calmodulin. We assayed these parameters in erythrocyte membranes from lithium carbonate-treated bipolar subjects and from normal controls. Bipolar subjects have significantly increased levels of E-t compared with normal controls.

Adult↗
PubMed1987

Renal tolerance of rubidium chloride: short-term clinical evaluation.

The rubidium and lithium ions are known to have opposite effects on a wide range of biochemical and behavioral parameters in experimental animals. Based on the proven effectiveness of lithium as an antimanic agent, several trials have been conducted with rubidium in the acute treatment of the depressive phase of bipolar illness. The results to date are promising. However, the 30- to 60-day biologic half-life of rubidium has mandated careful studies of potential toxicity before engaging in long-term administration of this ion to depressive subjects. One area of potential concern is the possibility of renal toxicity, which could be expressed as unexpectedly increased retention of rubidium. The data in this paper show that after 15 days of rubidium administration, there are no changes beyond the normal range in a variety of kidney function tests, including in four enzymes which are specific markers of tubule cell function.

Aged↗
PubMed1986

Lithium mechanisms in bipolar illness and altered intracellular calcium functions.

Calcium functions as an intracellular second messenger, transducing a variety of hormonal, electrical, and mechanical stimuli by activating a wide range of enzymes. There is evidence, ranging from definitive to strongly presumptive in quality, that lithium can alter many calcium-dependent processes. The list of enzyme systems dependent on calcium and altered by lithium includes adenylate cyclase, glycogen synthase, inositol-1-phosphatase, and calcium adenosine triphosphatase (ATPase). Lithium also interferes with calcium regulation of receptor sensitivity, parathyroid hormone release, microtubule structure, and other systems. All of the neural mechanisms that are hypothesized to explain various psychopharmacological treatments of bipolar illness involve functions that are critically controlled by calcium. Moreover, in every instance, a known action of lithium on calcium function could account for lithium's therapeutic or prophylactic results. From these considerations the dual hypotheses emerge that bipolar illnesses arise from disorders in calcium-regulated functions and that lithium acts by reversing or counterbalancing the effects of these calcium dysfunctions.

Adenylyl Cyclases↗
PubMed1984

Factors associated with the preincubation effect of hypoxic cell sensitizers in vitro and their possible implications in chemosensitization.

The enhancement of melphalan toxicity was observed by preincubation of V-79- 379A cells in spinner culture with multiple doses of misonidazole (miso) or SR-2508 under hypoxic conditions. Chemosensitization was shown to be a function of sensitizer concentration and duration of exposure to the alkylating agent. A preincubation exposure of cells with 5 mM miso reduced endogenous cell thiols to less than 5% of controls and enhanced melphalan toxicity by a factor of 4.7. Cells preincubated with miso not only had lower levels of nonprotein thiols, but also were shown to have altered levels of intracellular calcium and a lower threshold to oxidative stress as measured by toxicity to cysteamine or H2O2. Preincubated cells, hypoxic cells, and cells receiving moderate hyperthermia (42.5 degrees C for 3 hr) all showed increased sensitivity to either cysteamine or H2O2. The increased killing of preincubated cells by cysteamine was shown to be similar to that of H2O2, and the dramatic reduction of cysteamine toxicity by catalase indicated H2O2 was the major reaction associated with this effect. These results indicate that preincubated cells exhibit a variety of biological effects that may significantly influence their response to further treatment with drugs or radiation, especially where peroxidative and free radical mechanisms are involved. The depletion of endogenous thiols, calcium disturbance, and vulnerability to oxidative stress are factors to be considered when interpreting mechanisms of combined drug action and effects that may potentially be exploited in terms of therapeutic gains.

Animals↗
PubMed1983

Inhibition of calmodulin-activated Ca2+-ATPase by propranolol and nadolol.

Propranolol, at concentrations ranging from 0.05 to 0.5 mM, inhibits the calmodulin-activated Ca2+-ATPase of human erythrocyte membranes. In the same concentration range it is without effect on the basal Ca2+-ATPase. The inhibition is competitive and appears to be due to membrane binding, rather than to combination with cytoplasmic calmodulin as is the case for phenothiazines. This effect of propranolol may explain its ability to open the calcium-gated potassium channel, and could also be related to its action as a beta-adrenergic blocker. Nadolol, another beta-adrenergic blocker, is also an inhibitor of calmodulin-activated Ca2+-ATPase.

Binding, Competitive↗
PubMed1982

Increased erythrocyte calcium in alcoholism.

The intraerythrocyte calcium concentration in blood samples of 42 hospitalized alcoholic subjects was initially elevated but declined over a period of several weeks toward normal values. The abnormally high values, which appear to be a direct consequence of prior alcohol ingestion, may explain previous reports of lowered erythrocyte potassium in chronic alcoholics, since there is a specific calcium-gated potassium channel in erythrocyte membranes.

Alcoholism↗
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↗
PubMed1982

Regulation of calcium entry into the extracellular environment of the rat brain.

Since neuronal activity is critically related to both intra- and extracellular calcium ion concentrations, there must be a mechanism for regulating the transfer of calcium from the blood into the extracellular environment of the brain. The data presented here support the hypothesis that, within or close to the site of passive permeation of calcium in the choroid plexus, there is a calcium pump capable of recycling the filtered calcium back into the capillary circulation. This pump can be blocked by ruthenium red, a known inhibitor of active calcium transport. The activity of the calcium pump is shown to increase in proportion to the concentration of calcium in the cerebroventricular fluid. Its physiological role therefore would be to insure that the calcium concentration available to the brain will be maintained within a narrow range even in the presence of severe hypercalcemic states.

Animals↗
PubMed1981

Enhanced activation of human erythrocyte Ca2+-ATPase by calmodulin after storage or brief exposure to disulfite.

Ca2+-ATPase of human erythrocyte membranes which are prepared from freshly drawn human blood can be activated by the calmodulin present in the hemolysate to 1.5-times the basal level. However, when the membranes are prepared from blood stored for 5-14 days the activation by calmodulin reaches 2.5-times the basal level. An enhanced reactivity to calmodulin of similar magnitude was produced by brief exposure of fresh erythrocytes to 25 mM Na2S2O5 prior to isolation of the membranes. Reincubation of the activated cells in a disulfite-free medium restored the membrane-bound Ca2+-ATPase to a state of normal reactivity to calmodulin. It is hypothesized that these results are related to the level of cytoplasmic Ca2+ which is partly controlled by complex formation with 2,3-diphosphoglycerate, the concentration of which is diminished when its specific phosphatase is activated by Na2S2O5.

Blood Specimen Collection↗
PubMed1981

Lithium elimination half-life and duration of therapy.

The elimination half-life (t1/2E) of lithium carbonate in red blood cells, plasma, and urine was measured in 30 patients hospitalized for primary affective disorder. Duration of Li treatment at time of sampling was found to have a direct effect on lengthening time course. Patients on their initial course of Li had the lowest t1/2s: 1.12 (urine), 1.28 (plasma), and 1.22 days (red blood cells); those less than 1 yr on Li had intermediate values: 1.85, and 1.65, and 1.75 days; and those more than 1 continuous year on Li had the longest mean t1/2s: 2.40, 2.43, and 2.24 days. These results for urine (p less than 0.01) and plasma (p less than 0.05) are further evidence that Li may stimulate the production of an endogenous regulator of Li efflux. This regulator may prove to be an important factor in planning of long-term Li prophylaxis.

Female↗