The distribution of lithium and its effects on the distribution and excretion of other ions in the rat.

1. In rats, lithium (ca 1 mEquiv/kg body weight) decreased brain sodium and magnesium, bone sodium and calcium and increased muscle calcium, plasma magnesium, urinary calcium and urine volume.2. Lithium was particularly concentrated in bone.

Effect of lithium in immunodeficiency: improved blood cell formation in mice with decreased hematopoiesis as the result of LP-BM5 MuLV infection.

Lithium salts have been demonstrated to induce the production of hematopoietic cells following administration in vivo and to minimize the reduction of these cells following treatment with either radiation, chemotherapeutic or antiviral drugs. We have previously demonstrated that lithium, when administered in vivo to immunodeficient mice infected with LP-BM5 MuLV (MAIDS) significantly reduced the development of lymphadenopathy, splenomegaly, and the lymphoma associated with late-stage immunodeficiency disease in this model, and increased the survival of these animals compared to virus-infected controls not receiving lithium. We report here the results of in vivo studies in the MAIDS model that determined the effect of lithium on peripheral blood indices and the number of myeloid (CFU-GM), erythroid (BFU-E) and megakaryocyte (CFU-Meg) hematopoietic progenitors from bone marrow and spleen harvested from immunodeficient mice receiving lithium carbonate (1 mM) placed in their drinking water compared to virus-infected controls not receiving lithium. Time-points evaluated were at weeks 1, 5, 9, 13, 17, and 21 postviral infection. Virus-control mice not receiving lithium demonstrated all the signs that are characteristic of MAIDS, i.e., splenomegaly, lymphadenopathy, hypergammaglobulinemia, reduced hematopoiesis, and death. Infected mice receiving lithium demonstrated diminished presence of splenomegaly, lymphadenopathy, hypergammaglobulinemia, no suppression of hematopoiesis nor mortality. Enhanced hematopoiesis was demonstrated by neutrophilia, lymphocytosis, thrombocytosis, and erythrocytosis that was evident by increased myeloid, erythroid, and megakaryocyte progenitor cells cultured from bone marrow and spleen. These studies further demonstrate that lithium influences the disease process in the MAIDS model and restricts the development of hematopoietic suppression that develops in this retroviral animal model of immunodeficiency.

Recovery of cellular activity in cryopreserved human foetal brain tissue.

Since long-term cryopreservation can cause losses in neural tissue viability and function a prerequisite would be the ability to monitor and promote functional recovery in donor tissue intended for neural transplantation. Rapid assessment of cryopreserved tissue's functional status prior to grafting is presently difficult in a clinical setting. A convenient indicator of functional status may be the level of DNA synthesis activity taking place in the tissue. Using immunocytochemical detection of incorporated bromodeox-yuridine we have quantified and compared DNA synthesis activity (expressed as proliferative capacity (PC)) in human foetal mesencephalic, striatal, cortical and cerebellar tissue before and after a 275-376 day storage in liquid nitrogen. There was a post-storage reduction in viability of 48-73% and in PC of 26-59%; the higher the PC before storage the greater the reduction after. Incubation of cryopreserved tissue with fetal calf serum resulted in 2-4-fold higher PC levels than serum-untreated controls and reached 80% of fresh tissue levels in mesencephalic cells after 3-4 h incubation. Assuming that quantification of proliferative activity is a practical indicator of the tissue's functional status, these findings suggest that treatment of the tissue with serum can largely restore the lost function caused by cryopreservation.

Increased hematopoietic toxicity following administration of interferon-a with combination dideoxynucleoside therapy (zidovudine plus ddI) administered in normal mice.

Because of the urgency to develop drugs which will effectively combat HIV infection, many combination therapies which have proved effective against HIV in vitro have undergone, or are undergoing clinical trial. Unfortunately many of drugs are being used without rigorous and exhaustive preclinical evaluation to assess their potential to develop hematopoietic toxicity. We report here the results of two in vivo studies performed to analyze the effect of combined zidovudine (AZT) plus didanosine (ddI) therapy, either with or without interferon-a (IFN-a), on murine hematopoiesis. Normal C57BL/6 female mice were administered AZT (1.0 mg/ml) plus dose-escalation ddI (0.1, 1.0 and 2.5 mg/ml) placed in their drinking water. Control mice received IFN-å (100 units/ml) alone. Mice were serially bled and sacrificed over a six-week period for assessment of hematopoietic toxicity measured by peripheral blood indices and assays of hematopoietic progenitors, i.e., erythroid (BFU-E), myeloid (CFU-GM), and megakaryocyte (CFU-Meg) cultured from bone marrow and spleen. AZT plus dose-escalation ddI decreased the hematocrit and white blood cell count when administered to normal mice compared to untreated controls during the six-week examination period. Marrow derived BFU-E, CFU-GM, and CFU-Meg were all reduced, however an increase was observed from the spleen for all three progenitor cell types. Use of IFN-a, in addition to combination AZT plus ddI further decreased the hematocrit, white blood cells and platelets. Marrow derived CFU-GM and CFU-Meg were increased slightly and only marginally for BFU-E with a similar response observed from the spleen. These results demonstrate that combination AZT plus ddI when used in vivo may produce synergistic hematopoietic toxicity, and that the addition of IFN-a to this treatment regimen increases this toxicity. These data indicate caution when this therapeutic approach is suggested for patients infected with HIV. If used, these patients will require careful monitoring for blood cell toxicity.

Lithium inhibition of phosphofructokinase.

The mode of action of lithium in prophylaxis of recurrent affective disorder is unknown although it has been suggested that lithium might compete with magnesium in magnesium dependent processes. We have previously shown pyruvate kinase to be inhibited by lithium and the present study demonstrates a small inhibition by lithium of phosphofructokinase that is also a major regulatory step in glycolysis. Inhibition of PFK was competitive with respect to ATP and magnesium and noncompetitive with respect to potassium and fructose-6-phosphate. Inhibition was enhanced at reduced concentrations of magnesium.

Rat-brain pyruvate kinase: purification and effects of lithium.

Purified pyruvate kinase was prepared from pooled brains obtained from untreated rats. Its properties suggest that it is similar to type 'M' pyruvate kinase. Lithium inhibition was demonstrated at pharmacologically significant lithium concentrations (7%-12% at 2 mmol 1-1 Li) and this was similar in character to that previously seen in rabbit muscle pyruvate kinase, namely noncompetitive with respect to phosphoenol pyruvate, K+, and Mg2+ but competitive with ADP.

Pharmacokinetics of lithium in patients treated with controlled release lithium formulations.

There has long been discussion as to the relative merits of the lithium formulations available in the UK. Two of these have been shown to exhibit similar pharmacokinetics in normal volunteers and both are now marketed as controlled release formulations. In this study the serum lithium profiles of these formulations were compared in patients at two centres during the first 4 h after the dose, and at 24 h. We were unable to show any significant difference between the formulations in respect of maximum serum lithium concentrations or the concentration at each time point.

Lithium-6 stable isotope determination by atomic absorption spectroscopy and its application to pharmacokinetic studies in man.

No useful radioisotope of lithium exists to assist in the study of its biochemical pharmacology. A simple method has been developed for the determination of the stable isotope 6Li by atomic absorption spectroscopy (AAS). The technique is applicable in any laboratory equipped with simple AAS apparatus. Analysis of total lithium content (E) by flame emission spectroscopy is followed by separate determination (A6 and A7) of atomic absorption by the sample of the light emitted by separate hollow cathode lamps manufactured from the isotopes 6Li and 7Li. The standard curve of absorption ratio (A6/A7) against isotopic ratio (6Li/7Li) at any concentration (E) is an exponential which may be solved using a simple programmable calculator. Application of this method to the study of the pharmacokinetics of 6Li administered to 4 normal volunteers previously loaded with 7Li suggests that the rate of appearance of lithium in blood is unaffected by the previous state of lithium loading.

Magnesium inhibition of carbachol-induced contractions of the rat uterus and gastrointestinal tract: ex vivo effect of long term streptozotocin-induced diabetes.

Rats were rendered diabetic by a single administration of streptozotocin (STZ). They were maintained in the diabetic state for six weeks before being killed, and diabetic state was confirmed by routine urine and blood glucose estimations. The contractile sensitivity of jejunum, colon, stomach fundus and uterus to carbachol was reduced in control animals by increasing buffer magnesium concentration from 1.9 mmol/litre to 23.8 mmol/litre. This magnesium effect was reversed in the colon, stomach fundus and uterus of streptozotocin-diabetic animals, with contractile sensitivity being enhanced in the presence of increased magnesium concentration. In the jejunum, however, the magnesium effect was not reversed by STZ-induced diabetes. In diabetic animals, magnesium generally had the opposite effect on gastrointestinal and uterine tissues when compared with control animals. This suggests that, in the diabetic condition, any altered gastrointestinal function may be due to an underlying difference in the sensitivity to changes in magnesium.

Magnesium interactions with lithium and sodium salts of adenosine triphosphate: an investigation by phosphorus-31 nuclear magnetic resonance spectroscopy.

Phosphorus NMR spectra were recorded for complexes of Na2ATP and Li4ATP with varying concentrations of magnesium, calcium and lithium. Each ion caused a shift in the phosphorus resonances, usually downfield, and a decrease in the 31P-31P coupling constant. The sodium ATP formed a 1:1 complex with each ion and a 1:2, ATP:Mg complex with magnesium whilst lithium ATP gave evidence to suggest the formation of bis(nucleotide) complexes.

Magnesium, adenosine triphosphate, and catecholamine complexes: application of new means of identifying solute-solute interactions of biological significance using NMR chemical shift data.

The interaction of magnesium ions with biomolecular species is fundamental to the regulation of many biological processes. A mathematical technique to investigate such interactions is described. The concept of a pseudo-formation curve is discussed and the relevance and applicability of such constructions to the study of solute-solute interactions is outlined. Analysis of curves based on the published variation of chemical shift data of various nuclei of adrenaline and dichloroisoprenaline in aqueous solution, in the presence of increasing concentration of the complex Mg-ATP, is described. Unambiguous indentification of specific interactions and the stability of the species produced is shown to be feasible. Some variation of the values of formation constants deriving from different nuclei reflects the significance of molecular environmental factors on the parameters used.

Magnesium and lithium antagonism of carbachol- and electrically-induced smooth muscle contractions in the rat gastrointestinal tract.

The pharmacological actions of lithium and magnesium have been investigated using isolated smooth muscle preparations from the rat gastrointestinal tract. Tissue contraction was evoked by means of carbachol or electrical field stimulation and the degree of inhibition of contraction caused by lithium was measured. Lithium effects were compared with those of the chemically similar ions, magnesium and calcium, by manipulation of the physiological buffer solutions. Lithium antagonism was enhanced when tissue contractile mechanisms were dependent on extracellular calcium concentration in the bathing fluid. This suggests that lithium is acting at the cell membrane by preventing calcium entry via ion channels. These results are consistent with evidence from clinical studies which indicate low cellular accumulation of lithium at therapeutic concentrations.

Dental conditions in patients with bipolar disorder on long-term lithium maintenance therapy.

Bipolar disorder (manic depressive disease) affects 1% of the United States population. These persons suffer from episodes of extreme elation followed by long periods of depression. Dental screening examinations of 40 patients consecutively admitted to the medical center with this diagnosis were performed. Poor oral hygiene, accumulations of supragingival and subgingival calculus, extensive dental caries, and numerous missing teeth were commonly identified. The majority of patients with bipolar disorder are treated with lithium carbonate. The physiological effects of lithium, and its interaction with drugs used in dentistry are reviewed, and disease-specific modifications in dental treatment are recommended.

Use of an international faculty/student exchange program as a process to establish and improve graduate education and research within an allied health discipline.

It has been recognized in the allied health professions that allied health disciplines must enhance and increase their research and scholarly activity. If faculty/staff are to be judged in the academic environment in which they work, their efforts to conduct research must be supported. Recognition for academic scholarship measured by the performance of research and scholarly activity is often difficult for faculty/staff to attain because of increased demands for scheduled time devoted to classroom instruction and student advising. This inability for faculty/staff to engage in research and scholarly activity often is enhanced by the lack of proper and adequate facilities and equipment. Also important is the role of graduate education, which itself, provides a stimulus for the performance of research and scholarly activity. This article reports outcomes achieved by an international faculty/staff-student program that provides an opportunity for faculty/staff and students within an allied health discipline to conduct research and scholarly activity. This program could serve as a model to identify the strengths and benefits that can be achieved by such programs. This program is capable of improving the research and scholarly activity of all academic units within an allied health discipline.