Perry F. Renshaw

In vivo measurement of lithium in humans by nuclear magnetic resonance spectroscopy

In vivo lithium-7 NMR spectroscopy was used to measure muscle and brain lithium levels following the administration of both single and multiple doses of lithium carbonate to normal volunteers. This is the first report of the noninvasive measurement of tissue lithium levels in humans. The results suggest that the relatively slow accumulation of lithium in the brain may be responsible for the delay in therapeutic response that is frequently observed after the initiation of therapy. Further application of this technique should provide a wealth of information on the pharmacokinetics and tissue distribution of lithium in humans.

Immunospecific NMR contrast agents

Most NMR contrast agents suggested to date have been paramagnetic. These agents, which include the transition and lanthanide metal ions as well as stable organic free radicals, do not provide effective contrast at concentrations much below 1 mM. However, the use of macromolecular ferromagnetic and superparamagnetic particles provides, for the first time, an NMR relaxation agent that is effective at subnanomolar concentrations. Two different sized superparamagnetic particles have been coupled to monoclonal antibodies with high affinity for a neuroblastoma-specific cell surface antigen. The specific binding of these particles, both in vivo and in vitro is demonstrated and the consequences for immunospecific NMR contrast are discussed.

Systemic lithium administration alters rat cerebral cortex phospholipids

Systemic lithium administration is known to alter the metabolism of myo-inositol and choline, both of which are precursors for phospholipid synthesis. We report that systemic administration also induces a number of changes in the relative levels of rat cerebral cortex phospholipids, including phosphatidylinositol, phosphatidylcholine, sphingomyelin, and phosphatidylethanolamine. As phospholipids play an integral role in the maintenance of biological membranes, these changes are functionally quite significant and may have implications for a better understanding of lithiums therapeutic actions.

Chronic dietary lithium induces increased levels of myo-inositol-1-phosphatase activity in rat cerebral cortex homogenates

The monovalent lithium ion inhibits the enzyme myo-inositol-1-phosphatase at concentrations comparable to those which are useful in the treatment of manic depressive illness. However, dialyzed cortical homogenates from rats which have been fed diets containing lithium carbonate demonstrate increased myo-inositol-1-phosphate phosphatase activity. Over a 4-week period, there is an approximate doubling of the lithium-sensitive myo-inositol-1-phosphatase activity in the homogenate.

Changes in the 31P-NMR spectra of cats receiving lithium chloride systemically

From the Department of Biochemistry and Biophysics. School of Medicine, University of Pennsylvania, Philadelphia. PA. P. R. is supported by NIH Medical Scientist Training Grant 5-T3?GM-07170. This work was also supported by the Ben Franklin P~~rship’s Advanced Technology Center of S.E. Pennsylvania (University City Science Center). Address reprint requests to Dr. Perry F. Renshaw, Department of Biochemistry and Biophysics. School of Medicine. University of Pennsylvania, Philadelphia, PA 19 104 Received August 19. 1985: revised December 2. 19X5 hibition of the enzyme myo-inositoli-phosphatase (Hallcher and Sherman 19801. Lithium inhibits this enzyme with a K, of 0.8 mM in vitro, which is comparable to the therapeutic serum lithium level of 0.X-l .S mM. As a result of this inhibition, systemic administration of’ lithium chloride can significantly lower myoinositol and raise myo-inos~t~~lI -phosphate (It P) levels in rat cerebral cortex (Sherman ct al. 19X I, 1985). As much as a 40-fold increase has been reported after administration of lithium chloride. As a therapeutic drug. lithium is administered chronically with a relatively low maintenance dose (approximately 0.5 meqikgiday). Thus, any attempt to explain lithium’s mechanism of ac.

Applications of Dextran-magnetite as a sodium relaxation enhancer in biological systems

Dextran-magnetite particles consist of macromolecular magnetite (Fe304) cores coated with the hydrophilic polymer dextran. These particles are completely soluble in aqueous solution and are similar to the iron-dextran complex which has been used to stimulate hematopoesis (I). However, unlike iron-dextran particles, dextran-magnetite particles are superparamaguetic and possess a large, inducible magnetic moment. In magnetic fields over a few thousand gauss, this magnetic moment approaches the saturation magnetization of 5660 G for ferromagnetic magnetite (2). This magnetic moment is two to three orders of magnitude larger than that for similarly sized paramagnetic materials at commonly used NMR field strengths (3). Almost a decade ago, dextran-magnetite was shown to be at least ten times more effective on a molar basis than the Mn2’ ion in reducing the T2 of water protons (4). Since this initial report, there has been relatively little use of this reagent in spectroscopic studies. Part of the reason for this may have been the fact that the reagent was not readily available. The particles used in the initial report were specially prepared and have not been commercially marketed. Recently, however, a simple synthetic procedure has been developed and published (5). Essentially, this protocol involves the precipitation of dextran-magnetite from a stoichiometric mixture of ferrous and ferric chlorides in a viscous dextran solution. The completely soluble particles possess a dense magnetite core ranging from 100-200 A in diameter and are approximately 30% dextran by weight. In addition to relaxing water protons, dextran-magnetite also effectively decreases the T2 of sodium in aqueous solution. In Fig. IA, the 23Na spectrum from a 140 nUI4 NaCl solution containing dextran-magnetite at an approximate molar particle concentration of 3.0 ti (14.5 g magnetite/liter) is displayed. This spectrum was recorded using a Bruker CXP-200 spectrometer operating at 52.9 MHz for sodium; the observed linewidth is slightly greater than 6900 Hz. In contrast, a well shimmed saline sample has a linewidth of only 20 Hz under the same conditions. Figure 1B also contains a spectrum obtained from fresh human erythrocytes which have been washed in 140 mM NaCl containing 3.0 N dextran-magnetite particles. Due to the relatively large size of the particles, they do not enter cells in solution. The resulting spectrum is readily seen to contain two components; a larger, broader component arising from the extracellular sodium and a smaller, narrower component arising from the intra-

A diffusional contribution to lithium isotope effects

The two lithium isotopes 6Li and 7Li behave differently in biological systems. One possible explanation for these effects is that the isotopes diffuse at slightly different rates due to their different masses. Using nuclear magnetic resonance (NMR) techniques, the aqueous diffusion constants of both 6Li and 7Li were measured. A small difference in these diffusion constants was detected, the magnitude of which is consistent with that predicted theoretically.

Superparamagnetic And Paramagnetic MRI Contrast Agents: Application Of Rapid Magnetic Resonance Imaging To Assess Renal Function

The paramagnetic chelate complex, gadolinium-diethylene-triamine-pentaacetic acid, Gd-DTPA, and superparamagnetic particles, such as those composed of dextran coated magnetite, function as magnetic resonance contrast agents by changing the relaxation rates, 1/T1 and 1/T2. The effects that these agents have upon MR signal intensity are determined by: the inherent biophysical properties of the tissue being imaged, the concentration of the contrast agent and the data acquisition scheme (pulse sequence parameters) employed. Following the time course of MR signal change in the first minutes after the injection of contrast agent(s) allows a dynamic assessment of organ functions in a manner analogous to certain nuclear medicine studies. In order to study renal function, sequential MR fast scan images, gradient echo (TR=35/TE=7 msec, flip angle=25 degrees), were acquired, one every 12 seconds, after intravenous injection of Gd-DTPA and/or dextran-magnetite. Gd-DTPA, which is freely filtered at the glomerulus and is neither secreted nor reabsorbed, provides information concerning renal perfusion, glomerular filtration and tubular concentrating ability. Dextran-magnetite (200 A diameter), which is primarily contained within the intravascular space shortly after injection, provides information on blood flow to and distribution within the kidney. The MR signal change observed after administration of contrast agents varied dramatically depending upon the agents injected and the imaging parameters used. Hence a broad range of physiolgic processes may be described using these techniques, i.e. contrast agent enhanced functional MR examinations.