Effect of antipsychotics on serum lithium levels and white blood cell counts.

Lithium carbonate is used to increase white blood cell counts as a means of counteracting leukopenia caused by the administration of antipsychotic drugs. To evaluate the effect of antipsychotics on the leukocyte-enhancing effect of lithium, we compared white blood cell counts, serum lithium levels, and lithium dosage in patients receiving antipsychotics and lithium in combination and patients receiving lithium alone. Chlorpromazine equivalent values were used as an indicator of the antipsychotic dose. Lithium serum levels were measured in 41 hospitalized patients. The lithium dose in the combination group (median, 800 mg) was significantly higher than that in group receiving only lithium (median, 400 mg) (P = 0.03). The lithium doses in the combination group receiving ≥1000 mg chlorpromazine equivalents (overdosing; median lithium dose 800 mg) and the combination group treated with 600-999 mg chlorpromazine equivalents (high dosing; median lithium dose 800 mg) were significantly higher than the group that was not treated with antipsychotic medication, with median lithium dose 400 mg (P < 0.05).There were no significant differences in the white blood cell counts and serum lithium levels. Because of the large variety of antipsychotic drugs used in combination with lithium and the various doses used, it was difficult to evaluate the effects of lithium, with or without antipsychotic administration, on leukocyte count enhancement. We are planning to study a larger number of patients and, since renal function could not be assessed in this study, we will also focus on renal function, including urine output.

Effect of food thickener and jelly wafer on the pharmacokinetics of levofloxacin orally disintegrating tablets.

This study was designed to determine the effects of a food thickener and deglutition aid jelly for oral administration, jelly wafer, on the pharmacokinetics of levofloxacin orally disintegrating tablets. With an increase in immersion time, the disintegration time of levofloxacin orally disintegrating tablets immersed in food thickener was prolonged, whereas that of the tablets immersed in jelly wafer was shortened. The dissolution behavior of non-immersed levofloxacin orally disintegrating tablets was not similar to that of tablets immersed in food thickener, but was similar to that of tablets immersed in jelly wafer. The time to reach the maximum systemic levofloxacin concentration was the same for non-immersed orally disintegrating tablets and tablets immersed in food thickener and jelly wafer. Moreover, there was no significant difference in the maximum concentration after administration between non-immersed orally disintegrating tablets and tablets immersed in food thickener or jelly wafer. These findings suggest that drugs with a high bioavailability, such as levofloxacin, enter the systemic circulation even when administered with a food thickener or jelly wafer.

Effect of deglutition aids on the inhibitory effect of orally disintegrating tablets of voglibose on the postprandial elevation of blood glucose levels: a case investigating the interaction between xanthan gum and voglibose.

In this study, we first performed a disintegration test of the voglibose orally disintegrating (V-OD) tablet immersed in jelly-wafer (JW, V-ODims/jw) for 10 min and compared it with the disintegration time of V-OD that was not immersed in JW. We then orally administered the V-ODims/jw tablet to 7 healthy adults and compared the shift in blood glucose levels (BGLs), after loading with a sucrose solution (Suc-sol, 100 g/150 mL), with that after administration of the non-immersed V-OD tablet. The disintegration time of V-ODims/jw tablet was shorter than that of V-OD. When administered to healthy adults, the BGL after loading with Suc-sol was higher with V-ODims/jw tablet administration than with V-OD tablet. We predict that the expression of the efficacy of voglibose is reduced as a result of the interaction between voglibose and the polysaccharide, xanthan gum (XG), since it is a common additive in JW. This study shows that deglutition aids with additives that do not affect pharmacokinetics must be carefully selected for administering along with pharmaceuticals, because of a suggested possibility that the interaction between these pharmaceuticals and the additives in the deglutition aids weaken the drug efficacy. A more careful selection of deglutition aids from the wide selection of medication is especially important when administered to patients who use these deglutition aids often, such as elderly individuals or individuals with a deglutition disorder.

Effect of Food Thickener on the Inhibitory Effect of Mitiglinide Tablets on Post-prandial Elevation of Blood Glucose Levels.

The aim of this study was to examine the effect of food thickener on the pharmacodynamics of mitiglinide (MGN), a drug belonging to a class of rapid-acting insulin secretagogues. First, MGN tablets were coated by immersion in a xanthan gum-based food-thickening agent. This treatment was shown to delay disintegration rates of MGN tablets in vitro. The pharmacodynamics of MGN after ingestion of a single oral dose of an MGN tablet, with or without food thickener immersion, were then examined in an open-label crossover study comprising 5 healthy participants. It was observed that after administration of 75 g of oral glucose, the area under the blood glucose concentration-time curve was larger for treatment with MGN tablets that had been immersed in the food thickener than for nonimmersed tablets. The maximum blood glucose level was also higher in treatments with MGN tablets that had been immersed in food thickener. The extended time of higher glucose levels associated with thickener-immersed MGN tablets given to human volunteers may be associated with the reduced disintegration rates of immersed MGN tablets as observed in the in vitro experiment. Overall, our study suggests that commercially available food thickeners influence the pharmacodynamics of MGN and that their use should therefore be carefully assessed and monitored in certain clinical situations.

Efficacy of Adenine in the Treatment of Leukopenia and Neutropenia Associated with an Overdose of Antipsychotics or Discontinuation of Lithium Carbonate Administration: Three Case Studies.

Because adenine is effective for managing cases of radiation-induced and drug-induced leukopenia, it may be effective in cases of antipsychotic-induced leukopenia and neutropenia. Here, we report our experience with patients with leukopenia and neutropenia caused by an antipsychotic overdose or discontinuation of lithium carbonate, in whom adenine administration ameliorated the white blood cell and neutrophil counts. The progress of patients suggests that adenine is effective in cases of leukopenia and neutropenia associated with lithium carbonate discontinuation and an antipsychotic overdose.

Effects of Food Thickeners on the Inhibitory Effect of Voglibose Oral-disintegrating Tablets on Post-prandial Elevation of Blood Sugar Levels.

The aim of this study was to examine the effects of food thickeners on the pharmacodynamics of voglibose, an α-glucosidase inhibitor. The pharmacodynamics of voglibose were examined in an open-label study in 9 healthy participants after the ingestion of a single oral dose of a voglibose oral-disintegrating tablet, with and without food thickener immersion. The area under the incremental blood sugar concentration-time curve was larger and the rate of increments in the blood sugar concentration was higher with the voglibose oral-disintegrating tablets immersed in the food thickener than with the tablets that were not immersed. Immersing the voglibose oral-disintegrating tablets in the food thickener possibly delayed their disintegration rate. This suggests that commercially available food thickeners may be associated with changes in the disintegration of voglibose oral-disintegrating tablets and should therefore be used carefully in certain clinical situations.

Effect of Food Thickener on Dissolution and Laxative Activity of Magnesium Oxide Tablets in Mice.

The present study examined the dissolution of magnesium oxide (MgO) from MgO tablets placed in a food thickening agent (food thickener) and its effects on laxative activity. We prepared mixtures of MgO tablets suspended in an aqueous suspension and food thickeners in order to evaluate the dissolution of MgO. The results of the dissolution tests revealed that agar-based food thickeners did not affect the MgO dissolution. In contrast, some xanthan gum-based food-thickener products show dissolution rates with certain mixtures containing disintegrated MgO tablets suspended in a food thickener that decrease over time. However, other xanthan gum-based food-thickener products show dissolution rates that decrease immediately after mixing, regardless of the time they were allowed to stand. In order to investigate the laxative activity of MgO, we orally administered a mixture of MgO suspension and food thickener to mice and observed their bowel movements. The animal experiments showed that when agar-based food thickeners were used, the laxative activity of MgO was not affected, but it decreased when xanthan gum-based food thickeners were used.

Stabilization of the Serum Lithium Concentration by Regulation of Sodium Chloride Intake: Case Report.

To avoid fluctuation of the serum lithium concentration (CLi), sodium chloride (NaCl) intake was regulated in oral alimentation. A 62-year-old woman was hospitalized and orally administered 400 mg of lithium carbonate a day to treat her mania. Her CLi was found to be 0.75-0.81 mEq/L. Vomiting made it difficult for the patient to ingest meals orally, and therefore parenteral nutrition with additional oral intake of protein-fortified food was initiated. On day 22, parenteral nutrition was switched to oral alimentation to enable oral intake of food. The total NaCl equivalent amount was decreased to 1.2 g/d, and the CLi increased to 1.15 mEq/L on day 26. Oral alimentation with semi-solid food blended in a mixer was immediately initiated. Although the total NaCl equivalent amount was increased to 4.5-5.0 g/d, her CLi remained high at 1.14-1.17 mEq/L on days 33 and 49, respectively. We investigated oral administration of NaCl (1.8 g/d) on day 52. The total NaCl equivalent amount was increased to 6.3-6.8 g/d, and the CLi decreased to 1.08-0.97 mEq/L on days 63 and 104, respectively. After the start of the orally administered NaCl, her diet was changed to a completely blended diet on day 125. The total NaCl equivalent amount was increased to 9.0-14.5 g/d, and the CLi decreased to 0.53 mEq/L on day 152; therefore, the oral administration of NaCl was discontinued on day 166. The CLi was found to be 0.70-0.85 mEq/L on days 176 and 220.

[Effect of food thickener on disintegration and dissolution of magnesium oxide tablets].

It has been reported that magnesium oxide tablets are excreted in a non-disintegrated state in the stool of patients when the tablets are administered after being immersed in a food thickener. Therefore we examined whether immersion in a food thickener affects the pharmacological effect in patients taking magnesium oxide tablets, and whether immersion affects its disintegration and solubility. The mean dosage (1705 mg/d) was higher for patients who took tablets after immersion in a food thickener than for those who took non-immersed tablets (1380 mg/d). The disintegration time and dissolution rate of the immersed tablets were lower than those of non-immersed tablets in vitro. Furthermore, components that constitute the food thickener and differences in composition concentrations differentially affect the disintegration and solubility of magnesium oxide tablets. This suggests that commercially available food thickeners are likely to be associated with changes in the degradation of magnesium oxide tablets, and they therefore should be carefully used in certain clinical situations.

[Elevated serum lithium concentration due to switch from parenteral nutrition alone to parenteral with enteral nutrition].

We report a patient with elevated serum lithium concentration caused by switching from parenteral nutrition alone to parenteral with enteral nutrition. A 73-year-old female inpatient was treated with lithium carbonate 600 mg/d for manic episodes of bipolar disorder. Her serum lithium level was maintained at 0.57-0.79 mEq/L. She was administered total parenteral nutrition owing to difficulty in oral intake. Her diet contained 4.8-5.8 g/d of sodium chloride. After this, parenteral with enteral nutrition was initiated. The total sodium chloride intake decreased from 6.3 to 3.0-4.0 g/d following this change. On day 15 after initiation of parenteral with enteral nutrition, her serum lithium level increased to 1.17 mEq/L, which is closer to the upper therapeutic range limit. Therefore enteral nutrition was stopped immediately, and an electrolyte solution was administered instead of enteral nutrition. An antibiotic agent was also simultaneously administered because of infection. The total amount of sodium chloride administered was increased to 7.0 g/d during this treatment. Four days after treatment, the serum lithium level returned to 0.57 mEq/L. This case suggests that administration of appropriate sodium chloride nutrition is important during treatment with lithium carbonate, because disposition of lithium ion is paralleled to that of sodium.

Dose-dependent valproate-induced alopecia in patients with mental disorders.

Drug-induced hair loss may occur as a side effect in patients treated with valproate. However, few studies have reported a relationship between the blood levels of valproate and the occurrence of hair loss. We report three cases of alopecia that occurred in patients who received sodium valproate for mental disorders. In all three cases, alopecia appeared after long-term valproate exposure with a plasma concentration of 100 µg/ml approximately. However, the alopecia resolved in all cases after dose reduction or treatment discontinuation. Therefore, alopecia may develop in patients with chronic exposure to high plasma concentrations of valproate. Based on these findings, we believe that patients with high plasma concentrations of valproate should be closely monitored for the occurrence of side effects, particularly alopecia.

Essentially exact ground-state calculations by superpositions of nonorthogonal Slater determinants.

An essentially exact ground-state calculation algorithm for few-electron systems based on superposition of nonorthogonal Slater determinants (SDs) is described, and its convergence properties to ground states are examined. A linear combination of SDs is adopted as many-electron wave functions, and all one-electron wave functions are updated by employing linearly independent multiple correction vectors on the basis of the variational principle. The improvement of the convergence performance to the ground state given by the multi-direction search is shown through comparisons with the conventional steepest descent method. The accuracy and applicability of the proposed scheme are also demonstrated by calculations of the potential energy curves of few-electron molecular systems, compared with the conventional quantum chemistry calculation techniques.

Real-space finite-difference approach for multi-body systems: path-integral renormalization group method and direct energy minimization method.

The path-integral renormalization group and direct energy minimization method of practical first-principles electronic structure calculations for multi-body systems within the framework of the real-space finite-difference scheme are introduced. These two methods can handle higher dimensional systems with consideration of the correlation effect. Furthermore, they can be easily extended to the multicomponent quantum systems which contain more than two kinds of quantum particles. The key to the present methods is employing linear combinations of nonorthogonal Slater determinants (SDs) as multi-body wavefunctions. As one of the noticeable results, the same accuracy as the variational Monte Carlo method is achieved with a few SDs. This enables us to study the entire ground state consisting of electrons and nuclei without the need to use the Born-Oppenheimer approximation. Recent activities on methodological developments aiming towards practical calculations such as the implementation of auxiliary field for Coulombic interaction, the treatment of the kinetic operator in imaginary-time evolutions, the time-saving double-grid technique for bare-Coulomb atomic potentials and the optimization scheme for minimizing the total-energy functional are also introduced. As test examples, the total energy of the hydrogen molecule, the atomic configuration of the methylene and the electronic structures of two-dimensional quantum dots are calculated, and the accuracy, availability and possibility of the present methods are demonstrated.

Electron-electron correlations in square-well quantum dots: direct energy minimization approach.

Electron-electron correlations in two-dimensional square-well quantum dots are investigated using the direct energy minimization scheme. Searches for groundstate charges and spin configurations are performed with varying the sizes of dots and the number of electrons. For a two-electron system, a standout difference between the configurations with and without counting correlation energy is demonstrated. The emergence and melting of Wigner-molecule-like structures arising from the interplay between the kinetic energy and Coulombic interaction energy are described. Electron-electron correlation energies and addition energy spectra are calculated, and special electron numbers related to peculiar effects of the square well are extracted.

Total-energy minimization of few-body electron systems in the real-space finite-difference scheme.

A practical and high-accuracy computation method to search for ground states of few-electron systems is presented on the basis of the real-space finite-difference scheme. A linear combination of Slater determinants is employed as a many-electron wavefunction, and the total-energy functional is described in terms of overlap integrals of one-electron orbitals without the constraints of orthogonality and normalization. In order to execute a direct energy minimization process of the energy functional, the steepest-descent method is used. For accurate descriptions of integrals which include bare-Coulomb potentials of ions, the time-saving double-grid technique is introduced. As an example of the present method, calculations for the ground state of the hydrogen molecule are demonstrated. An adiabatic potential curve is illustrated, and the accessibility and accuracy of the present method are discussed.

A path-integration calculation method based on the real-space finite-difference scheme.

We propose a new path-integration calculation method to treat the time evolution of a wavefunction within the framework of the real-space finite-difference formalism, and also develop an effective scheme to compute the scattering wavefunction for an incident electron with arbitrary energy, in which an impulse wavefunction is adopted as an initial state of the time evolution. In this method, once the time evolution of the initial impulse wavefunction is calculated, all of the solutions in the scattering problem can be derived by means of Fourier analysis of the time-evolved wavefunction, which leads to a reduction of the calculation time. In order to test the applicability of our newly developed simulation procedures, we implemented simulations for the one-dimensional scattering problem. Each simulation showed the usefulness of the present scheme by yielding the steady scattering states in agreement with exact ones.