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 CYP2D6 genetic polymorphism on peak propafenone concentration: no significant effect of CYP2D6*10.

Aim: The study aims to investigate the clinical implication of nonfunctional poor metabolizer (PM) alleles and intermediate metabolizer (IM) alleles of CYP2D6, including the CYP2D6*10 allele which shows substrate-dependent decrease in enzymatic activity, in antiarrhythmic therapy using propafenone. Materials & methods: We examined serum propafenone concentrations and metabolic ratio, which was expressed as serum concentrations of propafenone to 5-hydroxypropafenone, in 66 Japanese patients with tachyarrhythmias. Results: The peak propafenone concentration and metabolic ratio in CYP2D6 PM allele carriers were higher than those in extensive metabolizer (EM)/EM, EM/IM and IM/IM genotype groups. Conclusion: Results suggest that CYP2D6 PM alleles affect peak propafenone concentration, but the CYP2D6 IM allele CYP2D6*10 has no clinical implication in propafenone dosing.

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.

Optimal sampling time and clinical implication of the SCN5A promoter haplotype in propafenone therapeutic drug monitoring.

PURPOSE: The clinical usefulness of therapeutic drug monitoring (TDM) of propafenone, a sodium channel blocker, has been unclear due to the lack of information regarding optimal blood sampling time and therapeutic concentration range. Antiarrhythmic effects of sodium channel blockers are affected by the activity of the cardiac sodium channel (SCN5A). We investigated the optimal sampling time and the clinical implication of the SCN5A promoter haplotype in propafenone TDM. METHODS: We evaluated serum concentrations of propafenone, the SCN5A promoter haplotype, and antiarrhythmic efficacy in 55 patients with supraventricular tachy-arrhythmias. Blood samples obtained 1.5-6 and 10-24 h after the last dose were categorized as peak and trough samples, respectively. RESULTS: The peak propafenone concentration was significantly higher in effectively treated patients than that in patients showing insufficient response (337 ± 213 vs. 177 ± 93 ng/mL, P = 0.005), but the trough propafenone concentration was not significantly different between the two groups (68 ± 48 vs. 42 ± 36 ng/mL). Clinically relevant propafenone efficacy was achieved significantly more often in SCN5A haplotype B carriers than in wild-type haplotype A homozygotes (90 vs. 60%, P < 0.05). Among the haplotype A homozygotes, peak propafenone concentration was higher in effectively treated patients than that in patients showing insufficient response (299 ± 177 vs. 177 ± 93 ng/mL, P = 0.061). CONCLUSION: The present study found that antiarrhythmic efficacy of propafenone was associated with peak propafenone concentration rather than trough concentration and was affected by the SCN5A promoter haplotype.

[Effect of Food Thickeners on the Disintegration, Dissolution, and Drug Activity of Rapid Oral-disintegrating Tablets].

　For patients with dysphagia in medical facilities and nursing homes, food thickeners are routinely used to aid the ingestion of medicines such as tablets. However, some types of thickeners affect the disintegration and dissolution of tablets, such as rapidly-disintegrating magnesium oxide tablets and donepezil hydrochloride orally disintegrating tablets. Additionally, delayed disintegration and dissolution of tablets affect a drug's efficacy. As an example, with Voglibose orally disintegrating tablets, marked differences are observed in changes in glucose levels during glucose tolerance testing. When using food thickeners to aid tablet ingestion, it is therefore necessary to select a product that has little effect on drug disintegration, dissolution, and activity.

Simultaneous determination of serum propafenone and its metabolites using high-performance liquid chromatography.

Propafenone, a class Ic antiarrhythmic agent, is metabolized to 5-hydroxypropafeone (5-OHP) and N-depropylpropafenone (NDPP). Simultaneous determination of serum propafenone and its metabolites was performed using HPLC equipped with a conventional octadecylsilyl silica column and ultraviolet detector. The wavelength was set at 250 nm. Propafenone and its metabolites in the serum were extracted using diethyl ether. The mobile phase solution, comprising 1-pentanesulfonic acid sodium salt (0.1 m), acetonitrile and acetic acid (280:185:2.5, v/v/v), was pumped at a flow rate of 1 mL/min. The recoveries of propafenone, 5-OHP and NDPP were greater than 85, 82 and 60%, respectively, with the coefficients of variation (CVs) less than 5.4, 1.9 and 2.9%, respectively. The calibration curves were linear for a concentration range of 12.5-1500 ng/mL for propafenone and 2-500 ng/mL for 5-OHP and NDPP (r > 0.999). CVs in the intraday assays were 1.0-3.8% for propafenone, 0.6-2.0% for 5-OHP and 0.6-1.7% for NDPP. CVs in interday assays were 1.3-7.7% for propafenone, 1.1-6.5% for 5-OHP and 5.4-8.0% for NDPP. The present HPLC method can be used to assess the disposition of propafenone and its metabolites for pharmacokinetic studies and therapeutic drug monitoring of propafenone.

Assessment of indomethacin oral spray for the treatment of oropharyngeal mucositis-induced pain during anticancer therapy.

PURPOSE: The efficacy and safety of indomethacin (IM) oral spray (OS) as a pain control therapy for oropharyngeal mucositis due to anticancer chemo- and radiotherapy were assessed in patients with head and neck carcinomas and haematological tumours. METHOD: We observed 35 patients (male/female, 20/15; 53 ± 17 years) with oropharyngeal mucositis who were treated with IM-OS preparation for pain relief at University of Tsukuba Hospital, Japan. Analgesic effects were assessed using the six-grade face scale for pain in 28 patients at the start of IM oral spray treatment. Systemic exposure was assessed by determining urinary excretions of IM in seven patients. RESULTS: Pain relief was achieved in 26 (93%) patients at 25 (5-60) min after applying the IM-OS preparation (15.6 ± 3.4 µg/kg) and analgesic effects were maintained for 120 (10-360) min. The pain was significantly decreased after using the spray (3.6 ± 0.7 vs. 2.4 ± 0.9, p < 0.01). Moreover, urinary IM excretion rates after applying the IM spray preparation were 1.8 ± 0.8% of the IM oral spray dose (130.5 ± 77.7 µg/kg/day), which was markedly lower than that following oral administration of IM (60%). No adverse events were observed following application of the spray. CONCLUSIONS: The present IM spray is an effective and safe preparation for pain relief and can be used as an alternative therapeutic option for oropharyngeal mucositis in cancer patients.

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.

Stereoselective analysis of flecainide enantiomers using reversed-phase liquid chromatography for assessing CYP2D6 activity.

Stereoselective analyses of flecainide enantiomers were performed using reversed-phase high-performance liquid chromatography (HPLC) equipped with a polysaccharide-based chiral column (Chiralpak AS-RH) and fluorescence detector. Excitation and emission wavelengths were set at 300 and 370 nm, respectively. Flecainide enantiomers in serum and urine were extracted using diethyl ether. The mobile phase solution, comprising 0.1 m potassium hexafluorophosphate and acetonitrile (65:35, v/v), was pumped at a flow rate of 0.5 mL/min. The recoveries of flecainide enantiomers were greater than 94%, with the coefficients of variation (CVs) <6%. The calibration curves of flecainide enantiomers in serum and urine were linear in the concentration range 5-500 ng/mL and 0.75-15 µg/mL (r > 0.999), respectively. CVs in intra-day and inter-day assays were 1.8-5.8 and 3.4-7.5%, respectively. In a pharmacokinetic study, the ratios of (S)- to (R)-flecainide (S/R ratio) in the area under the curve and the amount of flecainide enantiomers excreted in urine were lower in a subject carrying CYP2D6*10/*10 than in subjects carrying CYP2D6*1/*2. The S/R ratio of trough serum flecainide concentration ranged from 0.79 to 1.16 in patients receiving oral flecainide. The present HPLC method can be used to assess hepatic flecainide metabolism in a pharmacokinetic study and therapeutic drug monitoring.

Lower metabolic clearance of tizanidine in Japanese subjects.

Our aim was to determine whether metabolic clearance, renal clearance, or both elimination pathways contribute to ethnic differences in tizanidine clearance, which is ~ 2-fold higher in Caucasians than in Asians. The pharmacokinetic parameters of tizanidine in 9 healthy male Japanese subjects were compared with those of Caucasians in previous studies. Metabolic clearance of tizanidine was lower in Japanese than in Caucasian subjects (5.9 vs. 8.1 - 10.9 l/h/kg), although renal clearances were similar (0.040 vs. 0.047 - 0.055 l/h/kg). The results suggest that ethnic differences in tizanidine clearance are due to differences in metabolic clearance.

SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients.

OBJECTIVE: An increased slowing of cardiac conduction induced by sodium channel blockers is remarkably observed in carriers of an Asian-specific promoter haplotype [haplotype B (HapB)] of the cardiac sodium channel gene (SCN5A). We investigated the effect of HapB on the therapeutic range for serum flecainide concentration in Asian patients. PATIENTS AND METHODS: We examined the serum concentration and antiarrhythmic efficacy of flecainide, together with the SCN5A promoter haplotype, in 146 patients with supraventricular tachyarrhythmias. Trough serum flecainide concentrations were determined by HPLC. The antiarrhythmic efficacy of flecainide was assessed for at least 2 months through examination of symptomatology, ECG, and Holter monitoring. RESULTS: The serum flecainide concentration did not differ between the wild-type HapA homozygotes and HapB carriers under treatment with the usual dose. A genetic difference in the antiarrhythmic efficacy of flecainide was observed between the HapA homozygotes and HapB carriers at serum flecainide concentrations less than 300 ng/ml (42.9 vs. 68.8%; P=0.022). PR prolongation and QRS widening were observed more commonly among the HapB carriers with serum flecainide concentrations of at least 300 ng/ml than in the HapA homozygotes (PR, 210 ± 25 vs. 195 ± 25 ms; P=0.036; and QRS, 112 ± 10 vs. 105 ± 9 ms; P=0.030). CONCLUSION: These findings suggest that the therapeutic range for serum flecainide concentration is lower in HapB carriers than in HapA homozygotes.