Masanori Sueyasu

Micellar electrokinetic capillary chromatography for therapeutic drug monitoring of zonisamide

The simultaneous determination of zonisamide, a new type of antiepileptic drug, and the typical antiepileptic drugs phenobarbital, phenytoin and carbamazepine in human serum was developed using micellar electrokinetic capillary chromatography (MECC) with a diode array detector. A high correlation was revealed between the zonisamide levels in human serum obtained by MECC and those obtained by high-performance liquid chromatography (r=0.981). The serum levels of phenobarbital, phenytoin and carbamazepine determined by MECC were almost equal to those obtained by fluorescence polarization immunoassay. The reproducibility of separation and quantification with MECC analysis was appropriate for the intra- and inter-day assay coefficients. Therefore, the MECC method established here could provide a simple and efficient therapeutic drug monitoring method for antiepileptic drugs in patients, especially those treated with a combination of zonisamide and other antiepileptic drugs.

Inhibition of GABA system involved in cyclosporine-induced convulsions.

In this study, we attempted to clarify the mechanisms mediating cyclosporine-evoked convulsions. Cyclosporine (50 mg/kg, i.p.) significantly enhanced the intensity of convulsions induced by bicuculline (GABA receptor antagonist), but not those induced by strychnine (glycine receptor antagonist), N-methyl-D-aspartic acid, quisqualic acid or kainic acid (glutamate receptor agonists). Bicuculline plus cyclosporine-induced convulsions were significantly suppressed by an activation of GABAergic transmission with diazepam, phenobarbital and valproate. The GABA turnover estimated by measuring aminooxyacetic acid-induced GABA accumulation in the mouse brain was significantly inhibited by cyclosporine (50 mg/kg, i.p.). When cultured rat cerebellar granule cells were exposed to 1 microM cyclosporine for 24 hr, the specific [3H]muscimol (10 nM) binding to intact granule cells decreased to 53% of vehicle controls. The present study provides the first evidence suggesting that cyclosporine inhibits GABAergic neural activity and binding properties of the GABAA receptor. These events are closely related to the occurrence of adverse central effects including tremors, convulsions, coma and encephalopathy under cyclosporine therapy.

Enhancement of serotonergic neural activity contributes to cyclosporine-induced tremors in mice.

A single cyclosporine injection (50 mg/kg, i.p.) significantly enhanced harmine- but not oxotremorine-induced tremors in mice. This potentiation became more apparent when cyclosporine (50 mg/kg, i.p.) was administered once a day for seven days. These findings suggest an involvement of monoaminergic mechanisms in cyclosporine-induced tremors. The effects of cyclosporine were examined on the dynamics of noradrenaline, dopamine and serotonin in the mouse brain. Both single and repeated treatment with cyclosporine significantly facilitated the serotonin turnover as estimated from the probenecid-induced accumulation of 5-hydroxyindoleacetic acid, but either mode of treatment failed to change the contents of monoamines and their metabolites or the turnover of noradrenaline and dopamine. Therefore, the cyclosporine-enhanced activity of serotonin neurons may be interpreted as producing adverse central effects, including tremors.

Protein binding and the metabolism of thiamylal enantiomers in vitro.

Thiamylal, a chiral thiobarbiturate, is marketed as a racemic product. We studied the serum protein binding and microsomal metabolism of thiamylal enantiomers in vitro. The unbound fraction of R(+)-thiamylal was greater than that of S(−)-thiamylal. The analysis of binding data revealed that both enantiomers bound to human serum albumin through only one site. In displacement studies with site-specific probes, dansylsarcosine, but not warfarin, significantly decreased the binding of both enantiomers. The bindings of enantiomers were also decreased by octanoate and a large concentration of oleate. These findings suggest that both enantiomers bind to Site II of albumin with higher affinity for S(−)-enantiomer. R(+)-thiamylal was metabolized more rapidly than S(−)-enantiomer by human liver microsomes. An experiment with isoform-selective inhibitors and cytochrome P-450 (CYP) isoforms showed that CYP2C9 had the highest activity for the metabolism of both enantiomers, the activity being 7 to 10 times that of CYP2E1 and CYP3A4. CYP2C9 showed a significantly rapid metabolism of R(+)-enantiomer, suggesting that CYP2C9 is mainly involved in the enantioselective metabolism of thiamylal. Implications Because clinically marketed thiamylal is a racemic compound, a pharmacokinetic study of each enantiomer may be beneficial. We found that the enantioselectivity of thiamylal existed in protein binding and metabolism. This may be caused by the differences in the affinities of enantiomers for albumin and cytochrome P-450 isoform.

Protection Against the Extravasation of Anticancer Drugs by Standardization of the Management System

The extravasation of anticancer drugs is a serious complication. On the basis of data regarding extravasation prevention and treatment obtained primarily by pharmacists, the management system for extravasation of anticancer drugs was standardized at an outpatient chemotherapy center. A kit was prepared so that physicians could promptly and safely perform venipuncture; the kit included a classification list of anticancer drugs. Prior to administration of vesicant or irritant drugs, pharmacists and nurses educated the patients. When anticancer drugs were administered via peripheral vein without using an implanted venous access device, extravasation occurred in 10 out of 7,059 courses (0.14%) during the 2-year study period postintroduction of the present management system. This incidence is remarkably low as compared with those previously reported. The extravasated drugs were epirubicin (n = 3), paclitaxel (n = 3), vinorelbine (n = 1), 5–fluorouracil (n = 1), carboplatin (n = 1), and cyclophosphamide (n = 1). Cold packs were applied around the injection site except in the cases involving vinorelbine, in which warm packs were used. In all cases of extravasation of vesicant drugs, glucocorticoid was injected locally. There were no cases involving continuous pain or skin ulcers. The standardization of the management system for extravasation of anticancer drugs was very effective in decreasing the occurrence, as well as decreasing skin damage if it occurred.

Risk factors for predicting severe neutropenia induced by amrubicin in patients with advanced lung cancer

Background: Neutropenia is one of the most frequent and dose-limiting toxicities in amrubicin (AMR) therapy. However, the predictive factors for the development of severe neutropenia in AMR therapy remain unknown. Methods: The subjects were 61 advanced lung cancer patients treated with AMR monotherapy. All data were retrospectively collected from the electronic medical record system. A stepwise logistic regression analysis was performed to identify risk factors for grade 3–4 neutropenia. Results: Of a total 61 patients, 50 were male and 11 were female. The median dose of AMR was 35.0 mg/m2. The incidence of grade 3–4 neutropenia during the first course was 62%. In multivariate analysis, female gender (OR = 6.68; 95% CI 1.01–134.15; p = 0.049), higher AMR doses (40 mg/m2 or more) (OR = 5.98; 95% CI 1.77–23.74; p = 0.003), and lower hematocrit values (OR = 2.04 per 5% decrease; 95% CI 1.04–4.38; p = 0.036) were significantly associated with severe neutropenia induced by AMR. Conclusion: The present results suggest that female gender, higher doses of AMR, and lower baseline hematocrit values are predictive factors associated with severe neutropenia induced by AMR in patients with advanced lung cancer. Patients who have these predictive factors should be monitored carefully and considered for early granulocyte colony-stimulating factor support.

Improved method of determining thiamylal enantiomers in human serum by high-performance liquid chromatography.

Thiamylal, a widely used anesthetic drug, has two enantiomers. We developed a simple and rapid method for measuring the thiamylal enantiomers in human serum. The method involves a liquid-liquid extraction procedure followed by chiral resolution using a 5 microm silica-bonded alpha1-acid glycoprotein column (Chiral-AGP). The thiamylal enantiomers and internal standard were eluted within 15 min and were well-resolved. At concentrations of 1, 5 and 20 microg ml(-1), the relative standard deviations of R(+)- and S(-)-thiamylal were 1.35-2.88% and 1.37-3.01%, respectively, for the intra-day assay, and 2.93-4.46% and 2.46-4.84%, respectively, for the inter-day assay. This method facilitates the routine monitoring and pharmacokinetic studies of thiamylal enantiomers.

Enantioselective determination of thiamylal in human serum by high-performance liquid chromatography

Thiamylal, a widely used anesthetic drug, has two enantiomers. We developed a novel and simple method for measuring thiamylal enantiomers in human serum using reversed-phase high-performance liquid chromatography. R(+)- and S(-)-Thiamylal were separated using a chiral mobile phase containing beta-cyclodextrin, and detected at the range of 50 ng/ml-25 micrograms/ml in serum. The relative standard deviations of R(+)- and S(-)-thiamylal were 3.4-8.7% and 2.8-8.7% for the intra-day assay, and 2.8-12.0% and 2.8-13.0% for the inter-day assay. This method may be applied to enantioselective pharmacokinetic studies of thiamylal.

Relationship between incident types and impact on patients in drug name errors: a correlational study

BackgroundThere are many reports regarding various medical institutions’ attempts at incident prevention, but the relationship between incident types and impact on patients in drug name errors has not been studied. Therefore, we analyzed the relationship between them, while also assessing the relationship between preparation and inspection errors. Furthermore, the present study aimed to clarify the incident types that lead to severe patient damage.MethodsThe investigation object in this study was restricted to “drug name errors”, preparation and inspection errors in them were classified into three categories (similarity of drug efficacy, similarity of drug name, similarity of drug appearance) or two groups (drug efficacy similarity (+) group, drug efficacy similarity (−) group). Then, the relationship between preparation and inspection errors was investigated in three categories, the relationship between incident types and impact on patients was examined in two groups.ResultsThe frequency of preparation errors was liable to be caused by the following order: similarity of drug efficacy > similarity of drug name > similarity of drug appearance. In contrast, the rate of inspection errors was liable to be caused by the following order: similarity of drug efficacy < similarity of drug name < similarity of drug appearance. In addition, the number of preparation errors in the drug efficacy similarity (−) group was fewer than that in the drug efficacy similarity (+) group. However, the rate of inspection errors in the drug efficacy similarity (−) group was significantly higher than that in the drug efficacy similarity (+) group. Furthermore, the occupancy rate of preparation errors, incidents more than Level 0, 1, and 2 in the drug efficacy similarity (−) group increased gradually according to the rise of patient damage.ConclusionsOur results suggest that preparation errors caused by the similarity of drug appearance and/or drug name are likely to lead to the incidents (inspection errors), and these incidents are likely to cause severe damage to patients subsequently.

Monitoring of Neurological Adverse Effects Induced by Immunosuppressants.

Cyclosporine-or tacrolimus-induced neurotoxicity was retrospectively evaluated in five patients. Symptoms ranging from mild (tremor, insomnia, visual disturbance) to severe events (convulsion, leukoencephalopathy) were observed. The predisposing risk factors in these patients included hypomagnesemia, liver dysfunction and transient high blood concentrations of the immunosuppressants. Besed on our findings as well as those from other reports, the initial signs and symptoms of immunosuppressant-induced neurotoxicity were as follows ; tremor, headache, anorexia, nausea, vomiting, lethargy, insomnia, anxiety, amnesia, visual disturbance. However, not all of these events correlated with the blood concentrations of the immunosuppressants. The blood cyclosporine concentrations decreased by concomitant use of phenytoin. The blood tacrolimus concentrations varied markedly during the two-week-period after liver transplantation. To prevent patientsfrom developing serious events under immunosuppressant therapy, pharmacists should thus recognize the predisposing risk factors in patients, and carefully monitor the initial signs related to neurotoxicity and the blood concentrations of the patients receiving immunosuppressants.