Nobuo Kurokawa

In vitro inhibitory effects of Kampo medicines on metabolic reactions catalyzed by human liver microsomes.

Background:  Although it is well known that drug–drug interactions may lead to toxicity and therapeutic failure, little is known about the incidence and consequences of herb–drug interactions in patients receiving Kampo medicines.

Pharmacokinetic Behavior of Intravitreal Triamcinolone Acetonide Prepared by a Hospital Pharmacy

PurposeWe developed a new hospital pharmaceutical preparation of triamcinolone acetonide (TA) for intravitreal injections using sodium hyaluronate as the vehicle. The purpose of this study was to compare the pharmacokinetic behavior of this hospital pharmacy preparation of TA (HPP-TA) to that of a commercial preparation of TA (CP-TA) in rats.MethodsWe injected the two preparations of TA into the vitreous humor of male Wistar rats. The rats were killed between days 1 and 21, and the concentration of TA in the vitreous was measured by high-performance liquid chromatography to determine the pharmacokinetic parameters. We also examined the microscopic appearance of the TA particles in these preparations.ResultsThe elimination half-life was 6.08 days for the CP-TA and 5.78 days for the HPP-TA. A two-compartment model was suitable to approximate the pharmacokinetic behavior of HPP-TA in the vitreous body, but this model was not suitable for CP-TA, because its pharmacokinetic behavior was not sufficiently stable. The particle size of CP-TA was largest, followed by TA powder and HPP-TA. Many particles were agglutinated in the CP-TA preparation, whereas the TA particles were fine and dispersed in the HPP-TA medium.ConclusionsThe TA particle size and the suspension medium are likely important factors in the preparation of a safe and stable suspension of TA. HPP-TA satisfied these requirements and should be suitable for clinical use.

Microsomal Enzyme Induction and Clinical Aggravation of Porphyria: The Evaluation of Human Urinary 6β‐Hydroxycortisol/Cortisol Ratio as the Index of Hepatic CYP3A4 Activity

The clinical aspect of porphyria has been investigated, and it is well known that porphyrinogens such as estrogens and alcohol or other inducers of P450 isoenzymes exacerbate the porphyric state. However, there can be a delay in diagnosing porphyria and a difficulty in selecting safe medicine for it even today. A 21‐year‐old woman developed epilepsy, disturbance of mental state, and spastic tetraparesis during the convalescent period after acute viral encephalitis. She was diagnosed with porphyria after the fifth hospitalization. In the course of modifying her anticonvulsant regimen, the authors examined the 6β‐hydroxycortisol/cortisol ratio (6β‐OHF/F) in her urine, which can be the index of hepatic CYP3A4 activity, with electrospray ionization/mass spectrometry/mass spectrometry (ESI/MS/MS). Generalized and partial complex seizures, other neurological signs and symptoms, and laboratory data were improved after modification of her anticonvulsant regimen. This is the first report of evaluating the urinary 6β‐hydroxycortisol/cortisol ratio in a case of porphyria.

Efforts to Ensure Safety of Hospital Pharmacy Personnel Occupationally Exposed to Antineoplastic Drugs During a Preparation Task

Purpose Antineoplastic drugs are often detected in the plasma and urine of medical staff, despite the adoption of safety measures. This study involves ambulatory chemotherapy, which was prepared on a rotating schedule at the Department of Pharmacy. The first objective of this study was to evaluate occupational exposure by measuring epirubicin in the urine and plasma and sister chromatid exchanges (SCE) in the peripheral lymphocytes of the involved pharmacists. The second, to improve a previously reported method for ease of occupational exposure evaluation. The third, to determine environmental contamination. Methods Pharmacists were categorized into three groups based on three patterns, depending on the other tasks they performed. They were alternately responsible for the preparation in each group with the recommended protections. Samples were collected at the end of each work day. High-performance liquid chromatography (HPLC) analysis along with fluorescence detection was performed at a flow rate of 200 mcL/min using 0.1% formic acid, methanol, and acetonitrile (75:5:20). Epirubicin in the samples was extracted by solid-phase extraction. Chromosomes were prepared according to a standard protocol. Results A final concentration of 2 ng/mL was the lower quantification limit. Epirubicin was not detected in the urine and plasma, and the SCE levels were within the normal limits for all the subjects. However, epirubicin was detected in samples collected from the preparation gloves. Conclusions For personnel safety, it is important to periodically evaluate protective measures. Pharmacists on a rotating schedule who work less than 6 hours per week on preparatory tasks were not unduly exposed to antineoplastics.

In-vivo Distribution and Erythrocyte Binding Characteristics of Cyclosporin in Renal Transplant Patients

The pharmacokinetic parameters of cyclosporin, a potent immunosuppressive agent, show large intra‐and inter‐individual variability, possibly because of the different analytical methods used. A recently developed cyclosporin‐specific radioimmunoassay has been used to study the in‐vivo distribution and binding characteristics of cyclosporin in whole blood, plasma and erythrocytes of fifteen renal transplant patients.

Gel Chromatographic Analysis of Cyclosporin and Its Metabolites in Human Blood Compartments

Gel chromatography combined with specific and non‐specific cyclosporin radioimmunoassays was adopted for quantitative analysis of cyclosporin and metabolites in free and protein‐bound forms in blood compartments of kidney transplant patients. The analytical method was proved to be useful for the purpose, although plasma protein‐bound forms of neither cyclosporin nor metabolites could be quantitated in the system. The present study also provided, by gel chromatographic analysis, additional examples to prove that concentrations of cyclosporin metabolites in blood compartments may not be deduced or inferred simply from those of cyclosporin.

Enhancement effects of barbital on the teratogenicity of aminopyrine

Aminopyrine and its compound with barbital have been used in humans as analgesics and antipyretics. A compound, pyrabital (2 molecules of aminopyrine and 1 molecule of barbital) given daily on Days 9, 10 and 11 of gestation produced significant yields of fetal deaths and malformations in ICR/Jcl mice. Most malformations induced were ruptured omphaloceles (eventration of the abdominal viscera), which were associated with malrotation of the intestine, cleft palates, and tail anomalies, finger and toe anomalies. Aminopyrine also induced significant yields of fetal deaths and malformations. However, the incidence of fetal deaths and malformations induced by a dose of pyrabital was significantly higher than that by an equivalent dose of aminopyrine which was contained in pyrabital. When aminopyrine (0.21 mg/g) and barbital (0.09 mg/g) were given in 2 separate injections to pregnant mice, teratogenicity was approximately equal to that by the equivalent dose of pyrabital (0.3 mg/g). Consequently, potent teratogenicity of pyrabital is not caused by the compound, but only by the coexistence of barbital and aminopyrine. Such enhancement effects of barbital may be due to the induction of enzymes responsible for transforming aminopyrine to teratogenic forms, because pretreatment with barbital and phenobarbital similarly enhanced embryotoxicity of aminopyrine.

Intraocular Concentration of Intravenous Prednisolone in Experimental Autoimmune Uveoretinitis Mice

could be caused by a common primary immune-mediated process affecting both the lung and the eye, although the relationship between COP and intraocular infl ammation is still unknown. To our knowledge, intraocular infl ammation has not been previously reported in a patient with COP. In the future, ophthalmologists might need to accumulate cases of COP and intraocular infl ammation, and to consider the possibility of a new clinical entity.

Carcinogenicity of Sublimed Urethane in Mice through the Respiratory Tract

The carcinogenicity of sublimed urethane (ethyl carbamate) in air was examined with mice. JCL:ICR mice were nursed in a plastic cage inside a vinyl chamber which was ventilated 4 times per hour. The mice were exposed to urethane gas for various periods by passing air which contained a high concentration of sublimed urethane (1.29 μg/ml) into the vinyl chamber, or by placing a vessel containing crystalline urethane inside the vinyl chamber so that it was filled with spontaneously‐sublimed urethane gas at a low concentration (0.25 μg/ml). When female mice were killed 5 months after exposure, lung tumor frequency increased almost linearly with the number of days of exposure in the low concentration experiment, but increased in a non‐linear manner in the high concentration experiment. In terms of nearly the same total dose, i.e., (concentration of urethane gas in air) × (days of inhalation), one day of exposure to urethane gas at the low concentration induced lung tumors at a significantly higher frequency than 1/4 day of exposure to urethane gas at the high concentration. When male mice were killed at 12 months after exposure to examine the progressive change of induced tumors, malignant, invasive and metastatic tumors were found to have been induced more frequently in the lung after exposure to urethane gas at the low concentration (0.25 μg/ml for 10 days) than at the high concentration (1.29 μg/ml for 4 days), although the total dose in the former group was about half of that in the latter. Continuous exposure to urethane gas for a longer period at the low concentration seems to be more efficient for the induction, promotion and/or progression of lung tumors than the exposure for a shorter period at the high concentration.

Examination of purification methods and development of intravitreal injection of triamcinolone acetonide.

PurposeIntravitreal injection of triamcinolone acetonide (TA) is used in ophthalmic treatment, but the reliability of commercially available TA preparations has still not been established. We evaluated two previously reported purification methods, and developed a more reliable TA injection which can be prepared in a hospital pharmacy.MethodsWe tested the two methods previously reported for purifying commercial TA preparations, the sedimentation and the filtration and backflushing methods. We developed a new TA injection made of pure TA suspended in 0.5% sodium hyaluronate. We measured the TA content in each preparation by high-performance liquid chromatography to evaluate the three methods.ResultsIn the sedimentation purification method, the TA content of a nominal 4-mg preparation varied from 1.43 to 7.37 mg, and the average recovery rate was 91.6%. In the filtration and backflushing method, TA content was 0.10–10.33 mg and recovery was 59.5%. In the TA injection we developed, the mean TA content was 102.5% (SD, 0.24; CV, 2.9%). The stability of this preparation was 99% after sterilization, and 97% after 3 months of storage.ConclusionsThe results of our investigation showed that the purification methods used for commercial preparations are simple and easy but not precise enough for an intravitreal injection. In contrast, the TA injection prepared by our method is reliable, stable, and safe enough for clinical use. Jpn J Ophthalmol 2005;49:384–387