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Satoshi Kitamura

Publications and source records attributed to Satoshi Kitamura.

At least 19 recordsLinked to original sources
PubMed2006

Excipient hydrolysis and ester formation increase pH in a parenteral solution over aging.

Recently, the number of drug substances that are poorly water-soluble has increased dramatically. This makes improving solubility one of the most critical tasks in pharmaceutical development today. In this study, the physicochemical stability of an injectable solution of conivaptan hydrochloride salt was investigated. Because its free form is hydrophobic, the drug substance was solubilized in a co-solvent system, 40% of which was composed of different alcohols. Since the free form is also alkaline, lactic acid was added to the co-solvent system to further improve its solubility. Remarkably, the pH of the solution was found to increase gradually over time. Considering the physicochemical nature of the drug substance, uncontrolled increases in pH would pose a potential threat of reducing solubility and forming precipitates. For this reason, a risk evaluation was performed. The evaluation revealed that the pH increase was caused by the hydrolysis of lactic acid oligomers as well as by the ester formation occurring between lactic acid and the alcohols. High concentrations of lactic acid supplied as an excipient usually contain lactic acid oligomers, which are hydrolyzed into lactic acid monomers upon dilution with water. Commercial software was used to determine the pK(a) values of the lactic acid oligomers, which were found to be lower than that of lactic acid monomers. This indicates that hydrolysis causes the pH to increase. Ester formation consumes the acid, which also causes the pH to increase. However, both hydrolysis and ester formation equilibrated by the 16-month time point when stored at 25 degrees C. This information allowed the upper limit of the pH increase to be determined molecularly, thereby ensuring product quality through the prevention of precipitate formation due to reduced solubility. Increased awareness of the importance of risk evaluation in pharmaceutical development is critical as these kinds of chemical reactions between excipients constitute a potential risk factor, but tend to be overlooked.

Antidiuretic Hormone Receptor Antagonists↗
PubMed2005

Dissolution mechanism of poorly water-soluble drug from extended release solid dispersion system with ethylcellulose and hydroxypropylmethylcellulose.

The purpose of this study is to investigate the release mechanism of poorly water-soluble drug from the extended release solid dispersion systems with water-insoluble ethylcellulose (EC) and water-soluble hydroxypropylmethylcellulose (HPMC) (1:1). Indomethacin (IND) was used as a model of poorly water-soluble drug. Two kinds of solid dispersions were prepared by the solvent evaporation methods, which consist of the same formulation but exhibit different physical performance. It appeared that the dissolution behavior of IND depended on the structures of EC-HPMC matrices, which were governed by the preparation method. In addition, the dissolution behavior showed pH dependency that the dissolution rate of IND was slower in acidic medium than that in neutral medium. The experimental results revealed that the hydrophobic interaction between IND and EC occurred under lower pH and strongly delayed the dissolution rate of IND. The relationship between this hydrophobic interaction and the dissolution rate of IND was also proposed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Analysis of mutations induced by carbon ions in Arabidopsis thaliana.

To investigate the nature of mutations induced by accelerated ions in higher plants, the effects of carbon-ion-irradiation were compared with those of electron-irradiation in Arabidopsis thaliana. Point-like mutations and rearrangements were induced at a similar frequency after carbon-ion-irradiation, whereas point-like mutations were more frequently induced after electron-irradiation. Sequence analysis revealed that carbon-ion-induced point-like mutations were mostly short deletions. In the case of rearrangements, deletions, inversions, insertions, and translocations were found. The estimated frequency of deletion induction was comparable to that of fast neutrons. Analysis of chromosome breakpoints revealed that carbon ions frequently deleted small regions around the breakpoints, whereas electron-irradiation often duplicated these regions. Moreover, for both types of radiation, broken ends with microhomologies were frequently rejoined. Results of the breakpoint and broken end analyses suggest that non-homologous end-joining (NHEJ) leads to the rejoining of double strand breaks (dsbs) after cells are exposed to both types of radiation, but the type of NHEJ that occurs as a result of damage is different. The results indicated that carbon-ion-induced mutations are most likely nulls and that the induced rearrangements may arise through a unique mechanism. These findings indicate that accelerated ions are a useful mutagen for both forward and reverse genetics for plants.

Arabidopsis↗
PubMed2005

Quantitative determination method for trace amount of penicillin contaminants in commercially available drug product by HPLC coupled with tandem mass spectrometry.

A quantitative determination method for trace amount of penicillin contaminants in an active pharmaceutical ingredient (API) has been developed. Selective extraction of penicillin contaminants from the matrix containing API and specific separation among penicillin contaminants were achieved through an on-line column switching technique with gradient elution, followed by tandem mass spectrometric determination. Validation was conducted on the developed method in terms of specificity, linearity, accuracy, precision, and detection limit, and appeared reasonable. The detection limit was estimated as 0.03 ng/ml or lower of the concentration of penicillin contaminants in the preparation, corresponding to 4 parts par billion (ppb) against the API. This fulfilled the regulatory requirement by the authorities.

Amoxicillin↗
PubMed2005

Effect of structural relaxation on the physical and aerosol properties of amorphous form of FK888 (NK1 antagonist).

FK888 (NK1 antagonist) is a candidate drug for migraine and selected as a model of amorphous drug. FK888 was micronized to develop as dry powder inhalers (DPIs) taking into consideration of its water insoluble property. The glass transition temperature (Tg) and fragility (m) were 90 degrees C and 118, respectively, and it was categorized as a fragile glass based on Angell's concept. FK888 was structurally relaxed by aging below Tg, then the effect of aging on their physical and aerosol properties were investigated. The investigation on the moisture sorption-desorption isotherms of FK888 indicated that aged FK888 adsorbed less amount of water than that of unaged FK888. This unique moisture sorption-desorption behavior of the aged sample is explained by structural relaxation accompanying decrease of free volume and/or increase of density. As for the dissolution rate of unaged and aged FK888, they showed the similar value, suggesting that there would be no difference in bioavailability. In relation to the stability, FK888 DPIs prepared by unaged and aged FK888 were stored at 70 degrees C, and the respirable fraction of FK888 DPIs was evaluated by using multistage cascade impactor (USP apparatus 3). As a result, the respirable fraction of FK888 DPIs prepared by unaged sample was significantly decreased compared to the aged sample, suggesting that agglomeration may occur in the unaged sample during the storage. This phenomenon was supported by that the unaged sample showed a significant decrease in the surface area compared to that of the aged sample when stored at various conditions.

Aerosols↗
PubMed2005

Genomic relationships among Nicotiana species with different ploidy levels revealed by 5S rDNA spacer sequences and FISH/GISH.

We used the intergenic spacer sequences of the 5S ribosomal RNA genes (5S rDNA) to obtain insights into the genomic origin of putative amphidiploid/tetraploid species with 2n = 48 and their descendants in Nicotiana. Amplification of the spacer sequences and subsequent multiple alignment using the consensus sequences from each species, showed that two Australian species shared common large deletions, suggesting that the origin of the 5S rDNA is closely related in these species. Comparison of the spacer sequences with those from diploid (2n = 24) Nicotiana species made it possible to detect some groups consisting of the sequences from the 2n = 24 and 2n = 48 level species. Chromosomal localizations of the 5S rDNA arrays were similar in most groups. The relationships suggested by the 5S rDNA were also assessed at the genome level by using genomic in situ hybridization. We showed that the grouping based on the 5S rDNA spacer sequence reflects high genomic homology between 2n = 24 and 2n = 48 level species. As a result, the putative polyploid species such as N. debneyi, N. quadrivalvis, and N. africana were suggested to involve the close relatives of the diploid species such as N. glauca, N. obtusifolia and N. sylvestris, and N. langsdorffii, respectively, in their speciation. Our results are generally in agreement with the relationships previously suggested by morphological and cytogenetic observations, and some novel relationships were also revealed.

Base Sequence↗
PubMed2005

[CYFRA21-1].

Explore the source record for details and available documents.

Adenocarcinoma↗
PubMed2004

TRANSPARENT TESTA 19 is involved in the accumulation of both anthocyanins and proanthocyanidins in Arabidopsis.

Flavonoid compounds such as anthocyanins and proanthocyanidins (PAs; so-called condensed tannins) have a multitude of functions in plants. They must be transported from the site of synthesis in the cytosol to their final destination, the vacuoles. Three models have been proposed for sequestering anthocyanins in vacuoles, but the transport machinery for PAs is poorly understood. Novel Arabidopsis mutants, transparent testa 19 (tt19), which were induced by ion beam irradiation, showed a great reduction of anthocyanin pigments in the vegetative parts as well as brown pigments in the seed coat. The TT19 gene was isolated by chromosome walking and a candidate gene approach, and was shown to be a member of the Arabidopsis glutathione S-transferase (GST) gene family. Heterologous expression of a putative ortholog, petunia anthocyanin 9 (AN9), in tt19 complemented the anthocyanin accumulation but not the brown pigmentation in the seed coat. This suggests that the TT19 gene is required for vacuolar uptake of anthocyanins into vacuoles, but that it has also a function different from that of AN9. The depositional pattern of PA precursors in the mutant was different from that in the wild type. These results indicate that TT19 participates in the PA pathway as well as the anthocyanin pathway of Arabidopsis. As involvement of GST in the PA pathway was previously considered unlikely, the function of TT19 in the PA pathway is also discussed in the context of the putative transporter for PA precursors.

Alleles↗
PubMed2003

Mutation rate and novel tt mutants of Arabidopsis thaliana induced by carbon ions.

Irradiation of Arabidopsis thaliana by carbon ions was carried out to investigate the mutational effect of ion particles in higher plants. Frequencies of embryonic lethals and chlorophyll-deficient mutants were found to be significantly higher after carbon-ion irradiation than after electron irradiation (11-fold and 7.8-fold per unit dose, respectively). To estimate the mutation rate of carbon ions, mutants with no pigments on leaves and stems (tt) and no trichomes on leaves (gl) were isolated at the M2 generation and subjected to analysis. Averaged segregation rate of the backcrossed mutants was 0.25, which suggested that large deletions reducing the viability of the gametophytes were not transmitted, if generated, in most cases. During the isolation of mutants, two new classes of flavonoid mutants (tt18, tt19) were isolated from carbon-ion-mutagenized M2 plants. From PCR and sequence analysis, two of the three tt18 mutant alleles were found to have a small deletion within the LDOX gene and the other was revealed to contain a rearrangement. Using the segregation rates, the mutation rate of carbon ions was estimated to be 17-fold higher than that of electrons. The isolation of novel mutants and the high mutation rate suggest that ion particles can be used as a valuable mutagen for plant genetics.

Arabidopsis↗
PubMed2003

[COPD guideline of Japanese Respiratory Society].

Standard for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) was published from Japanese Respiratory Society in 1999. In this guideline the definition, epidemiology, risk factors, pathology, methods of diagnosis, methods of therapy and care were fully described. Especially, in this guideline, we used the thin slice CT for the diagnosis and classification of disease severity. After the publication, this guidelines were distributed to all of the JRS members(about 10,000 doctors).

Air Pollution↗
PubMed2002

Carcinogenicity test in B6C3F1 mice after parental and prenatal exposure to 50 Hz magnetic fields.

Some epidemiological studies suggest association of childhood cancer with occupational exposure of the parents to magnetic fields. To test this relationship, 50 each of C57BL/6J female and C3H/HeJ male mice were exposed for 2 and 9 weeks, respectively, to 50 Hz sham (group A), 0.5 (group B), and 5 mT (group C) sinusoidal alternating magnetic fields. They were mated under the exposure for up to 2 weeks, and the exposure was continued until parturition. All the B6C3F1 offspring, without adjusting numbers of animals, were clinically observed without exposure to magnetic field for a nominal 78 weeks from 6-8 weeks of age after weaning and then euthanized for pathological examination according to a routine carcinogenicity test. 540 pups entered the test, and the survival rate was 96.7%. No F1 mouse died of tumoral diseases before a male in A group died of stomach cancer at 43 weeks of age. The first animal death in the exposed groups due to tumor occurred at 71 weeks of age. Eighteen animals died before necropsy at 84-86 weeks of age. No significant difference was detected in the final number of survivors and incidence of tumors between groups A and B, or A and C. Concerning reproduction total implants in group B were less than in group A and the difference was on the borderline of significance (P=.05). This difference was not reproduced in a later duplicate experiment.

Animals↗