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134. Estimation of the electrical resistivity in field-reversed configuration plasmas from detailed interferometric measurements.

Author

Okada, S., Kiso, Y., Goto, S., and Ishimura, T.

Subjects
*PLASMA gases, *INTERFEROMETRY, *PINCH effect (Physics)
Abstract

Electrical resistivity at the magnetic axis η(R) and at the separatrix η(rs) of a field-reversed configuration (FRC) plasma produced by theta pinch machines are estimated from detailed interferometric measurements, assuming that the temperature is uniform within the separatrix. The ratio f0[=η(R)/η(rs)] increases with the beta value at the separatrix βs, which is consistent with the fact that f0 decreases when xs (separatrix radius normalized by the inner radius of a theta pinch coil) increases [Phys. Fluids 28, 888 (1985)]. This tendency is a natural consequence of the transport properties of the FRC plasma when the particle confinement time is nearly equal to the decay time of the trapped reversed magnetic flux, as is normally the case. Theoretical expectations of the anomaly of η(rs) over the classical resistivity η0 increases and decreases slightly with βs for the case of the lower hybrid drift and the low-frequency drift instability, respectively. On the other hand, the observed η(rs)/η0 decreases substantially with βs. [The value of η(rs)/η0 changes from about 15 to 5 as βs changes from 0.45 to 0.6.] [ABSTRACT FROM AUTHOR]

Published
1989
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137. No Auxiliary, No Byproduct Strategy for Water-Soluble Prodrugs of Taxoids:  Scope and Limitation of O−N Intramolecular Acyl and Acyloxy Migration Reactions

Author

Skwarczynski, M., Sohma, Y., Noguchi, M., Kimura, M., Hayashi, Y., Hamada, Y., Kimura, T., and Kiso, Y.

Abstract

Since numerous new taxoids active against multidrug resistant (MDR) tumors have been developed and their poor water-solubility is a very real problem in intravenous administration, we have designed and synthesized a series of novel water-soluble taxoid prodrugs (isotaxoids). These prodrugs, a 2‘-O-isoform of taxoids, showed promising results with higher water solubility (0.8−1.1 mg/mL) and proper kinetics for parent drug release by a simple pH-dependent chemical mechanism via O−N intramolecular acyl migration. No additional functional auxiliaries are released during the conversion to parent drugs, which would be an advantage in toxicology and general pharmacology, and the cost for the evaluations of auxiliary units in these fields could be saved in prodrug development. In addition, we demonstrate for the first time the successful application of the O−N intramolecular acyloxy migration reaction in the prodrug design, with the exception of the tert-butyloxycarbonyl group, and that this reaction can be provided with no organic solvent and no side products.

Published
2005

138. Development of Water-Soluble Prodrugs of the HIV-1 Protease Inhibitor KNI-727:  Importance of the Conversion Time for Higher Gastrointestinal Absorption of Prodrugs Based on Spontaneous Chemical Cleavage

Author

Sohma, Y., Hayashi, Y., Ito, T., Matsumoto, H., Kimura, T., and Kiso, Y.

Abstract

We designed and synthesized a series of water-soluble prodrugs of the HIV-1 protease inhibitor KNI-727 (1), which is a sparingly water-soluble drug with a water solubility of 5.5 μg/mL. These prodrugs, which contain a water-soluble auxiliary with two tandem-linked units, i.e., a self-cleavable spacer and a solubilizing moiety with an ionized amino function, exhibited a marked increase in water solubility (>104-fold) compared with the parent drug 1. The mechanism of conversion to the parent drug 1 is not enzymatic but through a chemical cleavage at the spacer via an intramolecular cyclization−elimination reaction through an imide formation under physiological conditions. To diversify the conversion time for the parent drug regeneration, chemical modification of the auxiliary was carried out focusing on the introduction of cyclic tertiary amines, which can modify the basicity and/or conformational flexibility of the terminal amino function at the solubilizing moiety, and the change in bond length, which can attenuate the five-membered ring intermediate formation in the cleavage. These newly synthesized water-soluble prodrugs exhibited a practical water solubility with values greater than 50 mg/mL and enabled the constant regeneration of the parent drug 1 with diversified conversion times ranging from 4 min to 34 h as t1/2 values under physiological conditions. All the water-soluble prodrugs tested regenerated the parent drug 1 in vivo as well as in vitro. A clear increase in the gastrointestinal absorption was observed in prodrugs 8, 12, and 13 with bioavailability (BA) values of 23%, 26%, and 29%, respectively. These BA values were 1.5−1.9-fold higher than that in the administration of the parent drug 1 alone. Other prodrugs showed only a similar or decreased BA compared to the parent drug 1. From these results, we found that not only a high water solubility but also an appropriate conversion time of the prodrug with a relatively narrow limit of around 35 min via intraduodenal administration was necessary for significant improvement of the gastrointestinal absorption in water-soluble prodrugs based on the spontaneous chemical cleavage. This is the first successful water-soluble prodrug that suggests an increased BA value greater than the parent drug in HIV-1 protease inhibitors and is the first study to show the importance of optimal conversion time in water-soluble prodrugs. Consequently, a water-soluble strategy that can control the conversion time would be extensively applicable to improve the gastrointestinal absorption of sparingly water-soluble drugs. The present information is an intriguing discovery and is one of the key factors that will contribute to the future design of practical water-soluble prodrugs.

Published
2003

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