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Volume 106, Issue 2
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TSUNEJI NAGAI1986 Volume 106 Issue 2 Pages 99-109
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESSThe recent advances in pharmaceutical technology have been promoted in a strong relation to taking the data to prove the efficacy and safety in drug development activities and also to designing new dosage forms with high stability and suitable bioavailability.
The development of pharmaceutical technology may be divided historically as follows: a) pre-pharmaceutical (without consideration on bioequivalence); b) first generation (conventional or regular preparations); c) second generation (regular controlled release preparations); d) third generation (precisely controlled release preparations, i. e., drug delivery systems (DDS) and transdermal therapeutic systems (TTS)); e) fourth generation (drug targeting, missile). We can find materialized ones on d) the third generation, as it may be promising on e) the fourth generation in future. In a wide sense, the above-mentioned d) and e) are classified into drug delivery systems (wide-DDS), as the former may be the first generation of wide-DDS and the latter the second generation of wide-DDS.
Noticeable ones in recent advances in pharmaceutical technology are concerned with developments of DDS and TTS. Generally these technologies are formed on the basis of utilization of interactions of drugs with surrounding components such as on a) inter-molecular level; b) particle coating; c) particle-particle interactions d) miscellaneous. The surrounding components thereby include body tissues and organs, and thus a triple interaction among drug, dosage form components and body components should be considered.
We have investigated several topical membrane adhesive dosage forms containing hydroxypropyl cellulose and Carbopol to find such an advanced technology as mentioned above. Here will be described:(1) topical dosage form for carcinoma colli, (2) oral mucosal dosage form for the absorption of insulin, (3) adhesive tablet for aphthous stomatitis, and powder dosage form of nasal absorption of insulin.View full abstractDownload PDF (5148K) -
MASAYUKI NAKAGAKI, EUN OCK LEE, IZUMI YAMAMOTO1986 Volume 106 Issue 2 Pages 110-116
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESSThe reaction rate constant k of phospholipase D on L-α-dimyristoyl phosphatidy Icholine (DMPC) liposome with cholesterol was measured by 8-anilino-1-naphthalenesulfonate (ANS) fluorometry. As a result, it has been found that the rate constant was increased by the addition of cholesterol, and that the promoting effect for enzyme reaction by cholesterol increased with an increase in the cholesterol concentration at first, but then decreased after the concentration of maximum promotion.View full abstractDownload PDF (947K) -
Synthesis of 7β-Amino-3-substituted Methyl-3-cephem-4-carboxylic AcidsHIROSHI SADAKI, HIROYUKI IMAIZUMI, TAKIHIRO INABA, TATSUO HIRAKAWA, YO ...1986 Volume 106 Issue 2 Pages 117-122
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESSIn order to develop oral cephalosporin having a new substitutent at 3 position, 7β-aminocephalosporanic acid was reacted with various nucleophilic reagents in CF3COOH or sulforan in the presence of BF3.
As a result, 7β-amino-3-substituted methyl-3-cephem-4-carboxylic acids (Ia-w)(substituent: phenyl, thienyl, furyl, sulfonylamino, 1, 1-dioxothiadiazinyl, triazolyl, tetrazolyl, monooxo-or dioxo-diazinyl group) and 3-acylaminomethyl-7β-amino-3-cephem-4-carboxylic acids (IIa-j)(acyl group: alkanoyl, alkenoyl, benzoyl or heterocyclic carbonyl group) were obtained in high yields.View full abstractDownload PDF (759K) -
Synthesis and Structure-Activity Relationships of 7β-[D (-)-α-Amino-α-(4-hydroxyphenyl) acetamido]-3-substituted Methyl-3-cephem-4-carboxylic AcidsHIROSHI SADAKI, HIROYUKI IMAIZUMI, TAKIHIRO INABA, TATSUO HIRAKAWA, YO ...1986 Volume 106 Issue 2 Pages 123-128
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESS7β-[D (-)-α-Amino-α-(4-hydroxyphenyl) acetamido]-3-substituted methyl-3-cephcm-4-carboxylic acids (IIa-j) were prepared by the acylation of 7β-amirlo-3-substituted methyl-3-cephem-4-carboxylic acids (substituent: phenyl, furyl, mesylamino, 1, 1-dioxothiadiazinyl, triazolyl, tetrazolyl, monooxo- or dioxo-diazinyl, acetylamino or benzoylamino group) with reactive derivatives of D (-)-α-amino-α-(4-hydroxyphenyl) acetic acid.
The structure-activity relationships of IIa-j indicated that compounds with phenyl group as a substituent were active against Gram positive bacteria, and that compounds with phenyl, 5-carboxy-furan-2-yl or benzoylamino group were active against Gram negative bacterial, but these compounds had weaker antibacterial activity than cephalexin (CEX). And urinary recovery after oral administration of IIa-j into mice was 1-27%, exhibiting lower rate than that of CEX.View full abstractDownload PDF (812K) -
Synthesis and Structre-Activity Relationships of 7β-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-substituted Methyl-3-cephem-4-carboxylic Acid DerivativesHIROSHI SADAKI, HIROYUKI IMAIZUMI, TAKIHIRO INABA, TATSUO HIRAKAWA, YO ...1986 Volume 106 Issue 2 Pages 129-146
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESS7β-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamidol]-3-substituted methyl-3-cephem-4-carboxylic acids (IIa-l) were prepared by the acylation of 7β-amino-3-substituted methyl-3-cephem-4-carboxylic acids (substituent: phenyl, 1, 1-dioxothiadiazinyl, monooxoor dioxo-diazinyl, triazolyl, tetrazolyl, acetylamino or benzoylamino group) with reactive derivatives of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid.
IIa-l had a wide antibacterial spectrum against Gram positive and Gram negative bacteria and showed the potent antibacterial activity, being similar to those of cefmenoxime.
For the purpose of developing new oral cephalosporin, various esters (IIIa-1, IVa-m, Va-d) of IIa-l were prepared as one form of prodrugs.
Urinary recoveries of these esters in mice weremeasured. Compounds having 5-methyl-2H-tetrazol-2-yl or 5-chloro-1, 2, 4-triazol-1-yl as a substituent of 3-position and pivaloyloxymethyl or 1-pivaloyloxyethyl as ester group showed high recoveries ranging from 31.2 to 37.3%.View full abstractDownload PDF (2290K) -
Synthesis and Structure-Activity Relationships of 7β-Acylamido-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-3-cephem-4-carboxylic AcidHIROSHI SADAKI, HIROYUKI IMAIZUMI, TAKIHIRO INABA, TATSUO HIRAKAWA, YO ...1986 Volume 106 Issue 2 Pages 147-153
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESS7β-Acylamido-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-3-cephem-4-carboxylic acids and 7β-acylamido-3-[(5-chloro-1, 2, 4-triazol-1-yl) methyl]-3-cephem-4-carboxylic acids (Ia-l) were prepared by the acylation of 7β-amino-3-substituted methyl-3-cephem-4-carboxylic acids with reactive derivatives of acetic acid.
The structure-activity relationships of Ia-l indicated that compounds with 2-(2-aminothiazol-4-yl) acetyl group as acyl group were active against Gram positive bacteria. And compounds with (Z)-2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetyl or (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl group were active against Gram negative bacteria, being active similarly to that of cefmenoxime.
Compounds having the above acyl groups were esterified with pivaloyloxymethyl group to obtain an efficiently absorble esters (VIg-j) through oral administration, whose urinary recoveries in mice were 19.6-37.5%.View full abstractDownload PDF (996K) -
Reaction of Methoxymethylene Meldrum's Acid with Amino Acid DerivativesTAKUO CHIBA, JUN-ICHI SAKAKI, CHIKARA KANEKO1986 Volume 106 Issue 2 Pages 154-157
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESSReaction of 2, 2, -dimethyl-5-methoxymethylene-1, 3-dioxane-4, 6-dione (1) with amino acid esters gave rise to N-(2, 2-dimethyl-4, 6-dioxo-1, 3-dioxan-5-ylidenemethyl) amino acid esters (2) in good yields. Similarly, free amino acids gave N-protected amino acids (3) which were coupled with amino acid esters in the presence of dicyclohexylcarbodiimide afford protected dipeptides. These N-protected amino acids 2a-e and 3a-e, and dipeptides 4a-d, and 5 were examined for antibacterial activity.View full abstractDownload PDF (615K) -
SHIN YOSHII, KUMIKO MIYAMOTO, TAMIO NISHIMURA1986 Volume 106 Issue 2 Pages 158-163
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESSN-Methyl amidinohydrazones (AH) of substituted benzalacetones were synthesized, and examined in their activities against influenza virus A2/Adachi strain, bacteria and fungi. These AHs exhibited 50% inhibitory concentrations of 4.5-70.5μg/ml and 50% virucidal concentrations of 0.01-2.3μg/ml against the virus in the chorio-allantoic membrane culture. Satisfactory quantitative structure-activity relationships were obtained for inhibitory and virucidal activities against the virus and toxicity to chorio-allantoic membrane.
Almost all AHs showed minimum inhibitory concentrations of 6.25-100μg/mlagainst Mycoplasma gallisepticum and 3.13-100μg/ml against S. aureus, B. subtilis and Pasteurella. Satisfactory quantitative structure-activity relationships were obtained for S. aureus and B. subtilis.View full abstractDownload PDF (747K) -
TAKETSUNE MIYAHARA1986 Volume 106 Issue 2 Pages 164-168
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESSAs metallofluorescent indicators, 2-naphthylamine-N, N-diacetic acid (I), 8-sulfo-2-naphthylamine-N, N-diacetic acid (II), and 7-sulfo-2-naphthylamine-N, N-diacetic acid (III) were studied.
Synthesis and purification of these compounds were easy, comparing with those of N, N, N', N'-tetra (carboxymethyl) dianisidine (Anisidine blue®), and they were stable in an alkaline solution. Acid dissociation constants of ligand [-N (CH2COOH) 2] were determined by potentiometric method. pKa1 (carboxyl) and pKa2 (ammonium) were 2.35 and 5.02 for I, 2.85 and 5.31 for II, 2.69 and 5.06 for III, respectively. Fluorescences of these reagents were quenched by copper (II), cobalt (II), and nickel (II), at pH 4.5-5.5, and copper (II) showed this effect more clearing than the others. Constitution of the copper (II) complexes were 1: 1. Stability constants of these copper (II) complexes which were determined potentiometrically, were 5.8 for II and 5.2 for III logarithmically. Stability constant of complex with I was not determined because ofthe insolubility.
By using these compounds as the indicators, fluorophotometric titration of copper (H)(0.64mg) with 0.01 M ethylenediaminetetraacetic acid (EDTA) yielded good recovery. But those of nickel (II) and cobalt (II) were not available because fluorescence was not shown up by EDTA on nickel (II) and end-point was not clear on cobalt (II).
II is a good indicator in fluorophotometric titration of copper (II) with EDTA, because it is stable in an aqueous solution and has shown stronger fluorescence than I and II.View full abstractDownload PDF (606K) -
IKUO JOHNO, TOSHI-AKI NAKAMURA, MASAYA HASEGAWA, MASAKO MAEDA, YOZO OG ...1986 Volume 106 Issue 2 Pages 169-175
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESSThe accuracy and precision studies and pharmacokinetic analyses for valproic acid (VPA) by using substrate-labeled fluorescent immunoassay (SLFIA method) were performed and the results obtained by SLFIA method were compared with those of gas-liquid chromatography (GLC method). Within- and between-day precision studies of SLFIA method by use of VPA spiked samples in the normal human and rabbit plasma showed a good reproducibilitywith less than 5% as coefficient of variation and there were no significant differences (p>0.05) between the measurements by GLC and SLFIA method. Good correlations between the determinations by GLC (horizontal axis) and SLFIA (vertical axis) method were obtained and the regression equation was y=0.874x+12.4 (n=77, r=0.971, p<0.001) for rabbit samples and y=0.985x+0.866 (n=38, r=0.980, p<0.001) for the samples of patients taking a VPA preparation. These mean values obtained by both of the methods were statistically identical. After a single intravenous bolus injection (VPA dose of 56-71mg/kg) in rabbits, pharmacokinetic parameters were obtained following one-compartment open model. Apparent elimination rate constant by use of SLFIA method was significantly smaller (p<0.001) than that by GLC method, but the volume of distribution by SLFIA method was significantly larger (p<0.05) than that by GLC method. On the other hand, no significant difference was observed (p>0.05) for systemic clearance. These results are reasonably understood that SLFIA method showed significantly higher values which may be due to cross-reaction in lower VPA concentration range (less than 25μg/ml) and moreover suggested significantly lower value which may be caused by the dilution of rabbit plasma samples with a protein-free buffer in higher VPA concentration range (more than 150μg/ml).
These observations showed that SLFIA method was a useful method for clinical measurement of plasma (or serum) VPA level. However, several problems on calculating pharmacokinetic parameters with rabbits with a very short half-life remained to be elucidated.View full abstractDownload PDF (1105K) -
Dielectric Studies of Colloid-Chemical Stability of W/O Type Anti-inflammatory Emulsive PreparationsHIDEO KANEKO, SADAO HIROTA1986 Volume 106 Issue 2 Pages 176-182
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESSThe purpose of the present study was to develop the W/O type anti-inflammatory emulsive preparation with the high volume fraction of dispersed phase and high colloidchemical stability.
The dielectric measurement was used to evaluate the degree of particle aggregation of W/O emulsion during preparation or storage. It was found that the values of limiting dielectric constant at low frequency, εl, increased or decreased and parameter of distribution of relaxation frequencies, α, decreased with the rotation time of paddle- and homomixer during preparation. During the storage test, in the case of W/O type emulsive preparation whose surfactant concentration was low, the value of αl became larger with storage time and soon the W/O emulsion separated into two phases. It was considered that the particle aggregation progressed and particle coalescence gave rise to in the W/O emulsive preparation. The W/O emulsion prepared with the sorbitol solution was colloidchemically more stable than with water alone.This stabilizing effect may be due to the orientation of sorbitol molecules onto the interface between dispersed particles and oil phase.View full abstractDownload PDF (783K) -
Cytotoxic Constituent against HeLa Cells in the Fruit of Trapa bispinosa ROXBTAKUO KOSUGE, MASAMI YOKOTA, KIYOSHI SUGIYAMA, ATSUSHI OKAMOTO, MASASH ...1986 Volume 106 Issue 2 Pages 183-185
Published: February 25, 1986
Released on J-STAGE: January 31, 2011
JOURNAL FREE ACCESSGallic acid was isolated as a cytotoxicconstituent from the fruit of Trapa bispinosa ROXB., by tracing the inhibitory activityagainst HeLa cells.View full abstractDownload PDF (317K)
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