Studies of γ-glutamyltranspeptidases purified from a variety of organs of several mammals revealed that organ- as well as species-specific differences exist in their sugar moieties. Comparative studies of the two subunits and various isozymic forms of the rat kidney enzyme revealed that high mannose-type sugar chains are included only in the large subunit and the difference in the numbers of acidic sugar chains is the molecular bases of the isozymic forms of the enzyme. Comparative study of the enzymes purified from rat liver and rat AH-66 hepatoma indicated that several structural differences exist in the sugar chains of the two enzymes. Among them, occurrence of bisecting GlcNAc residue in half of the sugar chains of hepatoma is most important because the residue is never found in the sugar chains of glycoproteins including γ-glutamyltranspeptidase produced in normal liver. By making used of the change, a new method for the diagnosis of hepatoma has been developed.
The stereoselective synthesis of several α-alkylidene-γ-butyrolactones from oxetanes obtained by photoaddition of aldehydes to furan is described. (E)-, and (Z)-selectivity was demonstrated at the elimination reaction of the final stage.
In the course of the chemical characterization of crude drug processing, the alkaloidal constituents of Aconiti Tuber ("chuan-wu", imported from Si Chuan, China), the dried tuber of Aconitum carmichaeli DEBX. were investigated. In addition to the known alkaloids such as aconitine (1), hypaconitine (2), mesaconitine (3), talatizamine (5), 14-acetyltalatizamine (6), isotalatizidine (7), karakoline (8), and neoline (9), four new lipo-alkaloids named lipoaconitine (10), lipohypaconitine (11), lipomesaconitine (12), and lipodeoxyaconitine (13), were isolated and their structures elucidated. It was also found that the acetyl functions attached to the C-8 hydroxyls of 1, 2, and 3 were readily interchanged by the fatty acid residues.
The alkaloidal constituents of two types of "pao-fuzi ( ?? ?? ?? )", the processed tuber of Aconitum carmichaeli DEBX., were investigated. Aconitine (1), hypaconitine (2), mesaconitine (3), talatizamine (5), 14-acetyltalatizamine (6), isotalatizidine (7), karakoline (8), neoline (9), lipoaconitine (10), lipohypaconitine (11), lipomesaconitine (12), and lipodeoxyaconitine (13) were identified from"banshu-fuzi ( ?? ?? ?? ?? )", while benzoylaconine (1a), benzoylhypaconine (2a), and benzoylmesaconine (3a) together with 1-3, 5-9 were identified from"fupian ( ?? ?? )". By use of a dual-wavelength thin layer chromatography scanner, lipo-alkaloids (10-13) were shown to be distributed as major alkaloids in thirteen out of fifteen kinds of "fuzi"and wutou". It was also found that these lipo-alkaloids were less toxic as compared with the corresponding fatally toxic alkaloids such as 1 and 3. However, lipomesaconitine (12) was found to exhibit antiinflammatory and analgesic activities. It was suggested that the substitutions of the acetyl residues attached to the C-8 hydroxyls of 1-4 for the fatty acid residues were the other possible chemical modifications in the decrease of toxicities of Aconiti Tuber.
As a continuing study on the chemical characterization of the processing of "fuzi", a quantitative method by high performance liquid chromatography (HPLC) for aconitine alkaloids : aconitine (1), hypaconitine (2), mesaconitine (3), lipoaconitine (4), lipohypaconitine (5), lipomesaconitine (6), lipodeoxyaconitine (7), benzoylaconine (1a), benzoylhypaconine (2a), and benzoylmesaconine (3a), has been developed. By the use of this HPLC method, aconitine alkaloid contents in 15 kinds of "fuzi"(processed and unprocessed, originated in Japan and China) were examined. It was found that 13 out of 15 kinds of "fuzi"contained lipo-alkaloids (4, 5, 6) as major alkaloids and the contents of fatally toxic alkaloids such as 1, 2, and 3 decreased in processed "fuzi"(e.g."pao-fuzi") whereas the contents of lipo-alkaloids increased.
Source of haze to some lyophilized parenterals when rubber stoppers were not applied in the lyophilization process were studied in this report. First, it was confirmed that phthalates contaminated in PL-385 raw material, a kind of antibiotics, are a large source of haze. Then, PL-385 solution after extracting the phthalates by chloroform was used in this study. As the result, it was found that n-butyl phthalate, di (2-ethylhexyl) phthalate, C20H42, C22H46, di (2-ethylhexyl) adipate, sulfur, etc., which are volatiled from the rubber bags used for pressing rubber stoppers, silicone packing, and covered rubber for the thermocouples, etc. are a source of haze. It was specifically confirmed from the relationship between turbidity and adsorbed amount of C20H42, that C20H42 volatiled from rubber bags is a main source of haze, when a M-1700 Freeze Dryer is used. In addition, 9 kinds of drugs containing PL-385 were lyophilized at the same time and under the same conditions, and it was proved that lyophilized PL-385 adsorbs most of phthalates and saturated hydrocarbons because of large specific surface area (1.3 m2/g) and therefore, PL-385 makes haze most strongly.
Pharmacokinetics and enzyme induction effects of rifampicin, an antituberculosis, were studied on 8 female and 2 male patients. Rifampicin (450 mg) was administered orally every morning before breakfast over a period of 8 weeks. On the 1st, 14th, 21st, 28th and 56th days of treatment, venous blood samples were drawn immediately, 2, 4 and 8 h after the administration of rifampicin. Rifampicin level in the serum was determined by high-performance liquid chromatography. Determination of rifampicin level was made in duplicate. Data of rifampicin levels in the serum (Ct) were calculated with a personal computer. Biexponential equation, Ct=A (e-Kat-e-Ket), and the pharmacokinetic parameters were non linear least squares regression analysis. The first-pass effect was obtained from calculated by the method of Gibaldi et al. Cmax and area under blood concentration curve gradually decreased until the 21st day of treatment and, thereafter, reached a steady-state until the 56th day of treatment. Biological half-life fluctuated until the 28th day of treatment and reached steady-state on day 28. Vd, Cl and first-pass effects showed a definite increase until the 21st day of treatment. After that, they reached a steady-state until the 56th day of treatment. In summary, pharmacokinetics of rifampicin was found to be time-dependent and closely related to the enzyme inducibility of the drug.
Cellulose acetate phthalate microcapsule containing phenacetin was used as a model and the effect of compression force and characteristics of excipients on the damage of microcapsule wall during compression process were studied. Calcium citrate with different particle sizes and microcrystalline cellulose were used as excipients. The degree of damage of the wall was evaluated from the dissolution rate of phenacetin and results observed by scanning electron microscopy. When calcium citrate was used as an excipient, microcapsule wall was damaged remarkably in the early stage of compression (P=100 kg/cm2), and the degree of damage was affected by particle size of calcium citrate. The larger particles caused more remarkable damage. In the case of microcrystalline cellulose which showed high compressibility, the degree of damage under high compression force (P=1000 kg/cm2) was less than that of calcium citrate under low compression force (P=100 kg/cm2). From these results, it was considered that the magnitude and distribution of shear stress on the wall were affected by particle size and compressibility of excipients and that the degree of damage of microcapsule wall was different between calcium citrate and microcrystalline cellulose.
By using the improved immersion method and the key refractive indices, about which the authors have already reported, polarizing microscopy has been practised for antibiotic drugs listed mainly in the JPX. As many as 17 drugs in 32 were classified into the group A, from which 2 key refractive indices were measured on the natural position of their thin plate or scale shaped crystals at the immersion process. Seven drugs were classified into the group B, from which one key refractive index was measured from the parallel direction to the elongated position of long prisms or needles showing parallel extinction. While, another 7 drugs did not show double refraction and they were classified into the group D, the cases of isometric or amorphous solids. As they showed irregular shapes, they were determined as amorphous solids, from which an unique refractive index was observed in each substance. It was found that the polarizing microscopy would be applicable for the identification or analysis of such antibiotic drugs. The figure of correlation between refractive indices and birefringence (n2-n1) was also conveniently utilized.
N-Substituted amidinohydrazone (AH) of alkoxyacetophenones and alkoxybenzalacetones (BZ) were synthesized and examined mainly for activities against influenza viruses. These AHs exhibited 50% inhibitory concentrations of 1.4-90 μg/ml (Index 10-159) and 50% virucidal concentrations of 0.001-0.7 μg/ml (Index 103-106) against influenza viruses such as A0/PR-8, A1/FM-1, A1/Fukuoka, A2/Adachi, A2/Aichi, B/Lee, B/Kagoshima and Horse/Miami in the chorio-allantoic membrane culture. N-Methyl AHs of p-decyloxy BZ and m-methoxy-p-decyloxy BZ showed excellent inhibitory activities, and N-methyl AHs of p-decyloxy BZ and m-methoxy-p-octyloxy BZ remarkable virucidal activities. It is inferred that introduction of methyl group on amidino moiety of AHs increases the activity and decreases the toxicity against host-cell. These AHs showed minimum inhibitory concentration of 0.78-100 μg/ml against mycoplasma gallisepticum, fungi and bacteria.
Photo-oxygenation of 4-(3, 5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline (1b) gave 2, 6-di-tert-butyl-p-benzoquinone (2), N-acetyl-N'-(3, 5-di-tert-butyl-4-hydroxybenzoyl) urea (3) and 4-(3, 5-di-tert-butyl-4-oxo-2, 5-cyclohexadien-1-ylidene)-5-methoxy-5-methyl-2-oxo-imidazoline (4b), and 4b was the main product. Base-catalyzed oxygenation of 1b and related derivatives was carried out. Base-catalyzed oxygenation of 1b also gave 2, N-(3, 5-di-tert-butyl-4-hydroxybenzoyl) urea (5) and 4b. The mechanism of the reaction between 1b and oxygen giving compounds 2, 3, 4b and 5 was proposed.