Since Sweadner demonstrated that there are two isozymes (α and α (+) isoforms) of (Na++K+)-adenosine triphosphatase (ATPase) in the brain about 10 years ago, the isozymes have been extensively studied at biochemical and molecular levels. We started the studies on the isozymes of (Na++K+)-ATPase soon after finding that pyrithiamin, an antimetabolite of thiamin is a selective inhibitor of the α (+) isoform. This review summarizes the previous studies on the isozymes of (Na++K+)-ATPase, which are now classified into α1, α2, and α3.
Various 7β-[2-(2-aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivatives (Ia-e, IIa-g) were synthesized in order to find a new orally active cephalosporin improving the antibacterial activity of cefixime (CFIX) against Staphylococcus aureus. These derivatives include three types of α-substituted 2-(2-aminothiazol-4-yl) acetyl side chain ; i) mono or non substituted acetyl moiety, ii) carboxyalkoxyimino acetyl moiety, iii) phosphonomethoxyimino and hydroxyimino acetyl moiety. Their structure-activity relationships and urinary recoversies in rats were studied. As a result, the compound with a hydroxyimino acetyl side chain (IIg, FK482) showed good oral absorption and excellent antibacterial activity against both gram-positive and gram-negative bacteria and was selected as a candidate for clinical trial.
7-(2-Aminoethoxy)-, 7-(2-aminoethylthio)-, and 7-(2-aminoethylamino)-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acids and their derivatives (11a-f, h, j, k, 12a-f, and 13a-f) were synthesized and their antibacterial activities were tested. Among them, compounds (13a, d) having a primary amino group at the terminal position of alkoxy and alkylthio groups were found to have excellent in vitro and in vivo antibacterial activity comparable to those of ciprofloxacin (5). Structure-activity relationship of these compounds was also stated.
The present study was carried out to evaluate an equivalence of pharmacological properties between natural crude drugs and their cultured cells. The effects of ether extract of Lithospermi Radix and cultured cells of Lithospermum erythrorhizon SIEB. et ZUCC. and aqueous extract of Coptidis Rizoma and cultured cells of Coptis japonica MAKINO var. dissecta NAKAI on proliferation of granulation tissue in rats were compared. The ether extracts of Lithospermi Radix and the cultured cells enhanced proliferation of granulation tissue by the cotton pellet method. The potency of both extract was about the same, if results were compared with the corresponding doses which contained the same quantity of shikonin derivatives. On the other hand, the aqueous extracts of Coptidis Rhizoma and the cultured cells inhibited it. The potency of both extract was about the same, if results were compared with the corresponding doses which contained the same quantity of berberine-type alkaloids. From these results, to evaluate an equivalence of pharmacological properties between natural crude drugs and their cultured cells, it is concluded that their qualities and quantities are not so different each other and the almost same pharmacological effect expected on the basis of their uses is required.
One M perchloric acid-soluble fraction separated from cyst fluid of a patient (blood group AB) with ovarian clear cell carcinoma in malignant was subjected to Sephacryl S-200 gel filtration and Fraction 1 which was eluted at void volume, reacted with both of the lectins of Vicia unijuga and Arachis hypogaea. This fraction was then separated into 6 fractions (DEAE-Frs. 1-6) in a DEAE-Sephacel column chromatography. DEAE-Frs. 3-6 were sugar-rich glycoprotein fractions which contained galactose and N-acetylglucosamine in remarkably high percentages, respectively. Reactivities against various hemagglutinins of these four fractions suggest that DEAE-Fr. 3 is a Thomsen-Friedenreich (T) glycoprotein fraction with AB activity and weak N antigen precursor activity and DEAE-Fr. 4 is an N antigen precursor glycoprotein fraction with AB activity and weak T activity.
The relationship between gastric acidity and bioavailability of a weakly basic drug, cinnarizine (CN) was investigated in the gastric acidity-controlled beagle dogs. The dissolution of CN from capsules was very fast at pH 1.2 but it decreased with an increase in pH. The capsules containing CN were orally administered to the beagle dogs of the following three groups : 1) the dogs whose gastric acidity were not controlled ; 2) the dogs whose gastric acidity were controlled to high levels (less than pH 2) with pentagastrin ; 3) the dogs whose gastric acidity were controlled to low levels (more than pH 6) with omeprazole. The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC0-8h) of CN were most variable in the first group. On the other hand, the variations of these parameters were small in the second and third groups. The Cmax and AUC0-8h of CN in the high acidity group were about 20 times larger than those in the low acidity group (p<0.01). The bioavailability of CN was markedly influenced by the gastric acidity. This finding was similar to that in human subjects. The gastric acidity-controlled beagle dogs are useful animal models to evaluate the bioavailability of weakly basic drugs such as CN, exhibiting pH-dependent dissolution behavior.
Biological activities of two galactomannans (CI-P and CI-A) isolated from the insectbody portion of Chan hua (fungus : Cordyceps cicadae) were studied. CI-P having low affinity for concanavalin A (Con A) exhibited potent carbon-clearance activity in mouse, although both polysaccharides had little antitumor activity against sarcoma 180 in mice. Furthermore, CI-P and CI-A was found to have potent hypoglycemic activity in normal mice, and CI-A having high affinity for Con A showed slightly higher activity than CI-P.
An automated method for determination of yohimbine (Yoh) in the serum was developed by means of column switching high performance liquid chromatography (HPLC). TSK-precolumn BSA-ODS and TSK-gel ODS-120T were used as a precolumn and analytical column, respectively. The wavelengths of detection were used at 280 nm (excitation) and 360 nm (emission). A 100 μl serum sample is directly injected onto the precolumn. Yoh is then eluted within 30 min with an methanol-potassium phosphate buffer mixture. The analytical recoveries (99.3-110.4%), reproducibilities (within-run, C.V.<2.27%), and detection limit (0.80 ng/ml, S/N=3) indicate that this system is suited for determination of Yoh. The five healthy volunteers received a single oral dose 10 mg of HYoh powder. The average of the maximal serum concentration and the area under the curve (AUC) from 0 to 4 h were 10.3±0.88 ng/ml and 19.70±0.87 ng·h·ml-1, respectively. The elimination rate constant (K01) was 0.52±0.03 h, and biological half-life (t1/2el) was 1.32±0.12 h.