Possible pharmacotherapy for nifedipine-induced gingival overgrowth: 18α-glycyrrhetinic acid inhibits human gingival fibroblast growth.

BACKGROUND AND PURPOSE: This investigation aimed to establish the basis of a pharmacotherapy for nifedipine-induced gingival overgrowth. Gingival overgrowth has been attributed to the enhanced growth of gingival fibroblasts. In this study, we investigated the effects of 18-α-glycyrrhetinic acid (18α-GA) on growth, the cell cycle, and apoptosis and on the regulators of these processes in gingival fibroblasts isolated from patients who presented with nifedipine-induced gingival overgrowth. EXPERIMENTAL APPROACH: Gingival fibroblasts were cultured in medium containing 1% FBS with/without 10 µM 18α-GA for 24 or 48 h, and the cell number, cell cycle phase distribution, relative DNA content, apoptotic cell number and morphological characteristics of the cells undergoing apoptosis were measured together with the levels of proteins that regulate these processes and the level of caspase activity. KEY RESULTS: 18α-GA significantly decreased cell numbers and significantly increased the percentage of cells in the sub-G1 and G0 /G1 phases of the cell cycle and the number of apoptotic cells. Nuclear condensation and fragmentation of cells into small apoptotic bodies appeared in the fibroblasts treated with 18α-GA. In addition, 18α-GA significantly decreased the protein levels of cyclins A and D1, CDKs 2 and 6, phosphorylated Rb (ser(780) and ser(807/811)), Bcl-xL and Bcl-2 and increased the protein levels of p27, cytosolic cytochrome c, pro-caspase-3, and cleaved caspase-3 and the activities of caspases 3 and 9. CONCLUSIONS AND IMPLICATIONS: 18α-GA inhibited gingival fibroblast growth by suppressing the G1 /S phase transition and inducing apoptosis. In conclusion, 18α-GA may be used as a pharmacotherapy for nifedipine-induced gingival overgrowth.

Novel, highly potent aldose reductase inhibitors: (R)-(-)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine -4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (AS-3201) and its congeners.

A series of novel tetrahydropyrrolo[1,2-a]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin-induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo[1, 2-a]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1, 2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10(-8) M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)-enantiomer 44 (SX-3202). From these results, AS-3201 was selected as the candidate for clinical development. The absolute configuration of AS-3201 was also established to be (R)-form by single-crystal X-ray analysis. In this article we report the preparation and structure-activity relationship (SAR) of tetrahydropyrrolopyrazine derivatives including a novel ARI, AS-3201.

Studies on the primary structure of bovine high-molecular-weight kininogen. Amino acid sequence of a fragment ("histidine-rich peptide") released by plasma kallikrein.

An unknown peptide fragment, which was released from bovine high-molecular-weight kininogen by bovine plasma kallikrein [EC 3.4.21.8], was isolated and its chemical structure was established. The fragment consisted of 41 amino acids with serine and arginine at the NH2- and COOH-termini, respectively. The molecular weight was calculated to be 4,584. It was very basic and contained eleven residues each of histidine and glycine and seven residues of lysine. Thus, the total number of these three amino acids accounted for about 70 percent of the total residues constituting the fragment. The amino acid sequence of the fragment, designated tentatively as "His-rich peptide," was studied by Edman degradation and standard enzymatic and chemical techniques. These data made it possible to deduce the following sequence: H-Ser-His-Gly-Leu-Gly-His-Gly-His-Gln-Lys-Gln-His-Gly-Leu-Gly-His-Gly-His-Lys-His-Gly-His-Gly-His-Gly-Lys-His-Lys-Asn-Lys-Gly-Lys-Asn-Asn-Gly-Lys-His-Tyr-Asp-Trp-Arg-OH. The fragment had an extremely interesting feature in that repeating sequences occur along the peptide chain. The repeats were of the type His-Gly-X or Gly-His-X and this sequence appeared six or seven times up to 26 residues from the N-terminal end. Moreover, three tetrapeptide sequences of Gly-His-Gly-His and two heptapeptide sequence consisting of His-Gly-Leu-Gly-His-Gly-His were found in the N-terminal portion. It should be noted that plasma kallikrein liberates such a histidine-rich peptide from the kininogen in addition to a physiologically active peptide, bradykinin. The location of the "His-rich peptide" fragment in the percursor protein is also discussed.

Gnathostomiasis in frog-eating snakes from Japan.

Gnathostoma doloresi parasitizes the gastric wall of wild (boars) and domestic (pigs) swine (Sus scrofa). Its larvae cause cutaneous larva migrans in humans. Amphibians, reptiles and a freshwater fish are infected with the advanced 3rd stage larvae. Prevalence of G. doloresi larvae were surveyed in several snakes, especially in a common frog-eating snake (Rhabdophis tigrinus). All species of snakes examined were infected with G. doloresi larvae suggesting that snakes are important reservoir hosts. Prevalence of G. doloresi larvae in frog-eating snakes was lower than that found in mammal-eating snakes. Thus, as a source of infection to snakes, small mammals may be more important than frogs in the natural life cycle of G. doloresi in Japan.

[Talampicillin hydrochloride: Comparison with amoxicillin and ampicillin in the antibacterial activity and pharmacokinetics (author's transl)].

The antibacterial activities, absorption and excretion of talampicillin hydrochloride were compared with those of amoxicillin and ampicillin. Talampicillin hydrochloride showed a broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria as seen in amoxicillin and ampicillin. The antibacterial activities of talampicillin hydrochloride, amoxicillin and ampicillin were quite similar. In experimental murine infection with Staphylococcus aureus, protective effect of talampicillin hydrochloride was superior to ampicillin. For Escherichia coli infection, protective effect of talampicillin hydrochloride was similar to that of amoxicillin, while ampicillin was less active than both talampicillin hydrochloride and amoxicillin. The absorption and excretion of 250 mg equivalent doses of talampicillin hydrochloride, amoxicillin and ampicillin were compared in nine fasting healthy volunteers after oral administration of these antibiotics in randomized triple crossover study. In order to calculate the pharmacokinetic parameters, plasma levels were analyzed using an one-compartment open model, as well as area under the plasma concentration curve (AUC) and urinary excretion. Maximum plasma levels calculated were 2.8 times higher for talampicillin hydrochloride and 1.45 times higher for amoxicillin than for ampicillin. AUC was greater for talampicillin hydrochloride than for amoxicillin and lowest for ampicillin. Urinary excretion of talampicillin hydrochloride as penicillin determined in biological assay was comparable to that of amoxicillin and 1.55 times higher than that of ampicillin. Penicillins can be metabolized to penicilloic acids in the body. After taking into account the penicilloic acid contents in urine, total excretion in urine was 61% for talampicillin hydrochloride, 67% for amoxicillin and 42% for ampicillin during 6 hours after dosing. The absorption of the drugs was evaluated according to the plasma levels, the area under plasma concentration curve and the percentage of excretion in urine. The results obtained showed that talampicillin hydrochloride was well absorbed from the gastro-intestinal tract.