Catechins are not major components responsible for anti-genotoxic effects of tea extracts against nitroarenes.

The anti-genotoxic properties of tea leaf extracts were examined in a Salmonella umu-test. Seven non-fermented teas (green tea), one semi-fermented tea (oolong tea), two fermented teas (black tea and Chinese pu er tea) and two other teas were examined for their anti-genotoxic abilities and for their catechins contents. This was to study the relationship between catechins contents and anti-genotoxic activity of various tea leaf extracts. All types of tea extracts showed more potent suppressive effects against umu gene expression of the SOS response in Salmonella typhimurium TA1535/pSK 1002 induced by four nitroarenes (1-nitropyrene, 2-nitrofluorene, 3-nitrofluoranthene and a mixture of 1,6- and 1,8-dinitropyrene) rather than 4-NQO, AF-2 and MNNG. The anti-genotoxic effect of 12 tea leaf extracts on 1-NP, 2-NF, 3-NF and DNP decreased in the order: oolong tea (semi-fermented tea)>black tea (fermented tea)>sencha (non-fermented tea, an ordinary grade green tea)>tocyucya (other tea)>Chinese pu er tea (fermented tea). The amount of catechins (EGC, C, EGCG, EC and ECG) in various teas in decreasing order was non-fermented tea>semi-fermented tea>fermented tea>other tea. A remarkable feature was the effectiveness of black tea and Chinese pu er tea in suppressing the genotoxicity induced by nitroarenes, in spite of the fact that these fermented teas do not have high catechins contents. Statistical analysis showed that no significant (P<0.01) correlation was found between the anti-genotoxicity of tea extracts against nitroarenes and the catechins contents in tea leaf extracts. In further experiment, fractionation of sencha extract by HPLC revealed that anti-genotoxicity of the peak fraction corresponding to catechins accounted for <10% of the total anti-genotoxic activity of sencha extract against for 1-nitropyrene. These results suggest that catechins are not major components responsible for the anti-genotoxic effects of tea leaf extracts against direct-acting nitroarenes.

Photoallergenicity of a fluoroquinolone antibacterial agent with a fluorine substituent at the 8-position in guinea pigs exposed to long-wavelength UV light.

The 8-position of the quinolone ring of balofloxacin (BLFX), one of fluoroquinolones, was replaced with fluorine to obtain the 8-F. When an aqueous solution of bovine serum albumin (BSA) containing the 8-F was exposed to long-wavelength UV light (UVA) at a rate of 2.5 J/cm2, the absorbance of BSA at 300 nm or longer wavelengths increased markedly in comparison to that of native BSA. In addition, when a homogenate of skin tissue from Hartley guinea pigs was exposed to UVA (2.5 J/cm2) in the presence of the 8-F and then injected subcutaneously into guinea pigs, the animals produced IgG class antibody specific to the 8-F and its UVA-irradiation product. No such phenomenon, however, was observed when the parent compound, i.e. , BLFX which possesses a methoxy group at the 8-position, was used instead of the 8-F. In a subsequent experiment, the 8-F was administered either orally or topically to the shaved neck of guinea pigs and then irradiated with UVA (5 J/cm2) once daily for 5 days. When the treated animals were challenged by a combination of UVA irradiation (5 J/cm2) and either an oral or intradermal administration of the 8-F, 2 and 3 of the 5 animals showed redness and erythema on the irradiated area, respectively. However, no change was observed when BLFX was used instead of the 8-F. These results suggest that the introduction of a fluorine substituent to the 8-position of quinoline ring of fluoroquinolones induces photoallergic responses in which the fluoroquinolone or its photo-denatured product(s) act as an allergen.

Liver injuries induced by herbal medicine, syo-saiko-to (xiao-chai-hu-tang).

Four patients treated with the herbal medicine syo-saiko-to (xiao-chai-hu-tang) exhibited acute drug-induced liver injury. The latent period was one and a half to three months. All of the patients showed a rise in aminotransferases after readministration or challenge test. The liver histology revealed centrilobular confluent necrosis or spotty necrosis, microvesicular fatty change, acidophilic degeneration, and a granuloma. Cholestasis was seen in two patients. The results of the [13C]aminopyrine breath test, performed in one patient, were low before the challenge test and even lower after the challenge. These findings suggest that the herbal medicine syo-saiko-to may induce acute injury or the hepatocellular pattern with variable cholestasis.

Reduced phototoxicity of a fluoroquinolone antibacterial agent with a methoxy group at the 8 position in mice irradiated with long-wavelength UV light.

A newly developed fluoroquinoline, Q-35 (8-OCH3), in which a methoxy group was substituted at the 8 position of the quinoline nucleus, was very stable under irradiation with long-wave UV light (UVA). Derivatives, a fluoroquinolone with no substitution (the 8-H analog) and one in which a fluorine was substituted (the 8-F analog), were degraded in their solutions by the UVA irradiation. The phototoxic inducibility by these derivatives was further studied in a murine model. When mice were dosed orally with 800 mg of Q-35 (8-OCH3) per kg of body weight, the maximum dose given, and exposed to the UVA light, no inflammatory lesions were observed in their ears. Ear redness was marked in mice given more than 12.5 mg of the 8-F analog or 200 mg of the 8-H analog per kg. Histopathological changes, edema, and infiltration of neutrophils were also observed microscopically in groups receiving the 8-H or 8-F analog but not in groups receiving Q-35 (8-OCH3). Similar inflammatory reactions were observed to occur in a dose-dependent manner with other available fluoroquinolone antibacterial agents such as lomefloxacin, enoxacin, norfloxacin, ciprofloxacin and ofloxacin. These results suggest that the introduction of a methoxy group at the 8 position of the quinolone nucleus is important for the reduction of phototoxicity.

Changes in ultrastructure of hepatocytes and liver test results before, during, and after treatment with interferon-beta in patients with HB(e)Ag-positive chronic active hepatitis.

We studied the histological and ultrastructural changes in the liver and alterations in the liver test results before, during, and after treatment with human interferon-beta from five patients with hepatitis B e antigen-positive chronic active hepatitis. A daily dose of 3 x 10(6) to 6 x 10(6) units of interferon-beta was given intravenously for four weeks. The total index of periportal and portal inflammation, intralobular degeneration, and focal necrosis before treatment was decreased significantly six months after treatment (P less than 0.05). Ultrastructurally, the structure of endoplasmic reticulum was irregularly shaped or fragmentally decreased during treatment, but these disappeared six or 12 months after treatment. Glycogen particles diminished greatly during treatment. The alanine aminotransferase concentrations in these patients increased during treatment. Serum albumin and cholinesterase levels decreased significantly at the fourth week of treatment (P less than 0.01) and at the third day (P less than 0.01) to the second week (P less than 0.05) of treatment, respectively. These results suggest that interferon-beta injures endoplasmic reticulum and glycogen areas and damages the cholinesterase activity in the early stage of treatment and protein synthesis in patients with hepatitis B e antigen-positive chronic active hepatitis.

[Nephrotoxicity of cefpirome sulfate in rabbits--single and multiple intravenous administration].

Nephrotoxic potential of cefpirome sulfate (CPR) was examined by single and multiple intravenous administrations to Japanese white male rabbits. In single administration studies, no nephrotoxic symptoms were observed at the dose level of 320 mg/kg of CPR or less. At the dose level of 500 mg/kg or more, nephrotoxic findings were noted in both CPR and cefazolin sodium(CEZ) groups, such as proteinuria, glucosuria, increase in serum level of urea nitrogen, creatinine and uric acid, and necrosis and calcification in the proximal tubular epithelium of kidney. Renal phenolsulfonphthalein(PSP) excretion was suppressed at the dose level of 500 mg/kg of CPR or more, and 2000 mg/kg of CEZ. In 14 and 21 days repeated administration studies, no nephrotoxic symptoms were observed at the dose level of 100 mg/kg of CPR and CEZ or less. At the dose level of 200 mg/kg of CPR or more, urinary and serum biochemical findings mentioned above were observed, and histopathological changes in the kidney described above were added in 400 mg/kg group. The similar nephrotoxic symptoms including histopathological changes of the kidney were observed in the groups of 100 mg/kg of cefaloridine(CER) and 200 mg/kg of CEZ. In addition, renal PSP excretion was suppressed in the group of 200 mg/kg of CEZ. The results would suggest that CPR is less nephrotoxic than CER and that the nephrotoxic potential of CPR is comparable to CEZ because CPR caused more severe renal failures in single administration study and less severe renal failures in multiple administration study than CEZ.

Triiodothyronine level and triiodothyronine/thyroxine ratio in HBeAg-positive chronic hepatitis patients treated with prednisolone withdrawal.

Twenty patients with hepatitis B e antigen (HBeAg) -positive chronic hepatitis, who received 40 mg of prednisolone per day for three weeks followed by withdrawal, were studied for changes in alanine aminotransferase (ALT), triiodothyronine (T3), thyroxine (T4), and hepatitis B virus DNA polymerase (HBV-DNAp) levels determined before and during prednisolone treatment and after its withdrawal. A decreased HBV-DNAp level of less than 100 cpm/ml three to five weeks after withdrawal was considered a sign of efficacy and was shown in 10 patients (50%). Significant differences were found between ALT levels, between T3 levels, and between the T3/T4 ratios assayed in the third and fourth weeks in total (P less than 0.02) and in the group in which efficacy was demonstrated (P less than 0.01). The T3/T4 ratio in the third week in the effectively treated group was significantly less than that in the noneffectively treated group (P less than 0.05). Prednisolone withdrawal effective for HBV-DNAp was shown in the patients with a decreased T3 level and the T3/T4 ratio at the third week and an increase in the ATL level after the withdrawal. The ALT level increased after the T3 level decreased. Changes in the T3 level or the T3/T4 ratio represent a marker for effectiveness of prednisolone withdrawal and for determination of combination therapy after steroid withdrawal.

Changes in liver calcium content in relation to serum triiodothyronine (T3), thyroxine (T4) and T3/T4 ratio in rats treated with CCL4.

To evaluate the relation between liver calcium content and microsomal function in liver injury, we determined liver calcium content, serum triiodothyronine (T3), thyroxine (T4), T3/T4 ratio and serum glutamic pyruvic transaminase (SGPT) content in rats treated with CCl4. The T3/T4 ratio decreased from 1.9 to 1.2 at 6 hr after treatment, but elevated immediately to 3.2 at 36 hr after, and returned to normal at 54 hr after treatment. The calcium content increased from 27 micrograms/g wet weight to 448 micrograms/g wet weight 24 hr after treatment and decreased to normal 78 hr after treatment. The SGPT concentration showed the highest 12 hr after and returned to normal 72 hr after treatment. The calcium content was significantly correlated with T3 (r = -0.5, p less than 0.05). These results suggest that the increase and decrease in liver calcium content are closely related to the decrease and increase in T3 and T3/T4 ratio, respectively.

Evaluation of submandibular gland function by sialo-scintigraphy following sialolithectomy.

Submandibular gland function following transoral sialolithectomy was examined by 99mTc-pertechnetate sialo-scintigraphy in 10 cases. An intraindividual comparison between the function of the treated gland and that of the contralateral normal gland was made using a time-activity curve. Although glandular recovery was not affected by the duration of symptoms or the existence of the symptom at mealtimes, it was inversely proportional to the size of the calculus. Furthermore, the prognosis was more favorable in patients when the anatomically normal orifice of the submandibular duct was preserved.