The mechanism and clinical relevance of the inhibitory effect of ciprofloxacin on the metabolism of selected drugs were studied in patients with bacterial infections. In study A, antipyrine tests were carried out in two groups of patients taking 1000 mg (group 1) and 250 mg (group 2) of oral ciprofloxacin for 7-10 days. Antipyrine was given intravenously in a dose of 15 mg/kg body weight before and after ciprofloxacin treatment. Blood samples were taken at 0, 2, 4, 6, and 10 hr after dosing. In group 1, ciprofloxacin administration resulted in a significant decrease in antipyrine elimination (t1/2, 9.45 +/- 3.74 vs. 14.92 +/- 3.32 hr). The average decrease in antipyrine clearance was 35% (0.85 +/- 0.45 vs. 0.52 +/- 0.24 ml/min/kg). In group 2, the change in antipyrine kinetics was less pronounced (t1/2, 9.79 +/- 3.06 vs. 11.22 +/- 2.64 hr). Antipyrine clearance was decreased by only 10% (0.77 +/- 0.13 vs. 0.70 +/- 0.14 ml/min/kg). These results support the hypothesis that ciprofloxacin inhibits the oxidative metabolism in the liver. However, according to the analysis of variance data, the inhibitory effect is dose dependent. At a dose of 1000 mg daily, ciprofloxacin may induce drug interactions whereas, at a dose of 250 mg daily, the likelihood of drug interactions is improbable. In study B, cimetidine (1000 mg orally daily) and ciprofloxacin (500 mg twice daily) were administered simultaneously to eight patients. Blood samples for the determination of ciprofloxacin concentrations were taken at 0, 1, 2, 4, 6, and 12 hr after dosing on the first and seventh day of drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

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Reactivity of glutathione adducts of 4-(dimethylamino)phenol. Involvement of reactive oxygen species during the interaction with oxyhemoglobin.

Ferrihemoglobin formation by 4-(dimethylamino)phenol (DMAP), a potent cyanide antidote, is influenced by GSH under formation of various glutathione S-conjugates. Two of these were shown to be still reactive and able to produce ferrihemoglobin. The mechanism of ferrihemoglobin formation is fundamentally different from that found with the parent compound. First of all, induction periods of ferrihemoglobin formation were observed when 4-(dimethylamino)-2-(glutathion-S-yl)-phenol (2-GS-DMAP) and 4-(dimethylamino)-2,6-bis(glutathion-S-yl)phenol (2,6-bis-GS-DMAP) reacted with oxyhemoglobin at 100% and 20% oxygen, but not at 2% oxygen. This behavior points to thioether activation by autoxidation. Autoxidation proceeded in an autocatalytic manner, and the process was markedly modified by reducing agents, e.g., ferrihemoglobin and GSH, and by nucleophiles like GSH. Superoxide dismutase extended the lag phase of autoxidation and ferrihemoglobin formation. Catalase diminished markedly ferrihemoglobin formation, particularly at low oxygen pressure. The extent of this effect was much higher than expected if H2O2 had formed ferrihemoglobin directly. Conceivably, H2O2 might react with the thioethers or their oxidation products to give hitherto unidentified compounds of high catalytic activity in ferrihemoglobin formation. The results indicate that ferrihemoglobin formation by reactive glutathione conjugates of DMAP is essentially not a co-oxidation process as found with the parent DMAP and other aminophenols, but is mainly caused by an autocatalytic autoxidation process with formation of various reactive intermediates including superoxide radical anions and hydrogen peroxide. It appears that glutathione conjugation of autoxidizable aromatics does not necessarily lead to inactive phase II metabolites but opens new avenues of toxication reactions that may be a broader toxicological significance.

Aminophenols↗

PubMedDate not supplied

Factor VIII inhibitor in a patient with mild hemophilia A.

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Adult↗

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Transforming growth factor beta 1 serum levels in patients with preinvasive and invasive lesions of the breast.

Transforming growth factor beta (TGF-beta)1 is thought to be involved in breast carcinogenesis. TGF-beta1 acts in an antiproliferative manner in the early stages of breast carcinogenesis, but promotes tumor progression and metastases in the advanced stages of the disease. No data have been published on serum TGF-beta1 in breast cancer. We investigated TGF-beta1 serum levels in patients with breast cancer (n=135), ductal carcinoma in situ (DCIS) I to III (n=67) or fibroadenoma (n=35), and in healthy women (n=40) to determine its value as a differentiation marker between malignant, pre-invasive and benign diseases and as a predictive marker for metastatic spread. Median (range) TGF-beta1 serum levels in patients with breast cancer, DCIS I-III or benign breast lesions and in healthy women were 48.8 (18-82.4) pg/mL, 45.3 (26.9-58.3) pg/mL, 47.2 (17.2-80.5) pg/mL and 51.6 (30.9-65.1) pg/mL, respectively (p=0.2). In breast cancer patients TGF-beta1 serum levels showed no statistically significant correlation with tumor stage, lymph node involvement, histological grade, estrogen receptor status and progesterone receptor status. Our data fail to indicate any correlation between serum TGF-beta1 levels and clinicopathological parameters of breast diseases. Serum TGF-beta1 levels do not provide clinical information in addition to established tumor markers.

Adult↗