Penetration of cefaclor into the interstitial space fluid of skeletal muscle and lung tissue in rats.

PURPOSE: To measure and compare the penetration of cefaclor from the plasma compartment into the interstitial space of lung and skeletal muscle in rats and to integrate the data in a pharmacokinetic model. METHODS: Unbound interstitial concentrations in muscle and lung were measured by in vivo microdialysis following i.v. bolus doses of 50 and 75 mg/kg cefaclor. Unbound muscle concentrations were also measured after a primed, continuous i.v. infusion at an infusion rate of 0.3 mg/kg/min. RESULTS: The cefaclor half-life in plasma, muscle and lung was approximately 1 h. Unbound cefaclor concentrations in muscle and lung were found to be virtually identical. A 2-compartment body model was fitted to the data with a tissue penetration factor (AUC(tissue(unbound)))/AUC(plasma(unbound))) of approximately 0.26 independent of dose, tissue and mode of administration. CONCLUSIONS: Unbound concentrations of cefaclor in the interstitial space fluid of lung and skeletal muscle are of similar magnitude and lower than those in plasma. Using total plasma concentrations would overestimate the antibacterial activity of the drug and therefore its clinical efficacy. Instead, therapeutically active levels of cefaclor at the site of action should be taken into account. Microdialysis allows direct measurement of these unbound concentrations.

Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol.

AIM: The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP2D6 allele (CYP2D6*1/CYP2D6*1) and heterozygous (CYP2D6*1/CYP2D6*4) Caucasians. METHODS: Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP2D6*3 and CYP2D6*4) using polymerase chain reaction (PCR). Twenty-four volunteers with a genotype suggesting a rapid hydroxylator phenotype were enrolled in a bioequivalence trial and each received in a randomized, cross-over fashion one of the three formulations compared. Each formulation contained 200 mg metoprolol tartrate/(tablet). In each of the three periods of the trial, one of the formulations was administered under fasting conditions in the morning on 4 consecutive days. Blood for quantification of metoprolol was drawn immediately before the last dose and in selected time intervals thereafter. A sensitive and specific high-performance liquid chromatography (HPLC) method with fluorescence detection was applied for the quantification of metoprolol. Pharmacokinetic parameters were determined for each subject and statistically compared in two groups of 16 homozygous (CYP2D6*1/CYP2D6*1) and six heterozygous (CYP2D6*1/CYP2D6*4) volunteers. RESULTS: Significant differences between homozygous and heterozygous individuals were observed for all pharmacokinetic parameters. The AUC in the course of one those interval of 24 h (AUCtau), minium steady-state concentration (C(min)ss) and average steady-state concentration (C(av)ss) values for heterozygous individuals were more than twice those of individuals. Significantly higher values for C(max)ss, t1/2, half-value duration (HVD) and mean residence time (MRT) were also observed in heterozygous volunteers. The higher concentrations of metoprolol in heterozygous individuals also had pharmacodynamic consequences, namely, greater heart rate and blood pressure reduction.

[Postmenopausal hormone substitution and its effects on the climacteric syndrome, body weight and blood pressure]. / Postmenopausale Hormonsubstitution und ihre Auswirkungen auf das Beschwerdebild des klimakterischen Syndroms, auf Gewicht und Blutdruck.

The effect of 0.6 mg conjugated equine estrogens in combination with sequential medrogestone (5 mg from day 11 to 21) on climacteric symptoms, blood pressure and weight were investigated in 46 postmenopausal women. The climacteric symptoms were quantified by a modified Kuppermann-Index. After a 3 months' treatment the index decreased from 20.58 to 8.47 (p < 0.001). 28 patients (65%) showed a 50% and more reduction of climacteric symptoms. 40 patients (93%) reported an improvement of their complaints. The body weight remained stable. One patient had to interrupt the treatment due to a cerebral ischemic disease (PRIND). The systolic blood pressure was decreased by 7% and the diastolic by 16% under treatment (p < 0.001). 11 patients with borderline or not treated hypertension returned to normal ranges. 3 of the 4 patients treated with antihypertensiva came off the medicines.

Influence of culture conditions on expression of antigens in Bordetella bronchiseptica.

Bordetella (B.) bronchiseptica isolates from the respiratory tract of rat and pig in their virulent phase-I and their spontaneously developed avirulent phase-III were investigated. The strains were cultured on Bordet-Gengou agar, on nutrition agar with 10% horse blood, and with 5% sheep blood, on yeast agar, on minimal nutrition agar (MM) and Simmon's citrate agar with glycerol, starch, and nicotinic acid. Antigenic modulation was induced by MgSO4 on Bordet-Gengou agar. The B. bronchiseptica strains were cultivated at 37 degrees C for 48 h. The influence of different MgSO4 concentrations after five passages (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 50, 100 mM/ml and low (20 degrees C) and high (42 degrees C) temperatures on antigenic modulation was investigated on Bordet-Gengou (B-G) agar. B. bronchiseptica colonies were characterized in relation to morphology, haemolysis, slide agglutination with B. bronchiseptica phase-I polyclonal antibodies, haemagglutination with horse and calf erythrocytes and polypeptide and LPS patterns in SDS-PAGE. Cultivation of B. bronchiseptica phase-I on B-G agar and ACMM agar at 37 degrees C for 48 h resulted in strong phase-I antigenic patterns, and, on peptone-rich media, in antigenic modulation. The morphology of B. bronchiseptica phase-I-strain colonies on peptone media was different from that of B-G and ACMM agar. The LPS pattern of both strains resembled that of phase-III strains. MgSO4 concentrations of 1 mM/ml (strain 1636 I) and 3 mM/ml (Ratte I) were able to induce LPS-pattern-like phase III.

Impact of hormone replacement therapy on postprandial lipoproteins and lipoprotein(a) in normolipidemic postmenopausal women.

In 43 normolipidemic postmenopausal women we studied fasting and postprandial (oral fat load with 50 g fat per square meter; blood sampling for 5 h) lipoprotein components and lipoprotein(a) levels before and with the administration of conjugated equine estrogens opposed by medrogestone (on days 11-21). Data was compared intraindividually; the second testing was performed during the last 5 days of the combined estrogen/progestogen phase of the third cycle. Fasting low-density lipoprotein (LDL) and total cholesterol concentrations decreased significantly; high-density lipoprotein (HDL) cholesterol, including subfractions HDL2 and HDL3, was not changed. Fasting triglyceride concentrations increased. All lipoprotein fractions measured showed a postprandial elevation with the exception of chylomicron cholesterol concentrations. There was a significant effect of hormone replacement therapy on the postprandial course of total cholesterol (decrease; P < 0.001), VLDL cholesterol (increase; P = 0.025), and the triglyceride proportion in the LDL plus HDL fraction (increase; P < 0.001). With hormone replacement therapy the postprandial curve of total triglycerides was increased only 1 h after the fat load while chylomicron triglyceride concentrations were lowered after 5 h. VLDL triglycerides were not influenced. In all patients with lipoprotein(a) levels above 10 mg/dl, this parameter decreased (about 25%). Although increasing fasting triglyceride concentrations, hormone replacement therapy does not bring about an exaggerated postprandial increase in triglycerides. Postprandial chylomicron clearance is evidently promoted. Hormone replacement therapy leads to a small increase in triglycerides in the LDL plus HDL fraction by inhibiting hepatic lipase activity. Moreover, the decrease in lipoprotein(a) levels may contribute to the antiatherosclerotic effect.

[The lipopolysaccharide structure of Haemophilus parasuis strains in SDS-PAGE]. / Untersuchungen zur Lipopolysaccharidstruktur von Haemophilus parasuis-Stämmen in der SDS-PAGE.

The LPS patterns of 231 H.p. strains were studied by using SDS-PAGE. The strains were isolated from the nasal mucous membrane of clinical healthy animals, from animals with GK and from animals with pneumonia without any symptoms of GK. The LPS patterns of H.p. strains consists of 2 to 4 bands of high electrophoretical mobility. In all it was possible to distinguish seven different LPS electrophoretic profiles. The distribution of the H.p. isolates from clinically healthy animals and animals with GK or pneumonia to the 7 LPS electrophoretic profiles shows a similar picture. Variation in the growth conditions showed a process of a standardization of the LPS structure as a result of an increased CO2 atmosphere or lack of O2 respectively.

Malignant fibrous histiocytoma presenting as a bleeding gastric ulcer.

A patient with malignant fibrous histiocytoma had hematemesis from an ulcerated metastatic tumor in the stomach 3 years after surgical removal of the sarcoma from its primary site. Despite surgical removal of the ulcer and abdominal irradiation, the patient died from recurrent gastric tumor. A discussion of malignant fibrous histiocytoma and gastric metastases are presented.